BMJ Open · vaccine: study protocol of a randomized non-inferiority trial in China Jing Jing...
Transcript of BMJ Open · vaccine: study protocol of a randomized non-inferiority trial in China Jing Jing...
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Safety and immunogenicity of a new 13-valent pneumococcal conjugate vaccine versus a licensed 7-valent
pneumococcal conjugate vaccine: study protocol of a randomized non-inferiority trial in China
Journal: BMJ Open
Manuscript ID bmjopen-2016-012488
Article Type: Protocol
Date Submitted by the Author: 01-May-2016
Complete List of Authors: Chen, Jing Jing; Fourth Military Medical University, Department of Health Statistics; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Yuan, Lin; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Huang, Zhen; Walvax Biotechnology Co., Ltd. Shi, Nian Min; Beijing Chaoyang District Centre for Disease Control and Prevention Zhao, Yu Liang; Heibei Province Centre for Disease Control and Prevention Xia, Sheng Li; Henan Province Centre for Disease Control and Prevention
Li, Guo Hua; Shanxi Province Centre for Disease Control and Prevention Li, Rong Cheng; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention Li, Yan Ping; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention Yang, Shu Yuan; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Xia, Jie-Lai; Fourth Military Medical University, Department of Health Statistics
<b>Primary Subject Heading</b>:
Immunology (including allergy)
Secondary Subject Heading: Epidemiology
Keywords: Pneumococcal conjugate vaccine, Sequential test, Non-inferiority
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Safety and immunogenicity of a new 13-valent pneumococcal
conjugate vaccine versus a licensed 7-valent pneumococcal conjugate
vaccine: study protocol of a randomized non-inferiority trial in China
Jing Jing Chen,1,2
Lin Yuan,2 Zhen Huang,
2 Nian Min Shi,
3 Yu Liang Zhao,
4 Sheng Li Xia,
5 Guo Hua
Li,6 Rong Cheng Li,
7 Yan Ping Li,
7 Shu Yuan Yang,
2 Jie Lai Xia
1*
Corresponding author: 1*Jie Lai Xia, Department of Health Statistics, Fourth Military Medical University, 169 Changle
Western Road, Xi’an, Shanxi Province, China, Tel: +86 029-84774861, Email: [email protected]
Co-authors:
1. Jing Jing Chen; Department of Health Statistics of Fourth Military Medical University, Xi’an,
Shanxi, China; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
2. Lin Yuan; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
3. Zhen Huang; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
4. Nian Min Shi; Beijing Chaoyang District Centre for Disease Control and Prevention, Beijing,
China
5. Yu Liang Zhao; Heibei Province Centre for Disease Control and Prevention, Shijiazhuang,
Heibei, China
6. Sheng Li Xia; Henan Province Centre for Disease Control and Prevention, Zhengzhou, Henan,
China
7. Guo Hua Li; Shanxi Province Centre for Disease Control and Prevention, Taiyuan, Shanxi,
China
8. Rong Cheng Li; Guangxi Zhuang Autonomous Region Center for Disease Control and
Prevention, Nanning, Guangxi, China
9. Yan Ping Li; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention,
Nanning, Guangxi, China
10. Shu Yuan Yang; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
Keywords: Pneumococcal conjugate vaccine, Sequential test, Non-inferiority
Word count: 4261
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ABSTRACT
Introduction: The invasive pneumococcal diseases (IPDs) caused by Streptococcus pneumoniae
pose an enormous threat to children under 5 years of age. However, routine use of
pneumococcal conjugate vaccines could aid in reducing the incidence of IPDs. The purpose of this
clinical trial is to assess the non-inferiority of the investigational 13-valent pneumococcal
conjugate vaccine (PCV13) to the currently licensed 7-valent pneumococcal conjugate vaccine
(PCV7).
Methods and analysis: 1,040 infants will receive a three-dose of either PCV13 or PCV7 at ages 3,
4 and 5 months respectively, and a booster dose at 12-15 months. Primary endpoints are the
percentage of subjects reaching a serotype-specific IgG concentration of ≥ 0.35µg/ml and the
IgG antibody geometric mean concentrations (GMCs) measured 30 days after the primary
immunization. Secondary endpoints include the percentage of vaccine recipients reaching
serotype-specific IgG concentration threshold of 1.0µg/ml, the percentage of subjects reaching
the pneumococcal opsonophagocytic assay (OPA) titer threshold of 1:8, and the geometric mean
titers (GMTs) of OPA measured 30 days after primary and booster doses. The number of standard
IgG responders and IgG GMCs measured 30 days after the booster immunization will also be
determined. To evaluate differences between two groups, the sequential testing of the
non-inferiority of PCV13 for the 7 common serotypes and its effectiveness in treating the 6
additional serotypes will be performed.
Ethics and dissemination: Ethics approvals have been granted by the Ethics Committees at the 3
provinces involved in this study: Shanxi, Henan and Hebei Provinces. The trial will be reported in
accordance with the CONSORT guidance.
Trial registration number: NCT02736240.
Strengths and limitations of this study
� This is the first study to investigate the immune responses induced by a locally developed
and manufactured 13-valent pneumococcal conjugate vaccine among Chinese infants.
� 1,040 infants will be recruited to support the randomized non-inferiority study design and a
sequential test method is adopted.
� Primary outcomes are proportions of vaccine recipients achieving a predefined
specific-serotype IgG concentration threshold and geometric mean IgG antibody
concentrations measured 30 days after primary immunization, both of which are
recommended by WHO.
� Besides the complete evaluation of immunogenicity and safety of the new PCV13, not
involving the assessment of concomitantly immunization with other vaccines specified in
pediatric vaccination might be seen as a potential limitation of this trial.
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INTRODUCTION
Background
Streptococcus pneumoniae (S. pneumoniae or pneumococcus) is a leading cause of bacterial
pneumonia, meningitis, and sepsis in children, and thus poses a major threat to public health
around the world. According to a World Health Organization (WHO) investigation in 2005, an
estimated 0.7 to 1 million children under the age of 5 die from pneumonia every year; most of
whom lived in developing countries.[1] The top ten countries with the highest number of
reported pneumococcal cases were all in Asia and Africa, with China accounting for 12% of the
total.[2] Immunization against Hib, pneumococcus, measles and pertussis is the most effective
way to prevent pneumonia.[3] Routine use of the 7-valent pneumococcal conjugate vaccine
(PCV7), has resulted in a dramatic reduction in the incidence of invasive pneumococcal disease
(IPD) attributable to pneumococcal serotypes contained in the vaccine.[4] However, there is still
an urgent need for a pneumococcal conjugate vaccine with expanded coverage for IPD resulting
from serotypes not included in the PCV7.[5]
On 24 February 2010, the US Food and Drug Administration licensed a 13-valent pneumococcal
conjugate vaccine (PCV13) for children from 2 months to 5 years old. Since then, several studies
have been conducted on PCV13 in many countries except China. The licensed PCV13 has been
shown to be as effective as PCV7 in the prevention of disease caused by the 7 common serotypes
and could provide expanded protection against the 6 additional serotypes with a comparable
safety profile.[6] When co-administered with diphtheria, tetanus and acellular pertussis vaccine
(DTaP), PCV13 is well tolerated and as immunogenic as PCV7.[7] The flexible primary
immunization schedules of PCV13 for infants found no significant differences in antibody levels
for almost all serotypes after the booster dose at 12 months of age,[8 9] and thus recommended
by WHO.[10] Furthermore, the clinical efficacy of PCV13 for multiple purposes in age groups
ranging from 6 to over 70 years old has been confirmed.[11-16] Nevertheless, it is still unknown
whether the licensed PCV13 or a new PCV13 will be effective for the Chinese population to date.
To address the issue, we plan to initiate this trial for a pre-licensing evaluation of a new PCV13.
The investigational PCV13 (batch number 201511003) is manufactured by Yuxi Walvax
Biotechnology Co. Ltd. (an affiliate of Walvax Biotechnology Co., Ltd.), and supplied in penicillin
bottles. Each 0.5ml dose contains 2.2µg pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 7F,
9V, 14, 18C, 19A, 19F, and 23F and 4.4µg pneumococcal polysaccharide serotype 6B; each
serotype is conjugated to a tetanus toxoid carrier protein and adsorbed on aluminum phosphate.
In accordance with the guidelines formulated by the WHO,[17] and the requirements established
by national regulatory authorities, licensing a new vaccine requires randomized clinical trials to
show the non-inferiority of the new vaccine to an existing pneumococcal conjugate vaccine. PCV7
will serve as the control vaccines, since it is the only pneumococcal conjugate vaccines that has
been licensed in mainland China. The control PCV7 (Prevnar, batch number H29315H13880) is
manufactured by Wyeth and supplied in pre-filled 0.5ml syringes. Each 0.5ml dose contains 2µg
pneumococcal polysaccharide serotypes 4, 9V, 14, 18C, 19F, and 23F and 4µg pneumococcal
polysaccharide serotype 6B; each serotype is conjugated to a CRM197 carrier protein and
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adsorbed on 0.5 mg aluminum phosphate.
Objectives
The purpose of this study is to i) determine if the 7 common serotype-specific pneumococcal IgG
responses elicited by PCV13 are all non-inferior to those elicited by PCV7 and ii) determine if the
6 additional serotype-specific pneumococcal IgG responses induced by PCV13 are all clinically
effective 30 days after the primary immunization.
We hypothesize that for each of the 7 common pneumococcal serotypes (4, 6B, 9V, 14, 18C,
19F, 23F) i) the lower bound of the 97.5% (98.25%, one-sided) Confidence Interval (CI) for the
difference (PCV13 – PCV7) in the proportion of vaccine recipients reaching the serotype-specific
IgG concentration threshold of 0.35μg/ml is no less than -10%; or ii)The lower bound of the 97.5%
(98.25%, one-sided) CI of the serotype-specific IgG geometric mean concentration (GMC) ratio
(PCV13/PCV7) is greater than 0.5 (-0.3, logarithmically transformed by base 10).
As a parallel hypothesis, we expect that for each of the 6 additional pneumococcal serotypes (1,
3, 5, 6A, 7F, 19A) i)The proportion of the serotype-specific IgG responders achieving an IgG
threshold of 0.35μg/ml in the PCV13 group is greater than that of the PCV7 group; and ii) the
lower limit of the 95% (2-sided) CI for the proportion of vaccine recipients reaching a
serotype-specific IgG concentration threshold of 0.35μg/ml is greater than or equal to 70%.
Trial design
This study is a multi-center phase III, randomized, parallel group, allocation concealed
non-inferiority trial with two groups to evaluate the immunogenicity and safety of PCV13
compared with PCV7 among healthy infants in China.
METHODS
Study setting
The study includes 6 sites scattered in 3 provinces in North China. Each site has been ratified by
the Center for Food and Drug Inspection (CFDI), a department of China Food and Drug
Administration (CFDA), to join the research team of this trial and recruit participants.
Eligibility criteria
Inclusion criteria
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Participants will only be recruited when he or she meets all of the following criteria at the time of
randomization:
• Healthy infants, as established by medical history and clinical examination before entering
into the study, that are 3 months old at the time of the first vaccination
• Obtained written informed consent from the legally responsible representative(s)
• Have the compliance of the subjects’ legally responsible representative(s) with the
requirements of the protocol
• No pneumococcal vaccine history or use of other preventive vaccine at least 7 days before
study entry
• Axillary temperature ≤ 37℃
In addition, participants must not encounter any of the following exclusion criteria:
• Vaccinated by on sale or other on trial pneumococcal vaccines
• Have had an invasive disease with streptococcus pneumonia as the verified cause
• Severely allergic to any vaccines or drugs, or sensitive to temperatures ≥ 39℃ associated
with biological products inoculation
• Birth weight < 2.5 kg
• History or family history of convulsion, seizure, encephalopathy or neurological disorder
• Born from abnormal labors (difficult labors, aided by instruments) or have a history of
asphyxia or nerve damage
• Confirmed thrombocytopenia or a history of blood coagulation disorder
• Confirmed pathological jaundice
• Any confirmed or suspected immunodeficiency involving immunosuppressive therapy
(radiotherapy, chemotherapy, corticosteroid hormone, antimetabolite, cytotoxic drugs),
human immunodeficiency virus (HIV) infection, etc.
• Any confirmed or suspected congenital defect or serious chronic illnesses (trisomy 21
syndrome, diabetes, sickle cell anemia, neurological disorder or Guillain-Barré syndrome)
• Any confirmed or suspected diseases including respiratory diseases, acute infection, active
period of chronic disease, cardiovascular disease, hepatic-nephrotic disease, cancer and
dermatosis
• Administration of immunoglobulin and/or any blood products, except Hepatitis B
hyper-immune globulin(HBlg)
• Concurrent participation in another clinical study
• Other exclusion criteria affirmed by investigators
Intervention
Eligible infants will be randomized to either the PCV13 or the PCV7 group to receive a three-dose
series of PCV13 or PCV7 at ages 3, 4 and 5 months respectively, and a booster dose between 12
and 15 months. For all subjects, blood samples will be obtained at four different time points:
immediately before the first dose, 30 days after the primary series, immediately before the
booster dose, and 30 days after the toddler dose.
Serum concentrations of anti-capsular polysaccharide IgG for each of the 13 pneumococcal
serotypes will be measured for all subjects at the previously mentioned time points, using the
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standardized enzyme-linked immunosorbent assay (ELISA) method.[18] Additionally, serum
functional opsonophagocytic activity (OPA) for each serotype will be assayed at the last 3 time
points for a randomly selected subset of approximately 100 subjects in each group (200 infants in
total), composed of infants assigned the first 20-36 subject numbers from each of the six sites.
Each participant will be observed for 30 min after each vaccination for any immediate reaction
by the research staff. Any noted adverse events (AEs) will be recorded at that time. After leaving
the site, local reactions (pain, redness, swelling, and pruritus), systemic events (somnolence,
vomiting, diarrhea, crying, and irritability), axially temperature, other AEs, and concomitant
medications to treat or prevent symptoms will be recorded in daily cards by the parents/legally
responsible representatives for 8 days. On the eighth day after vaccination, the documents will be
returned to the site. AEs occurring between the 8th and the 30th day after each dose together
with the usage of relevant concomitant medications will be recorded in connection cards and
handed in at the next visit. Serious adverse events (SAEs) will be collected throughout the study
until 6 months after the last dose. The intervention procedures are shown in Table 1.
Table 1 The intervention procedure
Interventions
Primary series Booster dose
3
months
4
months
5
months
30 days
postdose
12-15
months
30 days
postdose
6 months
postdose
Informed consent X
Eligibility screen X
Randomization X
Temperature X X X
X
Blood draw X
X X X
Vaccination X X X
X
Safety observations*
Immediate reaction ◎ ◎ ◎
◎
Local reactions and
systemic events ▲ ▲ ▲
▲
Adverse events ◆ ◆ ◆
◆
Serious adverse
events ★ ★ ★ ★ ★ ★ ★
*Safety observations occur after vaccination for a planned period.
◎Immediate reaction will be observed for 30 min after vaccination.
▲Local reactions and systemic events will be actively collected for 8 days after vaccination.
◆Other adverse events will be recorded by parents/ legally responsible representative(s) for 30 days
after vaccination.
★Serious adverse events will be self-reported by parents/ legally responsible representative(s) from
the first visit till the 6 months after the last dose.
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Outcome measures
Primary immunogenicity outcomes
For each of the 13 pneumococcal serotypes covered in PCV13:
• Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 0.35μg/ml 30 days after the primary series.
• GMC of serotype-specific IgG antibodies 30 days after the primary series.
Secondary immunogenicity outcomes
For each of the 13 pneumococcal serotypes covered in PCV13:
• Proportion of vaccine recipients reaching the OPA threshold of 1:8 30 days after the primary
series.
• Geometric mean titer (GMT) of OPA 30 days after the primary series.
• Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 1.0μg/ml 30 days after the primary series.
• Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 0.35μg/ml 30 days after the booster dose.
• GMC of serotype-specific IgG antibodies 30 days after the booster dose.
• Proportion of vaccine recipients reaching an OPA threshold of 1:8 30 days after the booster
dose.
• GMT of OPA 30 days after the booster dose.
• Proportion of vaccine recipients reaching a serotype-specific IgG concentration threshold of
1.0μg/ml 30 days after the booster dose.
Safety outcomes
Safety outcomes include all recorded local reactions and systemic AEs that occur within the 30
days following the primary series and booster doses and the percentage of vaccine recipients that
reported each AE.
Trial duration
The study will last for 26 months. If unsuspected acute abnormal reactions occur during the trial,
or the daily proportion of subjects who experienced AEs rated grade 3 or above reaches 15%
after any dose vaccination, the trial should be suspended. A panel will be involved in discussions
of the safety profile and decide whether the study should be continued.
Sample size
For each of the 7 common serotypes in both PCV13 and PCV7: Based on data from previous
studies, we assume the percentage of vaccine recipients reaching the serotype-specific IgG
concentration threshold of 0.35μg/ml will be 85%.[19] The non-inferior margin for the trial will
be set at 10%. If the non-inferiority does exist for a proportion of the test group, a sample size of
434 infants per group, 868 total, will provide 80% power to ensure that the lower limit of 97.5%
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two-sided CI for difference (test group – control group) will be no less than -10%. We also
postulate the common variance of serotype-specific IgG GMC, which has been logarithmically
transformed by base 10, will not be greater than 1.0. A sample size of 379 infants per group, 758
total, will have 80% power to detect whether the lower limit of 97.5% two-sided CI for
serotype-specific IgG GMC ratio (test group to control group) is above 0.5 or not. To take account
of α inflation and β consumption, Bonferroni correction will be employed to α, producing
corrected α= 0.025/2=0.0125 and corrected power = 1-0.2/7= 0.97.
For each of the 6 additional serotypes in PCV13 only: Based on the preclinical research, we
hypothesize that the proportion of vaccine recipients reaching the serotype-specific IgG
concentration threshold of 0.35μg/ml in the test group will be about 80% while that in the
control group will not be greater than 50%. We will still set the non-inferior difference for the
trial at 10%. If there is a notable difference between the two groups, a sample size of 274 infants
per group, 548 total, will provide 80% power to demonstrate that the lower limit of 95%
two-sided CI for a proportion of the test group will be no less than 70%. To control family-wise
type II error, power will be adjusted to 0.97 (equals to 1-0.2/6).
Final decision: Theoretically a total of 868 evaluable participants (434 per group) should enable
the trial to achieve the primary outcomes. To take blood draw failures and blood collection
refusals into consideration, we will allow for an anticipated 20% dropout rate.[20] Therefor, the
total sample size required is 1,040 infants (520 per group).
Randomization and allocation
The allocation sequence is generated by Department of Health Statistics of Fourth Military
Medical University using SAS (SAS Institute Inc., Cary, NC, USA) Plan procedure. In order to
guarantee the group balance in different sites, the block randomization kit will be used. Each site
will receive consecutively coded vaccines.
Because of the difference in appearance of PCV13 and PCV7, the administrators cannot be
blinded, but the group assigners, lab staff and investigators will be. Before recruitment, all
vaccines will be masked in identical white small boxes and labeled with vaccine numbers based
on the allocation schedule by those who are not involved in the clinical trial procedures. Each
vaccine number is composed of two parts: the subject identification number and the dose
specification number. Four vaccines with the same subject number prefix will belong to the same
participant. In case any unexpected situations arise, additional vaccines including PCV13 and
PCV7 in a ratio of 2:1 will be prepared and wrapped separately in individual white boxes labeled
with numbers from B0001 to B0540. The link between the additional vaccine number and subject
number will be established based on an allocation sequence list by Medidata Rave—the
electronic data capture (EDC) system for this study. Emergency letters will be sent to each of the
sites, and properly preserved until needed.
Each eligible participant will be sequentially allotted a unique subject number according to site
allocation list by authorized assigners, and thus will have an equal chance of being assigned to
either the test group or the control group. Blood samples will be labeled with subject numbers
and collected independently of the vaccination process. The inoculator is responsible for taking
out the vaccine related to a specific subject number and administering the injection. Inoculators
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must not share any allocation information to investigators or those involved in follow-up
procedures.
Withdrawal
The participations’ parents or legally responsible representatives will be aware that their decision
to take part in the study is voluntary and that they are free to withdraw consent at any time. All
withdrawals from the randomized intervention will be reported. The investigator may drop
participants during the study in the case of intercurrent illness, AEs, SAEs, protocol violations or
other reasons that meet the exclusion criteria.
Data management
The trial data will be managed using the Medidata Rave EDC system. The database software
provides several features to help maintain data quality. These features include, but are not
limited to keeping audit trails on all data fields, allowing custom functions in configurations and
opening both automatic and manual queries. At the same time, the original record cards will be
designed in accordance with the protocol to collect raw clinical data and to support the trial
procedures. The source data obtained from each participant will be examined and verified by
investigators and clinical research assistants (CRAs) at each study site. The entered data will be
systematically validated and audited not only by EDC system itself using edit checks but also by
CRAs and data managers (DMs). Data query forms generated by medically trained personnel will
be sent to the site investigators for identification. The electronic-Case Report Form (e-CRF) will be
inspected by DMs at regular intervals throughout the trial to verify the protocol compliance. The
entered data should be complete, consistent and accurate. The blinded immunology assay results
will be sent in an additional Excel spreadsheet via email to the data manager to be linked with
the central database.
Statistical methods
Data set: The full analysis set (FAS) will comply with the principles of intent-to-treat (ITT),[21] and
be comprised of all participants who receive at least one dose of vaccine and one follow-up visit.
The per-protocol analysis set (PPS) will be comprised of ITT participants who have received the
integrated vaccination schedule and participated in all follow-up visits. Whether a subject with
protocol deviations should be eliminated from the PPS set will be determined through blind data
review process before analyzing. The safety analysis set will be comprised of participants that
were randomized to a certain group and vaccinated including those with protocol deviations.
Analysis principle: Analysis will be conducted following the CONSORT[22] flow diagram (Figure 1)
of the phases of the study: enrollment, allocation, interventions, follow-up, and analysis. Baseline
characteristics analysis will be given for each group to depict the premises of this study using
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means, standard deviation (SD), minimum and maximum value as well as the 2-sided 95% CIs (if
any). Continuous data will be portrayed with means, SDs and CIs if a normal distribution
hypothesis of data is met. Binomial data will be summarized as frequencies and proportions. All
statistical tests will be demonstrated with a two-sided p-value, and all CIs will be calculated as 95%
at a two-sided level unless otherwise specified. A detailed statistical analysis plan will be finalized
before the first substantive statistical analysis.
Immunogenicity: The immunogenicity population consists of all subjects that belong to PPS and
have available serological data before and after immunization. The primary immunogenicity
endpoints for each of the pneumococcal serotypes are the proportion of subjects reaching the
serotype-specific IgG concentration threshold of 0.35µg/ml, and the geometric mean IgG
antibody concentration, in the PCV13 group measured 30 days after the primary series. Within
each group, for each pneumococcal serotype, the proportion of subjects with a specific-IgG
antibody concentration threshold of 0.35μg/ml and the two-sided 95% CI for the proportion will
be calculated; for each antibody concentration, the value will be logarithmically transformed to
the base 10, and the two-sided 95% Cl will be structured. To evaluate differences between two
groups, the sequential test (Figure 2) of hypotheses, including the non-inferiority for the 7
common serotypes and the efficacy for the 6 additional serotypes, will be performed. The
non-inferiority for each of the 7 common serotypes will be declared if the lower limit of the
two-sided 97.5% (one-sided 98.75%) CI, which is calculated using the exact binomial method,[23
24] for the difference in proportions (PCV13 - PCV7) is no less than -10%, or the lower bound of
the two-sided 97.5% (one-sided 98.75%) CI of the IgG GMC ratio (PCV13/ PCV7) is greater than
0.5. To control familywise Type I error, Bonferroni correction will be used to address multiple test,
and thus a two-sided significance level of 0.025 (0.0125, one-sided) will be adopted. Only after
each of the 7 common serotypes has been shown to be non-inferior, will the other 6 additional
serotypes be worth assessing. The efficacy criteria for each of the 6 additional serotypes will be
met if both the lower limit of the 2-sided 95% CI for the proportion of vaccine recipients reaching
the serotype-specific IgG concentration threshold of 0.35μg/ml conducted by normal
approximation method is no less than 70%, and the 2-sided 95% CI for the difference in
proportion (PCV13 - PCV7) compared by a Chi-squared test lies almost to the right of the zero
(zero or positive mean difference). A p-value of less than 0.05 is considered statistically
significant.
The secondary immunogenicity endpoints for each of the pneumococcal serotypes in the
PCV13 group are the percentage of vaccine recipients reaching a serotype-specific IgG
concentration threshold of 0.35µg/ml 30 days after the toddler dose and the percentages of
vaccine recipients reaching a serotype-specific IgG concentration threshold of 1.0µg/ml 30 days
after primary series and booster dose. The proportions of the subjects reaching the
pneumococcal opsonophagocytic assay (OPA) titer threshold of 1:8 after primary and booster
immunization in pre-defined subgroups also serve as the secondary immunogenicity endpoints.
Within each group and for each antibody concentration or OPA titer, geometric mean will be
calculated and each concentration or titer will be logarithmically transformed for analyzing. To
assess differences between the two groups and to test the non-inferiority of the PCV13 group,
the analysis method described in the primary endpoints section will be employed.
As reported in previous studies,[25 26] antibody responses to serotypes 19A, 6A, and 5 were
noted in the PCV7 group. Therefore, when evaluating the efficacy of 6A, 19A, and 5 in the PCV13
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group, the OPA results should be combined.[27]
Safety: The safety population includes all subjects in the safety analysis set that will receive at
least one dose of study vaccine. Safety analysis including comparisons of incidences of local
reactions, systemic events, use of concomitant medications, dropouts and AEs between PCV13
and PCV7 will be demonstrated with the corresponding 2-sided 95% CIs and p-values base on
Fisher’s exact test methodology for each dose respectively and for all in total as well. A p-value of
equal to or less than 0.05 indicates a statistically significant difference.
Harms
Any serious adverse events (SAEs) will be reported to regulatory authorities, sponsors and Ethics
Committees (ECs) within 24 hours by fax, email or in person. Any suspected or unexpected
serious events will be reported to regulatory authorities by sponsors within 7 calendar days and
its follow-up investigation report will be submitted within 8 calendar days of the first report
submission day.
Auditing
Monitoring of this trial will be conducted by a Contract Research Organization (CRO, Simoon
Record Pharma Information Consulting Co., Ltd). Guidelines of Good Clinical Practice (GCP) will
ensure compliance.
ETHICS AND DISSEMINATION
Research ethics approval
This study was approved by the ECs at 3 provinces (Shanxi, Henan and Hebei Province), and will
be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.[28] The
registration number of this trial is NCT02736240.
Informed consent
All participants’ parents/ legally responsible representatives will receive adequate information
about the nature, purpose, and possible risks and benefits of the trial by an informed consent
form approved by the EC. The original version of signed consent forms will be retained by the
investigators as a trial record, and a copy will be kept by the participants’ parents/legally
responsible representatives.
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Confidentiality
To assure confidentiality, all participants will be allotted a unique subject number throughout the
trial. Personal information will be collected with standardized paper forms by face to face
interviews. Paper-based data will be stored in locked cabinets with limited access at each site,
and the electronic data will be saved on password protected computers.
Access to data
The final dataset will be under the custody of the sponsor together with the CRO selected
beforehand. The data managers will be permitted to access the full analyzed final dataset. Access
to the final or identifiable data by others is subject to the sponsor's approval.
Dissemination policy
The trial will be reported in accordance with the CONSORT guidance.
Discussion
To date, the efficacy and safety of PCV13 among the Chinese population is still largely unknown.
Hence, this study intends to characterize the PCV13 among Chinese infants and develop a safety
profile for the vaccine. To fulfill these objectives, we calculated sample sizes under different
hypothetical conditions and determined the optimal sample size to use to take all of all factors
into consideration. In study design, we adopted the sequential test method to inspect the
non-inferiority of each of the 7 common pneumococcal serotypes and the efficacy of each of the
6 additional pneumococcal serotypes step by step to avoid false positive error inflation. To be
more discreet and conservative, instead of setting pneumococcal serotype 6B in PCV7 as a
baseline when verifying the immunogenicity of each of the 6 additional serotypes in PCV13, as
many other researchers have done, we defined 70% as the lower limit of the 2-sided 95% CI for
the percentage of responders that reach the serotype-specific IgG concentration threshold of
0.35μg/ml and supposed that the corresponding percentages in PCV7 are less than 50%.[29]
Allowing for the cross-reactivation between 6A and 6B as well as 19A and 19B in PCV7, we will
select a subgroup of which to obtain the OPA results for each of the 13 serotypes to correct for
potential bias.
Given the main focus of the research, this study is not designed to involve the assessment of
concomitant immunization with other vaccines specified in pediatric vaccination schedules such
as diphtheria, tetanus and acellular pertussis vaccine (DTaP), which might be regarded as a
potential limitation. Because the feasibility of PCV7 administered concomitantly with DTaP in
mainland Chinese infants has been shown in the research reported by Li RC et al.,[30] and the
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immunogenicity of PCV13 co-administered with DTaP was demonstrated by Togashi T et al.,[7]
we will not prohibit the usage of vaccines listed in the expanded program on immunization (EPI),
but we will compulsively demand at least a fortnight interval between two kinds of vaccination.
Footnotes
Author affiliations:
1 DHSFMMU, Department of Health Statistics of Fourth Military Medical University, Xi’an, Shanxi, China
2 Walvax, Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
3 Beijing Chaoyang CDC, Beijing Chaoyang District Centre for Disease Control and Prevention, Beijing, China
4 Hebei CDC, Heibei Province Centre for Disease Control and Prevention, Shijiazhuang, Heibei, China
5 Henan CDC, Henan Province Centre for Disease Control and Prevention, Zhengzhou, Henan, China
6 Shanxi CDC, Shanxi Province Centre for Disease Control and Prevention, Taiyuan, Shanxi, China
7 Guangxi CDC, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, Guangxi,
China
Contributors
JLX provided statistical expertise and created the study design together with JJC. ZH and LY conceived the study and
participated in study design. JJC drafted the manuscript and calculated the sample size. NMS, YLZ, SLX and GHL are
the primary investigators and helped with protocol revise. RCL and YPL are the senior consultants and contributed to
protocol development. SYY compiled the original protocol in Chinese and participated in study design discussion. All
authors read and proved the final manuscript.
Funding The study is supported by a grant from Bio-pharmaceutical Major Scientific & Technological Project
(biological product development section) of Yunnan Province (project number 2015ZJ005).
Disclaimer The views expressed are those of the author(s) and not necessarily those of the DHSFMMU, Walvax or
CDCs which involved.
Competing interests The authors declare that there is no interest conflict regarding the publication of this paper.
Ethics approval The trial is approved by: the Beijing Chaoyang District Centre for Disease Control and Prevention
Ethics Committee (the lead institution), the Heibei Province Centre for Disease Control and Prevention Ethics
Committee, the Henan Province Centre for Disease Control and Prevention Ethics Committee, and the Shanxi
Province Centre for Disease Control and Prevention Ethics Committee.
Provenance and peer review Not commissioned; internally peer reviewed.
REFERENCES
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22. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for
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25. Esposito S, Tansey S, Thompson A, et al. Safety and immunogenicity of a 13-valent
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April 2010].
26. Olivier C, Belohradsky BH, Stojanov S, et al. Immunogenicity, reactogenicity, and safety of a
seven-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a fully
liquid DTPa-IPV-HBV-Hib combination vaccine in healthy infants. Vaccine 2008;26(25):3142-52
doi: 10.1016/j.vaccine.2007.11.096[published Online First: 6 May 2008].
27. Cooper D, Yu X, Sidhu M, et al. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits
cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae
serotypes 6C and 7A. Vaccine 2011;29(41):7207-11 doi:
10.1016/j.vaccine.2011.06.056[published Online First: 22 September 2012].
28. ICH Efficacy Guidelines topic E6 guideline for good clinical practice, step 4 version.
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29. Elberse KE, de Greeff SC, Wattimena N, et al. Seroprevalence of IgG antibodies against 13
vaccine Streptococcus pneumoniae serotypes in the Netherlands. Vaccine 2011;29(5):1029-35
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30. Li RC, Li FX, Li YP, et al. Safety and immunogenicity of a 7-valent pneumococcal conjugate
vaccine (Prevenar): primary dosing series in healthy Chinese infants. Vaccine
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2008].
Figure 1 The study flow diagram
Figure 2 The sequential test flow chart
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Figure 1 The study flow diagram CONSORT flow diagram
281x174mm (96 x 96 DPI)
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Figure 2 The sequential test flow chart
281x182mm (96 x 96 DPI)
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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*
Section/item Item No
Description Addressed on page number
Administrative information
Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______1 _____
Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ______2______
2b All items from the World Health Organization Trial Registration Data Set _____N/A_ ___
Protocol version 3 Date and version identifier _____N/A_____
Funding 4 Sources and types of financial, material, and other support ______13_____
Roles and
responsibilities
5a Names, affiliations, and roles of protocol contributors _____1,13 ____
5b Name and contact information for the trial sponsor _____N/A_ ___
5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and
interpretation of data; writing of the report; and the decision to submit the report for publication, including
whether they will have ultimate authority over any of these activities
_____N/A_ ___
5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint
adjudication committee, data management team, and other individuals or groups overseeing the trial, if
applicable (see Item 21a for data monitoring committee)
_____N/A_ ___
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Introduction
Background and
rationale
6a Description of research question and justification for undertaking the trial, including summary of relevant
studies (published and unpublished) examining benefits and harms for each intervention
______3______
6b Explanation for choice of comparators ______3______
Objectives 7 Specific objectives or hypotheses ______4______
Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),
allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
______4______
Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will
be collected. Reference to where list of study sites can be obtained
______4______
Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and
individuals who will perform the interventions (eg, surgeons, psychotherapists)
______4______
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be
administered
______5______
11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose
change in response to harms, participant request, or improving/worsening disease)
_____N/A_ ___
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence
(eg, drug tablet return, laboratory tests)
______6______
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _____N/A_ ___
Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood
pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,
median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen
efficacy and harm outcomes is strongly recommended
______7______
Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for
participants. A schematic diagram is highly recommended (see Figure)
______6______
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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including
clinical and statistical assumptions supporting any sample size calculations
______6______
Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size _____N/A_ ___
Methods: Assignment of interventions (for controlled trials)
Allocation:
Sequence
generation
16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any
factors for stratification. To reduce predictability of a random sequence, details of any planned restriction
(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants
or assign interventions
______8______
Allocation
concealment
mechanism
16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,
opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned
______8______
Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to
interventions
______8______
Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome
assessors, data analysts), and how
______8______
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s
allocated intervention during the trial
______8______
Methods: Data collection, management, and analysis
Data collection
methods
18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related
processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of
study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.
Reference to where data collection forms can be found, if not in the protocol
______9______
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be
collected for participants who discontinue or deviate from intervention protocols
_____N/A_ ___
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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality
(eg, double data entry; range checks for data values). Reference to where details of data management
procedures can be found, if not in the protocol
______9______
Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the
statistical analysis plan can be found, if not in the protocol
______9______
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _____ 10 _____
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any
statistical methods to handle missing data (eg, multiple imputation)
______9______
Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of
whether it is independent from the sponsor and competing interests; and reference to where further details
about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not
needed
_____N/A_ ___
21b Description of any interim analyses and stopping guidelines, including who will have access to these interim
results and make the final decision to terminate the trial
_____N/A_ ___
Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse
events and other unintended effects of trial interventions or trial conduct
_____ 11 _____
Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent
from investigators and the sponsor
_____ 11 _____
Ethics and dissemination
Research ethics
approval
24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _____ 11 _____
Protocol
amendments
25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,
analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,
regulators)
_____N/A_ ___
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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and
how (see Item 32)
_____ 11 _____
26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
_____N/A_ ___
Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained
in order to protect confidentiality before, during, and after the trial
_____ 12 _____
Declaration of
interests
28 Financial and other competing interests for principal investigators for the overall trial and each study site _____ 12 _____
Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that
limit such access for investigators
_____ 12 _____
Ancillary and post-
trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial
participation
_____N/A_ ___
Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,
the public, and other relevant groups (eg, via publication, reporting in results databases, or other data
sharing arrangements), including any publication restrictions
_____ 12 _____
31b Authorship eligibility guidelines and any intended use of professional writers _____ 13 _____
31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _____N/A_ ___
Appendices
Informed consent
materials
32 Model consent form and other related documentation given to participants and authorised surrogates _____N/A_ ___
Biological
specimens
33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular
analysis in the current trial and for future use in ancillary studies, if applicable
_____N/A_ ___
*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.
Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons
“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.
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Safety and immunogenicity of a new 13-valent pneumococcal conjugate vaccine versus a licensed 7-valent
pneumococcal conjugate vaccine: study protocol of a randomized non-inferiority trial in China
Journal: BMJ Open
Manuscript ID bmjopen-2016-012488.R1
Article Type: Protocol
Date Submitted by the Author: 20-Jun-2016
Complete List of Authors: Chen, Jing Jing; Fourth Military Medical University, Department of Health Statistics; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Yuan, Lin; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Huang, Zhen; Walvax Biotechnology Co., Ltd. Shi, Nian Min; Beijing Chaoyang District Centre for Disease Control and Prevention Zhao, Yu Liang; Heibei Province Centre for Disease Control and Prevention Xia, Sheng Li; Henan Province Centre for Disease Control and Prevention
Li, Guo Hua; Shanxi Province Centre for Disease Control and Prevention Li, Rong Cheng; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention Li, Yan Ping; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention Yang, Shu Yuan; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Xia, Jie-Lai; Fourth Military Medical University, Department of Health Statistics
<b>Primary Subject Heading</b>:
Immunology (including allergy)
Secondary Subject Heading: Epidemiology
Keywords: Pneumococcal conjugate vaccine, Sequential test, Non-inferiority
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1
Safety and immunogenicity of a new 13-valent pneumococcal
conjugate vaccine versus a licensed 7-valent pneumococcal conjugate
vaccine: study protocol of a randomized non-inferiority trial in China
Jing Jing Chen,1,2
Lin Yuan,2 Zhen Huang,
2 Nian Min Shi,
3 Yu Liang Zhao,
4 Sheng Li Xia,
5 Guo Hua
Li,6 Rong Cheng Li,
7 Yan Ping Li,
7 Shu Yuan Yang,
2 Jie Lai Xia
1*
Corresponding author: 1*Jie Lai Xia, Department of Health Statistics, Fourth Military Medical University, 169 Changle
Western Road, Xi’an, Shanxi Province, China, Tel: +86 029-84774861, Email: [email protected]
Co-authors:
1. Jing Jing Chen; Department of Health Statistics of Fourth Military Medical University, Xi’an,
Shanxi, China; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
2. Lin Yuan; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
3. Zhen Huang; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
4. Nian Min Shi; Beijing Chaoyang District Centre for Disease Control and Prevention, Beijing,
China
5. Yu Liang Zhao; Heibei Province Centre for Disease Control and Prevention, Shijiazhuang,
Heibei, China
6. Sheng Li Xia; Henan Province Centre for Disease Control and Prevention, Zhengzhou, Henan,
China
7. Guo Hua Li; Shanxi Province Centre for Disease Control and Prevention, Taiyuan, Shanxi,
China
8. Rong Cheng Li; Guangxi Zhuang Autonomous Region Center for Disease Control and
Prevention, Nanning, Guangxi, China
9. Yan Ping Li; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention,
Nanning, Guangxi, China
10. Shu Yuan Yang; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
Keywords: Pneumococcal conjugate vaccine, Sequential test, Non-inferiority
Word count: 4280
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ABSTRACT
Introduction: The invasive pneumococcal diseases (IPDs) caused by Streptococcus pneumoniae
pose an enormous threat to children under 5 years of age. However, routine use of
pneumococcal conjugate vaccines could aid in reducing the incidence of IPDs. The purpose of this
clinical trial is to assess the non-inferiority of the investigational 13-valent pneumococcal
conjugate vaccine (PCV13) to the currently licensed 7-valent pneumococcal conjugate vaccine
(PCV7).
Methods and analysis: 1,040 infants will receive a three-dose of either PCV13 or PCV7 at ages 3,
4 and 5 months respectively, and a booster dose at 12-15 months. Primary endpoints are the
percentage of subjects reaching a serotype-specific IgG concentration of ≥ 0.35µg/ml and the
IgG antibody geometric mean concentrations (GMCs) measured 30 days after the primary
immunization. Secondary endpoints include the percentage of vaccine recipients reaching
serotype-specific IgG concentration threshold of 1.0µg/ml, the percentage of subjects reaching
the pneumococcal opsonophagocytic assay (OPA) titer threshold of 1:8, and the geometric mean
titers (GMTs) of OPA measured 30 days after primary and booster doses. The number of standard
IgG responders and IgG GMCs measured 30 days after the booster immunization will also be
determined. To evaluate differences between two groups, the sequential testing of the
non-inferiority of PCV13 for the 7 common serotypes and its effectiveness in treating the 6
additional serotypes will be performed.
Ethics and dissemination: Ethics approvals have been granted by the Ethics Committees at the 3
provinces involved in this study: Shanxi, Henan and Hebei Provinces. The trial will be reported in
accordance with the CONSORT guidance.
Trial registration number: NCT02736240.
Strengths and limitations of this study
� This is the first study to investigate the immune responses induced by a locally developed
and manufactured 13-valent pneumococcal conjugate vaccine among Chinese infants.
� 1,040 infants will be recruited to support the randomized non-inferiority study design and a
sequential test method is adopted.
� Primary outcomes are proportions of vaccine recipients achieving a predefined
specific-serotype IgG concentration threshold and geometric mean IgG antibody
concentrations measured 30 days after primary immunization, both of which are
recommended by WHO.
� Besides the complete evaluation of immunogenicity and safety of the new PCV13, not
involving the assessment of concomitant immunization with other vaccines specified in
pediatric vaccination might be seen as a potential limitation of this trial.
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INTRODUCTION
Background
Streptococcus pneumoniae (S. pneumoniae or pneumococcus) is a leading cause of bacterial
pneumonia, meningitis, and sepsis in children, and thus poses a major threat to public health
around the world. According to a World Health Organization (WHO) investigation in 2005, an
estimated 0.7 to 1 million children under the age of 5 die from pneumonia every year; most of
whom lived in developing countries.[1] The top ten countries with the highest number of
reported pneumococcal cases were all in Asia and Africa, with China accounting for 12% of the
total.[2] Immunization against Hib, pneumococcus, measles and pertussis is the most effective
way to prevent pneumonia.[3] Routine use of the 7-valent pneumococcal conjugate vaccine
(PCV7), has resulted in a dramatic reduction in the incidence of invasive pneumococcal disease
(IPD) attributable to pneumococcal serotypes contained in the vaccine.[4] However, there is still
an urgent need for a pneumococcal conjugate vaccine with expanded coverage for IPD resulting
from serotypes not included in the PCV7.[5]
On 24 February 2010, the US Food and Drug Administration licensed a 13-valent pneumococcal
conjugate vaccine (PCV13) for children from 2 months to 5 years old. Since then, several studies
have been conducted on PCV13 in many countries except China. The licensed PCV13 has been
shown to be as effective as PCV7 in the prevention of disease caused by the 7 common serotypes
and could provide expanded protection against the 6 additional serotypes with a comparable
safety profile.[6] When co-administered with diphtheria, tetanus and acellular pertussis vaccine
(DTaP), PCV13 is well tolerated and as immunogenic as PCV7.[7] The flexible primary
immunization schedules of PCV13 for infants found no significant differences in antibody levels
for almost all serotypes after the booster dose at 12 months of age,[8 9] and thus recommended
by WHO.[10] Furthermore, the clinical efficacy of PCV13 for multiple purposes in age groups
ranging from 6 to over 70 years old has been confirmed.[11-16] Nevertheless, it is still unknown
whether the licensed PCV13 or a new PCV13 will be effective for the Chinese population to date.
To address the issue, we plan to initiate this trial for a pre-licensing evaluation of a new PCV13.
The investigational PCV13 (batch number 201511003) is manufactured by Yuxi Walvax
Biotechnology Co. Ltd. (an affiliate of Walvax Biotechnology Co., Ltd.), and supplied in penicillin
bottles. Each 0.5ml dose contains 2.2µg pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 7F,
9V, 14, 18C, 19A, 19F, and 23F and 4.4µg pneumococcal polysaccharide serotype 6B; each
serotype is conjugated to a tetanus toxoid carrier protein and adsorbed on aluminum phosphate.
In accordance with the guidelines formulated by WHO,[17] and the requirements established by
national regulatory authorities, licensing a new vaccine requires randomized clinical trials to
show the non-inferiority of the new vaccine to an existing pneumococcal conjugate vaccine. PCV7
will serve as the control vaccines, since it is the only pneumococcal conjugate vaccines that has
been licensed in mainland China. The control PCV7 (Prevnar, batch number H29315H13880) is
manufactured by Wyeth and supplied in pre-filled 0.5ml syringes. Each 0.5ml dose contains 2µg
pneumococcal polysaccharide serotypes 4, 9V, 14, 18C, 19F, and 23F and 4µg pneumococcal
polysaccharide serotype 6B; each serotype is conjugated to a CRM197 carrier protein and
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adsorbed on 0.5 mg aluminum phosphate.
Objectives
The purpose of this study is to i) determine if the 7 common serotype-specific pneumococcal IgG
responses elicited by PCV13 are all non-inferior to those elicited by PCV7 and ii) determine if the
6 additional serotype-specific pneumococcal IgG responses induced by PCV13 are all clinically
effective 30 days after the primary immunization.
We hypothesize that for each of the 7 common pneumococcal serotypes (4, 6B, 9V, 14, 18C,
19F, 23F) i) the lower bound of the 97.5% (98.75%, one-sided) Confidence Interval (CI) for the
difference (PCV13 – PCV7) in the proportion of vaccine recipients reaching the serotype-specific
IgG concentration threshold of 0.35μg/ml is no less than -10%; or ii)The lower bound of the 97.5%
(98.75%, one-sided) CI of the serotype-specific IgG geometric mean concentration (GMC) ratio
(PCV13/PCV7) is greater than 0.5 (-0.3, logarithmically transformed by base 10).
As a parallel hypothesis, we expect that for each of the 6 additional pneumococcal serotypes (1,
3, 5, 6A, 7F, 19A) i)The proportion of the serotype-specific IgG responders achieving an IgG
threshold of 0.35μg/ml in the PCV13 group is greater than that of the PCV7 group; and ii) the
lower limit of the 95% (2-sided) CI for the proportion of vaccine recipients reaching a
serotype-specific IgG concentration threshold of 0.35μg/ml is greater than or equal to 70%.
Trial design
This study is a multi-center phase III, randomized, parallel group, allocation concealed
non-inferiority trial with two groups to evaluate the immunogenicity and safety of PCV13
compared with PCV7 among healthy infants in China.
METHODS
Study setting
The study includes 6 sites scattered in 3 provinces in North China. Each site has been ratified by
the Center for Food and Drug Inspection (CFDI), a department of China Food and Drug
Administration (CFDA), to join the research team of this trial and recruit participants.
Eligibility criteria
Inclusion criteria
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Participants will only be recruited when he or she meets all of the following criteria at the time of
randomization:
1. Healthy infants, as established by medical history and clinical examination before entering
into the study, that are 3 months old at the time of the first vaccination
2. Obtained written informed consent from the legally responsible representative(s)
3. Have the compliance of the subjects’ legally responsible representative(s) with the
requirements of the protocol
4. No pneumococcal vaccine history or use of other preventive vaccine at least 7 days before
study entry
5. Axillary temperature ≤ 37℃
In addition, participants must not encounter any of the following exclusion criteria:
1. Vaccinated by on sale or other on trial pneumococcal vaccines
2. Have had an invasive disease with streptococcus pneumonia as the verified cause
3. Severely allergic to any vaccines or drugs, or sensitive to temperatures ≥ 39℃ associated
with biological products inoculation
4. Birth weight < 2.5 kg
5. History or family history of convulsion, seizure, encephalopathy or neurological disorder
6. Born from abnormal labors (difficult labors, aided by instruments) or have a history of
asphyxia or nerve damage
7. Confirmed thrombocytopenia or a history of blood coagulation disorder
8. Confirmed pathological jaundice
9. Any confirmed or suspected immunodeficiency involving immunosuppressive therapy
(radiotherapy, chemotherapy, corticosteroid hormone, antimetabolite, cytotoxic drugs),
human immunodeficiency virus (HIV) infection, etc.
10. Any confirmed or suspected congenital defect or serious chronic illnesses (trisomy 21
syndrome, diabetes, sickle cell anemia, neurological disorder or Guillain-Barré syndrome)
11. Any confirmed or suspected diseases including respiratory diseases, acute infection, active
period of chronic disease, cardiovascular disease, hepatic-nephrotic disease, cancer and
dermatosis
12. Administration of immunoglobulin and/or any blood products, except Hepatitis B
hyper-immune globulin(HBlg)
13. Concurrent participation in another clinical study
14. Other exclusion criteria affirmed by investigators
Intervention
Eligible infants will be randomized to either the PCV13 or the PCV7 group to receive a three-dose
series of PCV13 or PCV7 at ages 3, 4 and 5 months respectively, and a booster dose between 12
and 15 months. For all subjects, blood samples will be obtained at four different time points:
immediately before the first dose, 30 days after the primary series, immediately before the
booster dose, and 30 days after the toddler dose.
Serum concentrations of anti-capsular polysaccharide IgG for each of the 13 pneumococcal
serotypes will be measured for all subjects at the previously mentioned time points, using the
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standardized enzyme-linked immunosorbent assay (ELISA) method.[18] Additionally, serum
functional opsonophagocytic activity (OPA) for each serotype will be assayed at the last 3 time
points for a randomly selected subset of approximately 100 subjects in each group (200 infants in
total), composed of infants assigned the first 20-36 subject numbers from each of the six sites.
Each participant will be observed for 30 min after each vaccination for any immediate reaction
by the research staff. Any noted adverse events (AEs) will be recorded at that time. After leaving
the site, local reactions (pain, redness, swelling, and pruritus), systemic events (somnolence,
vomiting, diarrhea, crying, and irritability), axillary temperature, other AEs, and concomitant
medications to treat or prevent symptoms will be recorded in daily cards by the parents/legally
responsible representatives for 8 days. On the eighth day after vaccination, the documents will be
returned to the site. AEs occurring between the 8th and the 30th day after each dose together
with the usage of relevant concomitant medications will be recorded in connection cards and
handed in at the next visit. Serious adverse events (SAEs) will be collected throughout the study
until 6 months after the last dose. The intervention procedures are shown in Table 1.
Table 1 The intervention procedure
Interventions
Primary series Booster dose
3
months
4
months
5
months
30 days
postdose
12-15
months
30 days
postdose
6 months
postdose
Informed consent X
Eligibility screen X
Randomization X
Temperature X X X
X
Blood draw X
X X X
Vaccination X X X
X
Safety observations*
Immediate reaction ◎ ◎ ◎
◎
Local reactions and
systemic events ▲ ▲ ▲
▲
Adverse events ◆ ◆ ◆
◆
Serious adverse
events ★ ★ ★ ★ ★ ★ ★
*Safety observations occur after vaccination for a planned period.
◎Immediate reaction will be observed for 30 min after vaccination.
▲Local reactions and systemic events will be actively collected for 8 days after vaccination.
◆Other adverse events will be recorded by parents/ legally responsible representative(s) for 30 days
after vaccination.
★Serious adverse events will be self-reported by parents/ legally responsible representative(s) from
the first visit till the 6 months after the last dose.
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Outcome measures
Primary immunogenicity outcomes
For each of the 13 pneumococcal serotypes covered in PCV13:
1. Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 0.35μg/ml 30 days after the primary series.
2. GMC of serotype-specific IgG antibodies 30 days after the primary series.
Secondary immunogenicity outcomes
For each of the 13 pneumococcal serotypes covered in PCV13:
1. Proportion of vaccine recipients reaching the OPA threshold of 1:8 30 days after the primary
series.
2. Geometric mean titer (GMT) of OPA 30 days after the primary series.
3. Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 1.0μg/ml 30 days after the primary series.
4. Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 0.35μg/ml 30 days after the booster dose.
5. GMC of serotype-specific IgG antibodies 30 days after the booster dose.
6. Proportion of vaccine recipients reaching an OPA threshold of 1:8 30 days after the booster
dose.
7. GMT of OPA 30 days after the booster dose.
8. Proportion of vaccine recipients reaching a serotype-specific IgG concentration threshold of
1.0μg/ml 30 days after the booster dose.
Safety outcomes
Safety outcomes include all recorded local reactions and systemic AEs that occur within the 30
days following the primary series and booster doses and the percentage of vaccine recipients that
reported each AE.
Trial duration
The study will last for 26 months. If unsuspected acute abnormal reactions occur during the trial,
or the daily proportion of subjects who experienced AEs rated grade 3 or above reaches 15%
after any dose vaccination, the trial should be suspended. A panel will be involved in discussions
of the safety profile and decide whether the study should be continued.
Sample size
For each of the 7 common serotypes in both PCV13 and PCV7: Based on data from previous
studies, we assume the percentage of vaccine recipients reaching the serotype-specific IgG
concentration threshold of 0.35μg/ml will be 85%.[19] The non-inferior margin for the trial will
be set at 10%. If the non-inferiority does exist for a proportion of the test group, a sample size of
434 infants per group, 868 total, will provide 80% power to ensure that the lower limit of 97.5%
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two-sided CI for difference (test group – control group) will be no less than -10%. We also
postulate the common variance of serotype-specific IgG GMC, which has been logarithmically
transformed by base 10, will not be greater than 1.0. A sample size of 379 infants per group, 758
total, will have 80% power to detect whether the lower limit of 97.5% two-sided CI for
serotype-specific IgG GMC ratio (test group to control group) is above 0.5 or not. To take account
of α inflation and β consumption, Bonferroni correction will be employed to α, producing
corrected α= 0.025/2=0.0125 and corrected power = 1-0.2/7= 0.97.
For each of the 6 additional serotypes in PCV13 only: Based on the preclinical research, we
hypothesize that the proportion of vaccine recipients reaching the serotype-specific IgG
concentration threshold of 0.35μg/ml in the test group will be about 80% while that in the
control group will not be greater than 50%. If there is a notable difference between the two
groups, a sample size of 274 infants per group, 548 total, will provide 80% power to demonstrate
that the lower limit of 95% two-sided CI for a proportion of the test group will be no less than 70%
(the target rate). To control family-wise type II error, power will be adjusted to 0.97 (equals to
1-0.2/6).
Final decision: Theoretically a total of 868 evaluable participants (434 per group) should enable
the trial to achieve the primary outcomes. To take blood draw failures and blood collection
refusals into consideration, we will allow for an anticipated 20% dropout rate.[20] Therefor, the
total sample size required is 1,040 infants (520 per group).
Randomization and allocation
The allocation sequence is generated by Department of Health Statistics of Fourth Military
Medical University using SAS (SAS Institute Inc., Cary, NC, USA) Plan procedure. In order to
guarantee the group balance in different sites, the block randomization kit will be used. Each site
will receive consecutively coded vaccines.
Because of the difference in appearance of PCV13 and PCV7, the administrators cannot be
blinded, but the group assigners, lab staff and investigators will be. Before recruitment, all
vaccines will be masked in identical white small boxes and labeled with vaccine numbers based
on the allocation schedule by those who are not involved in the clinical trial procedures. Each
vaccine number is composed of two parts: the subject identification number and the dose
specification number. Four vaccines with the same subject number prefix will belong to the same
participant. In case any unexpected situations arise, additional vaccines including PCV13 and
PCV7 in a ratio of 2:1 will be prepared and wrapped separately in individual white boxes labeled
with numbers from B0001 to B0540. The link between the additional vaccine number and subject
number will be established based on an allocation sequence list by Medidata Rave—the
electronic data capture (EDC) system for this study. Emergency letters will be sent to each of the
sites, and properly preserved until needed.
Each eligible participant will be sequentially allotted a unique subject number according to site
allocation list by authorized assigners, and thus will have an equal chance of being assigned to
either the test group or the control group. Blood samples will be labeled with subject numbers
and collected independently of the vaccination process. The inoculator is responsible for taking
out the vaccine related to a specific subject number and administering the injection. Inoculators
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must not share any allocation information to investigators or those involved in follow-up
procedures.
Withdrawal
The participations’ parents or legally responsible representatives will be aware that their decision
to take part in the study is voluntary and that they are free to withdraw consent at any time. All
withdrawals from the randomized intervention will be reported. The investigator may drop
participants during the study in the case of intercurrent illness, AEs, SAEs, protocol violations or
other reasons that meet the exclusion criteria.
Data management
The trial data will be managed using the Medidata Rave EDC system. The database software
provides several features to help maintain data quality. These features include, but are not
limited to keeping audit trails on all data fields, allowing custom functions in configurations and
opening both automatic and manual queries. At the same time, the original record cards will be
designed in accordance with the protocol to collect raw clinical data and to support the trial
procedures. The source data obtained from each participant will be examined and verified by
investigators and clinical research assistants (CRAs) at each study site. The entered data will be
systematically validated and audited not only by EDC system itself using edit checks but also by
CRAs and data managers (DMs). Data query forms generated by medically trained personnel will
be sent to the site investigators for identification. The electronic-Case Report Form (e-CRF) will be
inspected by DMs at regular intervals throughout the trial to verify the protocol compliance. The
entered data should be complete, consistent and accurate. The blinded immunology assay results
will be sent in an additional Excel spreadsheet via email to the data manager to be linked with
the central database.
Statistical methods
Data set: The full analysis set (FAS) will comply with the principles of intent-to-treat (ITT),[21] and
be comprised of all participants who receive at least one dose of vaccine and one follow-up visit.
The per-protocol analysis set (PPS) will be comprised of ITT participants who have received the
integrated vaccination schedule and participated in all follow-up visits. Whether a subject with
protocol deviations should be eliminated from the PPS set will be determined through blind data
review process before analyzing. The safety analysis set will be comprised of participants that
were randomized to a certain group and vaccinated including those with protocol deviations.
Analysis principle: Analysis will be conducted following the CONSORT[22] flow diagram (Figure 1)
of the phases of the study: enrollment, allocation, interventions, follow-up, and analysis. Baseline
characteristics analysis will be given for each group to depict the premises of this study using
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means, standard deviation (SD), minimum and maximum value as well as the 2-sided 95% CIs (if
any). Continuous data will be portrayed with means, SDs and CIs if a normal distribution
hypothesis of data is met. Binomial data will be summarized as frequencies and proportions. All
statistical tests will be demonstrated with a two-sided p-value, and all CIs will be calculated as 95%
at a two-sided level unless otherwise specified. A detailed statistical analysis plan will be finalized
before the first substantive statistical analysis.
Immunogenicity: The immunogenicity population consists of all subjects that belong to PPS and
have available serological data before and after immunization. The primary immunogenicity
endpoints for each of the pneumococcal serotypes are the proportion of subjects reaching the
serotype-specific IgG concentration threshold of 0.35µg/ml, and the geometric mean IgG
antibody concentration, in the PCV13 group measured 30 days after the primary series. Within
each group, for each pneumococcal serotype, the proportion of subjects with a specific-IgG
antibody concentration threshold of 0.35μg/ml and the two-sided 95% CI for the proportion will
be calculated; for each antibody concentration, the value will be logarithmically transformed to
the base 10, and the two-sided 95% Cl will be structured. To evaluate differences between two
groups, the sequential test (Figure 2) of hypotheses, including the non-inferiority for the 7
common serotypes and the efficacy for the 6 additional serotypes, will be performed. The
non-inferiority for each of the 7 common serotypes will be declared if the lower limit of the
two-sided 97.5% (one-sided 98.75%) CI, which is calculated using the exact binomial method,[23
24] for the difference in proportions (PCV13 - PCV7) is no less than -10%, or the lower bound of
the two-sided 97.5% (one-sided 98.75%) CI of the IgG GMC ratio (PCV13/ PCV7) is greater than
0.5. To control familywise Type I error, Bonferroni correction will be used to address multiple test,
and thus a two-sided significance level of 0.025 (0.0125, one-sided) will be adopted. Only after
each of the 7 common serotypes has been shown to be non-inferior, will the other 6 additional
serotypes be worth assessing. The efficacy criteria for each of the 6 additional serotypes will be
met if both the lower limit of the 2-sided 95% CI for the proportion of vaccine recipients reaching
the serotype-specific IgG concentration threshold of 0.35μg/ml conducted by normal
approximation method is no less than 70%, and the 2-sided 95% CI for the difference in
proportion (PCV13 - PCV7) compared by a Chi-squared test lies almost to the right of the zero
(zero or positive mean difference). A p-value of less than 0.05 is considered statistically
significant.
The secondary immunogenicity endpoints for each of the pneumococcal serotypes in the
PCV13 group are the percentage of vaccine recipients reaching a serotype-specific IgG
concentration threshold of 0.35µg/ml 30 days after the toddler dose and the percentages of
vaccine recipients reaching a serotype-specific IgG concentration threshold of 1.0µg/ml 30 days
after primary series and booster dose. The proportions of the subjects reaching the
pneumococcal opsonophagocytic assay (OPA) titer threshold of 1:8 after primary and booster
immunization in pre-defined subgroups also serve as the secondary immunogenicity endpoints.
Within each group and for each antibody concentration or OPA titer, geometric mean will be
calculated and each concentration or titer will be logarithmically transformed for analyzing. To
assess differences between the two groups and to test the non-inferiority of the PCV13 group,
the analysis method described in the primary endpoints section will be employed.
As reported in previous studies,[25 26] antibody responses to serotypes 19A, 6A, and 5 were
noted in the PCV7 group. Therefore, when evaluating the efficacy of 6A, 19A, and 5 in the PCV13
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group, the OPA results should be combined.[27]
Safety: The safety population includes all subjects in the safety analysis set that will receive at
least one dose of study vaccine. Safety analysis including comparisons of incidences of local
reactions, systemic events, use of concomitant medications, dropouts and AEs between PCV13
and PCV7 will be demonstrated with the corresponding 2-sided 95% CIs and p-values base on
Fisher’s exact test methodology for each dose respectively and for all in total as well. A p-value of
equal to or less than 0.05 indicates a statistically significant difference.
Harms
Any serious adverse events (SAEs) will be reported to regulatory authorities, sponsors and Ethics
Committees (ECs) within 24 hours by fax, email or in person. Any suspected or unexpected
serious events will be reported to regulatory authorities by sponsors within 7 calendar days and
its follow-up investigation report will be submitted within 8 calendar days of the first report
submission day.
Auditing
Monitoring of this trial will be conducted by a Contract Research Organization (CRO, Simoon
Record Pharma Information Consulting Co., Ltd). Guidelines of Good Clinical Practice (GCP) will
ensure compliance.
ETHICS AND DISSEMINATION
Research ethics approval
This study was approved by the ECs at 3 provinces (Shanxi, Henan and Hebei Province), and will
be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.[28] The
registration number of this trial is NCT02736240.
Informed consent
All participants’ parents/ legally responsible representatives will receive adequate information
about the nature, purpose, and possible risks and benefits of the trial by an informed consent
form approved by the EC. The original version of signed consent forms will be retained by the
investigators as a trial record, and a copy will be kept by the participants’ parents/legally
responsible representatives.
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Confidentiality
To assure confidentiality, all participants will be allotted a unique subject number throughout the
trial. Personal information will be collected with standardized paper forms by face to face
interviews. Paper-based data will be stored in locked cabinets with limited access at each site,
and the electronic data will be saved on password protected computers.
Access to data
The final dataset will be under the custody of the sponsor together with the CRO selected
beforehand. The data managers will be permitted to access the full analyzed final dataset. Access
to the final or identifiable data by others is subject to the sponsor's approval.
Dissemination policy
The trial will be reported in accordance with the CONSORT guidance.
Discussion
To date, the efficacy and safety of PCV13 among the Chinese population is still largely unknown.
Hence, this study intends to characterize the PCV13 among Chinese infants and develop a safety
profile for the vaccine. To fulfill these objectives, we calculated sample sizes under different
hypothetical conditions and determined the optimal sample size to use to take all of all factors
into consideration. In study design, we adopted the sequential test method to inspect the
non-inferiority of each of the 7 common pneumococcal serotypes and the efficacy of each of the
6 additional pneumococcal serotypes step by step to avoid false positive error inflation. To be
more discreet and conservative, instead of setting pneumococcal serotype 6B in PCV7 as a
baseline when verifying the immunogenicity of each of the 6 additional serotypes in PCV13, as
many other researchers have done, we defined 70% as the lower limit of the 2-sided 95% CI for
the percentage of responders that reach the serotype-specific IgG concentration threshold of
0.35μg/ml and supposed that the corresponding percentages in PCV7 are less than 50%.[29]
Allowing for the cross-reactivation between 6A and 6B as well as 19A and 19B in PCV7, we will
select a subgroup of which to obtain the OPA results for each of the 13 serotypes to correct for
potential bias.
Given the main focus of the research, this study is not designed to involve the assessment of
concomitant immunization with other vaccines specified in pediatric vaccination schedules such
as diphtheria, tetanus and acellular pertussis vaccine (DTaP), which might be regarded as a
potential limitation. Because the feasibility of PCV7 administered concomitantly with DTaP in
mainland Chinese infants has been shown in the research reported by Li RC et al.,[30] and the
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immunogenicity of PCV13 co-administered with DTaP was demonstrated by Togashi T et al.,[7]
we will not prohibit the usage of vaccines listed in the expanded program on immunization (EPI),
but we will compulsively demand at least a fortnight interval between two kinds of vaccination.
Footnotes
Author affiliations:
1 DHSFMMU, Department of Health Statistics of Fourth Military Medical University, Xi’an, Shanxi, China
2 Walvax, Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
3 Beijing Chaoyang CDC, Beijing Chaoyang District Centre for Disease Control and Prevention, Beijing, China
4 Hebei CDC, Heibei Province Centre for Disease Control and Prevention, Shijiazhuang, Heibei, China
5 Henan CDC, Henan Province Centre for Disease Control and Prevention, Zhengzhou, Henan, China
6 Shanxi CDC, Shanxi Province Centre for Disease Control and Prevention, Taiyuan, Shanxi, China
7 Guangxi CDC, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, Guangxi,
China
Contributors
JLX provided statistical expertise and created the study design together with JJC. ZH and LY conceived the study and
participated in study design. JJC drafted the manuscript and calculated the sample size. NMS, YLZ, SLX and GHL are
the primary investigators and helped with protocol revise. RCL and YPL are the senior consultants and contributed to
protocol development. SYY compiled the original protocol in Chinese and participated in study design discussion. All
authors read and proved the final manuscript.
Funding The study is supported by a grant from Bio-pharmaceutical Major Scientific & Technological Project
(biological product development section) of Yunnan Province (project number 2015ZJ005).
Disclaimer The views expressed are those of the author(s) and not necessarily those of the DHSFMMU, Walvax or
CDCs which involved.
Competing interests The authors declare that there is no interest conflict regarding the publication of this paper.
Ethics approval The trial is approved by: the Beijing Chaoyang District Centre for Disease Control and Prevention
Ethics Committee (the lead institution), the Heibei Province Centre for Disease Control and Prevention Ethics
Committee, the Henan Province Centre for Disease Control and Prevention Ethics Committee, and the Shanxi
Province Centre for Disease Control and Prevention Ethics Committee.
Provenance and peer review Not commissioned; internally peer reviewed.
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22. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for
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23. NEWCOMBE RG. Interval estimation for the difference between independent proportions
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25. Esposito S, Tansey S, Thompson A, et al. Safety and immunogenicity of a 13-valent
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vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clin
Vaccine Immunol 2010;17(6):1017-26 doi: 10.1128/CVI.00062-10[published Online First: 28
April 2010].
26. Olivier C, Belohradsky BH, Stojanov S, et al. Immunogenicity, reactogenicity, and safety of a
seven-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a fully
liquid DTPa-IPV-HBV-Hib combination vaccine in healthy infants. Vaccine 2008;26(25):3142-52
doi: 10.1016/j.vaccine.2007.11.096[published Online First: 6 May 2008].
27. Cooper D, Yu X, Sidhu M, et al. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits
cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae
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29. Elberse KE, de Greeff SC, Wattimena N, et al. Seroprevalence of IgG antibodies against 13
vaccine Streptococcus pneumoniae serotypes in the Netherlands. Vaccine 2011;29(5):1029-35
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30. Li RC, Li FX, Li YP, et al. Safety and immunogenicity of a 7-valent pneumococcal conjugate
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2008].
Figure 1 The study flow diagram
Figure 2 The sequential test flow chart
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Figure 1 The study flow diagram
281x174mm (300 x 300 DPI)
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Figure 2 The sequential test flow chart
281x182mm (300 x 300 DPI)
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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*
Section/item Item No
Description Addressed on page number
Administrative information
Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______1 _____
Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ______2______
2b All items from the World Health Organization Trial Registration Data Set _____N/A_ ___
Protocol version 3 Date and version identifier _____N/A_____
Funding 4 Sources and types of financial, material, and other support ______13_____
Roles and
responsibilities
5a Names, affiliations, and roles of protocol contributors _____1,13 ____
5b Name and contact information for the trial sponsor _____N/A_ ___
5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and
interpretation of data; writing of the report; and the decision to submit the report for publication, including
whether they will have ultimate authority over any of these activities
_____N/A_ ___
5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint
adjudication committee, data management team, and other individuals or groups overseeing the trial, if
applicable (see Item 21a for data monitoring committee)
_____N/A_ ___
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Introduction
Background and
rationale
6a Description of research question and justification for undertaking the trial, including summary of relevant
studies (published and unpublished) examining benefits and harms for each intervention
______3______
6b Explanation for choice of comparators ______3______
Objectives 7 Specific objectives or hypotheses ______4______
Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),
allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
______4______
Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will
be collected. Reference to where list of study sites can be obtained
______4______
Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and
individuals who will perform the interventions (eg, surgeons, psychotherapists)
______4______
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be
administered
______5______
11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose
change in response to harms, participant request, or improving/worsening disease)
_____N/A_ ___
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence
(eg, drug tablet return, laboratory tests)
______6______
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _____N/A_ ___
Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood
pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,
median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen
efficacy and harm outcomes is strongly recommended
______7______
Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for
participants. A schematic diagram is highly recommended (see Figure)
______6______
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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including
clinical and statistical assumptions supporting any sample size calculations
______6______
Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size _____N/A_ ___
Methods: Assignment of interventions (for controlled trials)
Allocation:
Sequence
generation
16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any
factors for stratification. To reduce predictability of a random sequence, details of any planned restriction
(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants
or assign interventions
______8______
Allocation
concealment
mechanism
16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,
opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned
______8______
Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to
interventions
______8______
Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome
assessors, data analysts), and how
______8______
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s
allocated intervention during the trial
______8______
Methods: Data collection, management, and analysis
Data collection
methods
18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related
processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of
study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.
Reference to where data collection forms can be found, if not in the protocol
______9______
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be
collected for participants who discontinue or deviate from intervention protocols
_____N/A_ ___
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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality
(eg, double data entry; range checks for data values). Reference to where details of data management
procedures can be found, if not in the protocol
______9______
Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the
statistical analysis plan can be found, if not in the protocol
______9______
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _____ 10 _____
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any
statistical methods to handle missing data (eg, multiple imputation)
______9______
Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of
whether it is independent from the sponsor and competing interests; and reference to where further details
about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not
needed
_____N/A_ ___
21b Description of any interim analyses and stopping guidelines, including who will have access to these interim
results and make the final decision to terminate the trial
_____N/A_ ___
Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse
events and other unintended effects of trial interventions or trial conduct
_____ 11 _____
Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent
from investigators and the sponsor
_____ 11 _____
Ethics and dissemination
Research ethics
approval
24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _____ 11 _____
Protocol
amendments
25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,
analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,
regulators)
_____N/A_ ___
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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and
how (see Item 32)
_____ 11 _____
26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
_____N/A_ ___
Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained
in order to protect confidentiality before, during, and after the trial
_____ 12 _____
Declaration of
interests
28 Financial and other competing interests for principal investigators for the overall trial and each study site _____ 12 _____
Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that
limit such access for investigators
_____ 12 _____
Ancillary and post-
trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial
participation
_____N/A_ ___
Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,
the public, and other relevant groups (eg, via publication, reporting in results databases, or other data
sharing arrangements), including any publication restrictions
_____ 12 _____
31b Authorship eligibility guidelines and any intended use of professional writers _____ 13 _____
31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _____N/A_ ___
Appendices
Informed consent
materials
32 Model consent form and other related documentation given to participants and authorised surrogates _____N/A_ ___
Biological
specimens
33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular
analysis in the current trial and for future use in ancillary studies, if applicable
_____N/A_ ___
*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.
Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons
“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.
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Safety and immunogenicity of a new 13-valent pneumococcal conjugate vaccine versus a licensed 7-valent
pneumococcal conjugate vaccine: study protocol of a randomized non-inferiority trial in China
Journal: BMJ Open
Manuscript ID bmjopen-2016-012488.R2
Article Type: Protocol
Date Submitted by the Author: 03-Sep-2016
Complete List of Authors: Chen, Jing Jing; Fourth Military Medical University, Department of Health Statistics; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Yuan, Lin; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Huang, Zhen; Walvax Biotechnology Co., Ltd. Shi, Nian Min; Beijing Chaoyang District Centre for Disease Control and Prevention Zhao, Yu Liang; Heibei Province Centre for Disease Control and Prevention Xia, Sheng Li; Henan Province Centre for Disease Control and Prevention
Li, Guo Hua; Shanxi Province Centre for Disease Control and Prevention Li, Rong Cheng; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention Li, Yan Ping; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention Yang, Shu Yuan; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Xia, Jie-Lai; Fourth Military Medical University, Department of Health Statistics
<b>Primary Subject Heading</b>:
Immunology (including allergy)
Secondary Subject Heading: Epidemiology
Keywords: Pneumococcal conjugate vaccine, Sequential test, Non-inferiority
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Safety and immunogenicity of a new 13-valent pneumococcal
conjugate vaccine versus a licensed 7-valent pneumococcal conjugate
vaccine: study protocol of a randomized non-inferiority trial in China
Jing Jing Chen,1,2
Lin Yuan,2 Zhen Huang,
2 Nian Min Shi,
3 Yu Liang Zhao,
4 Sheng Li Xia,
5 Guo Hua
Li,6 Rong Cheng Li,
7 Yan Ping Li,
7 Shu Yuan Yang,
2 Jie Lai Xia
1*
Corresponding author: 1*Jie Lai Xia, Department of Health Statistics, Fourth Military Medical University, 169 Changle
Western Road, Xi’an, Shanxi Province, China, Tel: +86 029-84774861, Email: [email protected]
Co-authors:
1. Jing Jing Chen; Department of Health Statistics of Fourth Military Medical University, Xi’an,
Shanxi, China; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
2. Lin Yuan; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
3. Zhen Huang; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
4. Nian Min Shi; Beijing Chaoyang District Centre for Disease Control and Prevention, Beijing,
China
5. Yu Liang Zhao; Heibei Province Centre for Disease Control and Prevention, Shijiazhuang,
Heibei, China
6. Sheng Li Xia; Henan Province Centre for Disease Control and Prevention, Zhengzhou, Henan,
China
7. Guo Hua Li; Shanxi Province Centre for Disease Control and Prevention, Taiyuan, Shanxi,
China
8. Rong Cheng Li; Guangxi Zhuang Autonomous Region Center for Disease Control and
Prevention, Nanning, Guangxi, China
9. Yan Ping Li; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention,
Nanning, Guangxi, China
10. Shu Yuan Yang; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
Keywords: Pneumococcal conjugate vaccine, Sequential test, Non-inferiority
Word count: 4280
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ABSTRACT
Introduction: The invasive pneumococcal diseases (IPDs) caused by Streptococcus pneumoniae
pose an enormous threat to children under 5 years of age. However, routine use of
pneumococcal conjugate vaccines could aid in reducing the incidence of IPDs. The purpose of this
clinical trial is to assess the non-inferiority of the investigational 13-valent pneumococcal
conjugate vaccine (PCV13) to the currently licensed 7-valent pneumococcal conjugate vaccine
(PCV7).
Methods and analysis: 1,040 infants will receive a three-dose of either PCV13 or PCV7 at ages 3,
4 and 5 months respectively, and a booster dose at 12-15 months. Primary endpoints are the
percentage of subjects reaching a serotype-specific IgG concentration of ≥ 0.35µg/ml and the
IgG antibody geometric mean concentrations (GMCs) measured 30 days after the primary
immunization. Secondary endpoints include the percentage of vaccine recipients reaching
serotype-specific IgG concentration threshold of 1.0µg/ml, the percentage of subjects reaching
the pneumococcal opsonophagocytic assay (OPA) titer threshold of 1:8, and the geometric mean
titers (GMTs) of OPA measured 30 days after primary and booster doses. The number of standard
IgG responders and IgG GMCs measured 30 days after the booster immunization will also be
determined. To evaluate differences between two groups, the sequential testing of the
non-inferiority of PCV13 for the 7 common serotypes and its effectiveness in treating the 6
additional serotypes will be performed.
Ethics and dissemination: Ethics approvals have been granted by the Ethics Committees at the 3
provinces involved in this study: Shanxi, Henan and Hebei Provinces. The trial will be reported in
accordance with the CONSORT guidance.
Trial registration number: NCT02736240.
Strengths and limitations of this study
� This is the first study to investigate the immune responses induced by a locally developed
and manufactured 13-valent pneumococcal conjugate vaccine among Chinese infants.
� 1,040 infants will be recruited to support the randomized non-inferiority study design and a
sequential test method is adopted.
� Primary outcomes are proportions of vaccine recipients achieving a predefined
specific-serotype IgG concentration threshold and geometric mean IgG antibody
concentrations measured 30 days after primary immunization, both of which are
recommended by WHO.
� Besides the complete evaluation of immunogenicity and safety of the new PCV13, not
involving the assessment of concomitant immunization with other vaccines specified in
pediatric vaccination might be seen as a potential limitation of this trial.
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INTRODUCTION
Background
Streptococcus pneumoniae (S. pneumoniae or pneumococcus) is a leading cause of bacterial
pneumonia, meningitis, and sepsis in children, and thus poses a major threat to public health
around the world. According to a World Health Organization (WHO) investigation in 2005, an
estimated 0.7 to 1 million children under the age of 5 die from pneumonia every year; most of
whom lived in developing countries.[1] The top ten countries with the highest number of
reported pneumococcal cases were all in Asia and Africa, with China accounting for 12% of the
total.[2] Immunization against Hib, pneumococcus, measles and pertussis is the most effective
way to prevent pneumonia.[3] Routine use of the 7-valent pneumococcal conjugate vaccine
(PCV7), has resulted in a dramatic reduction in the incidence of invasive pneumococcal disease
(IPD) attributable to pneumococcal serotypes contained in the vaccine.[4] However, there is still
an urgent need for a pneumococcal conjugate vaccine with expanded coverage for IPD resulting
from serotypes not included in the PCV7.[5]
On 24 February 2010, the US Food and Drug Administration licensed a 13-valent pneumococcal
conjugate vaccine (PCV13) for children from 2 months to 5 years old. Since then, several studies
have been conducted on PCV13 in many countries except China. The licensed PCV13 has been
shown to be as effective as PCV7 in the prevention of disease caused by the 7 common serotypes
and could provide expanded protection against the 6 additional serotypes with a comparable
safety profile.[6] When co-administered with diphtheria, tetanus and acellular pertussis vaccine
(DTaP), PCV13 is well tolerated and as immunogenic as PCV7.[7] The flexible primary
immunization schedules of PCV13 for infants found no significant differences in antibody levels
for almost all serotypes after the booster dose at 12 months of age,[8 9] and thus recommended
by WHO.[10] Furthermore, the clinical efficacy of PCV13 for multiple purposes in age groups
ranging from 6 to over 70 years old has been confirmed.[11-16] Nevertheless, it is still unknown
whether the licensed PCV13 or a new PCV13 will be effective for the Chinese population to date.
To address the issue, we plan to initiate this trial for a pre-licensing evaluation of a new PCV13.
The investigational PCV13 (batch number 201511003) is manufactured by Yuxi Walvax
Biotechnology Co. Ltd. (an affiliate of Walvax Biotechnology Co., Ltd.), and supplied in penicillin
bottles. Each 0.5ml dose contains 2.2µg pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 7F,
9V, 14, 18C, 19A, 19F, and 23F and 4.4µg pneumococcal polysaccharide serotype 6B; each
serotype is conjugated to a tetanus toxoid carrier protein and adsorbed on aluminum phosphate.
In accordance with the guidelines formulated by WHO,[17] and the requirements established by
national regulatory authorities, licensing a new vaccine requires randomized clinical trials to
show the non-inferiority of the new vaccine to an existing pneumococcal conjugate vaccine. PCV7
will serve as the control vaccines, since it is the only pneumococcal conjugate vaccines that has
been licensed in mainland China. The control PCV7 (Prevnar, batch number H29315H13880) is
manufactured by Wyeth and supplied in pre-filled 0.5ml syringes. Each 0.5ml dose contains 2µg
pneumococcal polysaccharide serotypes 4, 9V, 14, 18C, 19F, and 23F and 4µg pneumococcal
polysaccharide serotype 6B; each serotype is conjugated to a CRM197 carrier protein and
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adsorbed on 0.5 mg aluminum phosphate.
Objectives
The purpose of this study is to i) determine if the 7 common serotype-specific pneumococcal IgG
responses elicited by PCV13 are all non-inferior to those elicited by PCV7 and ii) determine if the
6 additional serotype-specific pneumococcal IgG responses induced by PCV13 are all clinically
effective 30 days after the primary immunization.
We hypothesize that for each of the 7 common pneumococcal serotypes (4, 6B, 9V, 14, 18C,
19F, 23F) i) the lower bound of the 97.5% (98.75%, one-sided) Confidence Interval (CI) for the
difference (PCV13 – PCV7) in the proportion of vaccine recipients reaching the serotype-specific
IgG concentration threshold of 0.35μg/ml is no less than -10%; or ii)The lower bound of the 97.5%
(98.75%, one-sided) CI of the serotype-specific IgG geometric mean concentration (GMC) ratio
(PCV13/PCV7) is greater than 0.5 (-0.3, logarithmically transformed by base 10).
As a parallel hypothesis, we expect that for each of the 6 additional pneumococcal serotypes (1,
3, 5, 6A, 7F, 19A) i)The proportion of the serotype-specific IgG responders achieving an IgG
threshold of 0.35μg/ml in the PCV13 group is greater than that of the PCV7 group; and ii) the
lower limit of the 95% (2-sided) CI for the proportion of vaccine recipients reaching a
serotype-specific IgG concentration threshold of 0.35μg/ml is greater than or equal to 70%.
Trial design
This study is a multi-center phase III, randomized, parallel group, allocation concealed
non-inferiority trial with two groups to evaluate the immunogenicity and safety of PCV13
compared with PCV7 among healthy infants in China.
METHODS
Study setting
The study includes 6 sites scattered in 3 provinces in North China. Each site has been ratified by
the Center for Food and Drug Inspection (CFDI), a department of China Food and Drug
Administration (CFDA), to join the research team of this trial and recruit participants.
Eligibility criteria
Inclusion criteria
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Participants will only be recruited when he or she meets all of the following criteria at the time of
randomization:
1. Healthy infants, as established by medical history and clinical examination before entering
into the study, that are 3 months old at the time of the first vaccination
2. Obtained written informed consent from the legally responsible representative(s)
3. Have the compliance of the subjects’ legally responsible representative(s) with the
requirements of the protocol
4. No pneumococcal vaccine history or use of other preventive vaccine at least 7 days before
study entry
5. Axillary temperature ≤ 37℃
In addition, participants must not encounter any of the following exclusion criteria:
1. Vaccinated by on sale or other on trial pneumococcal vaccines
2. Have had an invasive disease with streptococcus pneumonia as the verified cause
3. Severely allergic to any vaccines or drugs, or sensitive to temperatures ≥ 39℃ associated
with biological products inoculation
4. Birth weight < 2.5 kg
5. History or family history of convulsion, seizure, encephalopathy or neurological disorder
6. Born from abnormal labors (difficult labors, aided by instruments) or have a history of
asphyxia or nerve damage
7. Confirmed thrombocytopenia or a history of blood coagulation disorder
8. Confirmed pathological jaundice
9. Any confirmed or suspected immunodeficiency involving immunosuppressive therapy
(radiotherapy, chemotherapy, corticosteroid hormone, antimetabolite, cytotoxic drugs),
human immunodeficiency virus (HIV) infection, etc.
10. Any confirmed or suspected congenital defect or serious chronic illnesses (trisomy 21
syndrome, diabetes, sickle cell anemia, neurological disorder or Guillain-Barré syndrome)
11. Any confirmed or suspected diseases including respiratory diseases, acute infection, active
period of chronic disease, cardiovascular disease, hepatic-nephrotic disease, cancer and
dermatosis
12. Administration of immunoglobulin and/or any blood products, except Hepatitis B
hyper-immune globulin(HBlg)
13. Concurrent participation in another clinical study
14. Other exclusion criteria affirmed by investigators
Intervention
Eligible infants will be randomized to either the PCV13 or the PCV7 group to receive a three-dose
series of PCV13 or PCV7 at ages 3, 4 and 5 months respectively, and a booster dose between 12
and 15 months. For all subjects, blood samples will be obtained at four different time points:
immediately before the first dose, 30 days after the primary series, immediately before the
booster dose, and 30 days after the toddler dose.
Serum concentrations of anti-capsular polysaccharide IgG for each of the 13 pneumococcal
serotypes will be measured for all subjects at the previously mentioned time points, using the
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standardized enzyme-linked immunosorbent assay (ELISA) method.[18] Additionally, serum
functional opsonophagocytic activity (OPA) for each serotype will be assayed at the last 3 time
points for a randomly selected subset of approximately 100 subjects in each group (200 infants in
total), composed of infants assigned the first 20-36 subject numbers from each of the six sites.
Each participant will be observed for 30 min after each vaccination for any immediate reaction
by the research staff. Any noted adverse events (AEs) will be recorded at that time. After leaving
the site, local reactions (pain, redness, swelling, and pruritus), systemic events (somnolence,
vomiting, diarrhea, crying, and irritability), axillary temperature, other AEs, and concomitant
medications to treat or prevent symptoms will be recorded in daily cards by the parents/legally
responsible representatives for 8 days. On the eighth day after vaccination, the documents will be
returned to the site. AEs occurring between the 8th and the 30th day after each dose together
with the usage of relevant concomitant medications will be recorded in connection cards and
handed in at the next visit. Serious adverse events (SAEs) will be collected throughout the study
until 6 months after the last dose. The intervention procedures are shown in Table 1.
Table 1 The intervention procedure
Interventions
Primary series Booster dose
3
months
4
months
5
months
30 days
postdose
12-15
months
30 days
postdose
6 months
postdose
Informed consent X
Eligibility screen X
Randomization X
Temperature X X X
X
Blood draw X
X X X
Vaccination X X X
X
Safety observations*
Immediate reaction ◎ ◎ ◎
◎
Local reactions and
systemic events ▲ ▲ ▲
▲
Adverse events ◆ ◆ ◆
◆
Serious adverse
events ★ ★ ★ ★ ★ ★ ★
*Safety observations occur after vaccination for a planned period.
◎Immediate reaction will be observed for 30 min after vaccination.
▲Local reactions and systemic events will be actively collected for 8 days after vaccination.
◆Other adverse events will be recorded by parents/ legally responsible representative(s) for 30 days
after vaccination.
★Serious adverse events will be self-reported by parents/ legally responsible representative(s) from
the first visit till the 6 months after the last dose.
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Outcome measures
Primary immunogenicity outcomes
For each of the 13 pneumococcal serotypes covered in PCV13:
1. Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 0.35μg/ml 30 days after the primary series.
2. GMC of serotype-specific IgG antibodies 30 days after the primary series.
Secondary immunogenicity outcomes
For each of the 13 pneumococcal serotypes covered in PCV13:
1. Proportion of vaccine recipients reaching the OPA threshold of 1:8 30 days after the primary
series.
2. Geometric mean titer (GMT) of OPA 30 days after the primary series.
3. Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 1.0μg/ml 30 days after the primary series.
4. Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold
of 0.35μg/ml 30 days after the booster dose.
5. GMC of serotype-specific IgG antibodies 30 days after the booster dose.
6. Proportion of vaccine recipients reaching an OPA threshold of 1:8 30 days after the booster
dose.
7. GMT of OPA 30 days after the booster dose.
8. Proportion of vaccine recipients reaching a serotype-specific IgG concentration threshold of
1.0μg/ml 30 days after the booster dose.
Safety outcomes
Safety outcomes include all recorded local reactions and systemic AEs that occur within the 30
days following the primary series and booster doses and the percentage of vaccine recipients that
reported each AE.
Trial duration
The study will last for 26 months. If unsuspected acute abnormal reactions occur during the trial,
or the daily proportion of subjects who experienced AEs rated grade 3 or above reaches 15%
after any dose vaccination, the trial should be suspended. A panel will be involved in discussions
of the safety profile and decide whether the study should be continued.
Sample size
For each of the 7 common serotypes in both PCV13 and PCV7: Based on data from previous
studies, we assume the percentage of vaccine recipients reaching the serotype-specific IgG
concentration threshold of 0.35μg/ml will be 85%.[19] The non-inferior margin for the trial will
be set at 10%. If the non-inferiority does exist for a proportion of the test group, a sample size of
434 infants per group, 868 total, will provide 80% power to ensure that the lower limit of 97.5%
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two-sided CI for difference (test group – control group) will be no less than -10%. We also
postulate the common variance of serotype-specific IgG GMC, which has been logarithmically
transformed by base 10, will not be greater than 1.0. A sample size of 379 infants per group, 758
total, will have 80% power to detect whether the lower limit of 97.5% two-sided CI for
serotype-specific IgG GMC ratio (test group to control group) is above 0.5 or not. To take account
of α inflation and β consumption, Bonferroni correction will be employed to α, producing
corrected α= 0.025/2=0.0125 and corrected power = 1-0.2/7= 0.97.
For each of the 6 additional serotypes in PCV13 only: Based on the preclinical research, we
hypothesize that the proportion of vaccine recipients reaching the serotype-specific IgG
concentration threshold of 0.35μg/ml in the test group will be about 80% while that in the
control group will not be greater than 50%. If there is a notable difference between the two
groups, a sample size of 274 infants per group, 548 total, will provide 80% power to demonstrate
that the lower limit of 95% two-sided CI for a proportion of the test group will be no less than 70%
(the target rate). To control family-wise type II error, power will be adjusted to 0.97 (equals to
1-0.2/6).
Final decision: Theoretically a total of 868 evaluable participants (434 per group) should enable
the trial to achieve the primary outcomes. To take blood draw failures and blood collection
refusals into consideration, we will allow for an anticipated 20% dropout rate.[20] Therefor, the
total sample size required is 1,040 infants (520 per group).
Randomization and allocation
The allocation sequence is generated by Department of Health Statistics of Fourth Military
Medical University using SAS (SAS Institute Inc., Cary, NC, USA) Plan procedure. In order to
guarantee the group balance in different sites, the block randomization kit will be used. Each site
will receive consecutively coded vaccines.
Because of the difference in appearance of PCV13 and PCV7, the administrators cannot be
blinded, but the group assigners, lab staff and investigators will be. Before recruitment, all
vaccines will be masked in identical white small boxes and labeled with vaccine numbers based
on the allocation schedule by those who are not involved in the clinical trial procedures. Each
vaccine number is composed of two parts: the subject identification number and the dose
specification number. Four vaccines with the same subject number prefix will belong to the same
participant. In case any unexpected situations arise, additional vaccines including PCV13 and
PCV7 in a ratio of 2:1 will be prepared and wrapped separately in individual white boxes labeled
with numbers from B0001 to B0540. The link between the additional vaccine number and subject
number will be established based on an allocation sequence list by Medidata Rave—the
electronic data capture (EDC) system for this study. Emergency letters will be sent to each of the
sites, and properly preserved until needed.
Each eligible participant will be sequentially allotted a unique subject number according to site
allocation list by authorized assigners, and thus will have an equal chance of being assigned to
either the test group or the control group. Blood samples will be labeled with subject numbers
and collected independently of the vaccination process. The inoculator is responsible for taking
out the vaccine related to a specific subject number and administering the injection. Inoculators
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must not share any allocation information to investigators or those involved in follow-up
procedures.
Withdrawal
The participations’ parents or legally responsible representatives will be aware that their decision
to take part in the study is voluntary and that they are free to withdraw consent at any time. All
withdrawals from the randomized intervention will be reported. The investigator may drop
participants during the study in the case of intercurrent illness, AEs, SAEs, protocol violations or
other reasons that meet the exclusion criteria.
Data management
The trial data will be managed using the Medidata Rave EDC system. The database software
provides several features to help maintain data quality. These features include, but are not
limited to keeping audit trails on all data fields, allowing custom functions in configurations and
opening both automatic and manual queries. At the same time, the original record cards will be
designed in accordance with the protocol to collect raw clinical data and to support the trial
procedures. The source data obtained from each participant will be examined and verified by
investigators and clinical research assistants (CRAs) at each study site. The entered data will be
systematically validated and audited not only by EDC system itself using edit checks but also by
CRAs and data managers (DMs). Data query forms generated by medically trained personnel will
be sent to the site investigators for identification. The electronic-Case Report Form (e-CRF) will be
inspected by DMs at regular intervals throughout the trial to verify the protocol compliance. The
entered data should be complete, consistent and accurate. The blinded immunology assay results
will be sent in an additional Excel spreadsheet via email to the data manager to be linked with
the central database.
Statistical methods
Data set: The full analysis set (FAS) will comply with the principles of intent-to-treat (ITT),[21] and
be comprised of all participants who receive at least one dose of vaccine and one follow-up visit.
The per-protocol analysis set (PPS) will be comprised of ITT participants who have received the
integrated vaccination schedule and participated in all follow-up visits. Whether a subject with
protocol deviations should be eliminated from the PPS set will be determined through blind data
review process before analyzing. The safety analysis set will be comprised of participants that
were randomized to a certain group and vaccinated including those with protocol deviations.
Analysis principle: Analysis will be conducted following the CONSORT[22] flow diagram (Figure 1)
of the phases of the study: enrollment, allocation, interventions, follow-up, and analysis. Baseline
characteristics analysis will be given for each group to depict the premises of this study using
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means, standard deviation (SD), minimum and maximum value as well as the 2-sided 95% CIs (if
any). Continuous data will be portrayed with means, SDs and CIs if a normal distribution
hypothesis of data is met. Binomial data will be summarized as frequencies and proportions. All
statistical tests will be demonstrated with a two-sided p-value, and all CIs will be calculated as 95%
at a two-sided level unless otherwise specified. A detailed statistical analysis plan will be finalized
before the first substantive statistical analysis.
Immunogenicity: The immunogenicity population consists of all subjects that belong to PPS and
have available serological data before and after immunization. The primary immunogenicity
endpoints for each of the pneumococcal serotypes are the proportion of subjects reaching the
serotype-specific IgG concentration threshold of 0.35µg/ml, and the geometric mean IgG
antibody concentration, in the PCV13 group measured 30 days after the primary series. Within
each group, for each pneumococcal serotype, the proportion of subjects with a specific-IgG
antibody concentration threshold of 0.35μg/ml and the two-sided 95% CI for the proportion will
be calculated; for each antibody concentration, the value will be logarithmically transformed to
the base 10, and the two-sided 95% Cl will be structured. To evaluate differences between two
groups, the sequential test (Figure 2) of hypotheses, including the non-inferiority for the 7
common serotypes and the efficacy for the 6 additional serotypes, will be performed. The
non-inferiority for each of the 7 common serotypes will be declared if the lower limit of the
two-sided 97.5% (one-sided 98.75%) CI, which is calculated using the exact binomial method,[23
24] for the difference in proportions (PCV13 - PCV7) is no less than -10%, or the lower bound of
the two-sided 97.5% (one-sided 98.75%) CI of the IgG GMC ratio (PCV13/ PCV7) is greater than
0.5. To control familywise Type I error, Bonferroni correction will be used to address multiple test,
and thus a two-sided significance level of 0.025 (0.0125, one-sided) will be adopted. Only after
each of the 7 common serotypes has been shown to be non-inferior, will the other 6 additional
serotypes be worth assessing. The efficacy criteria for each of the 6 additional serotypes will be
met if both the lower limit of the 2-sided 95% CI for the proportion of vaccine recipients reaching
the serotype-specific IgG concentration threshold of 0.35μg/ml conducted by normal
approximation method is no less than 70%, and the 2-sided 95% CI for the difference in
proportion (PCV13 - PCV7) compared by a Chi-squared test lies almost to the right of the zero
(zero or positive mean difference). A p-value of less than 0.05 is considered statistically
significant.
The secondary immunogenicity endpoints for each of the pneumococcal serotypes in the
PCV13 group are the percentage of vaccine recipients reaching a serotype-specific IgG
concentration threshold of 0.35µg/ml 30 days after the toddler dose and the percentages of
vaccine recipients reaching a serotype-specific IgG concentration threshold of 1.0µg/ml 30 days
after primary series and booster dose. The proportions of the subjects reaching the
pneumococcal opsonophagocytic assay (OPA) titer threshold of 1:8 after primary and booster
immunization in pre-defined subgroups also serve as the secondary immunogenicity endpoints.
Within each group and for each antibody concentration or OPA titer, geometric mean will be
calculated and each concentration or titer will be logarithmically transformed for analyzing. To
assess differences between the two groups and to test the non-inferiority of the PCV13 group,
the analysis method described in the primary endpoints section will be employed.
As reported in previous studies,[25 26] antibody responses to serotypes 19A, 6A, and 5 were
noted in the PCV7 group. Therefore, when evaluating the efficacy of 6A, 19A, and 5 in the PCV13
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group, the OPA results should be combined.[27]
Safety: The safety population includes all subjects in the safety analysis set that will receive at
least one dose of study vaccine. Safety analysis including comparisons of incidences of local
reactions, systemic events, use of concomitant medications, dropouts and AEs between PCV13
and PCV7 will be demonstrated with the corresponding 2-sided 95% CIs and p-values base on
Fisher’s exact test methodology for each dose respectively and for all in total as well. A p-value of
equal to or less than 0.05 indicates a statistically significant difference.
Harms
Any serious adverse events (SAEs) will be reported to regulatory authorities, sponsors and Ethics
Committees (ECs) within 24 hours by fax, email or in person. Any suspected or unexpected
serious events will be reported to regulatory authorities by sponsors within 7 calendar days and
its follow-up investigation report will be submitted within 8 calendar days of the first report
submission day.
Auditing
Monitoring of this trial will be conducted by a Contract Research Organization (CRO, Simoon
Record Pharma Information Consulting Co., Ltd). Guidelines of Good Clinical Practice (GCP) will
ensure compliance.
ETHICS AND DISSEMINATION
Research ethics approval
This study was approved by the ECs at 3 provinces (Shanxi, Henan and Hebei Province), and will
be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.[28] The
registration number of this trial is NCT02736240.
Informed consent
All participants’ parents/ legally responsible representatives will receive adequate information
about the nature, purpose, and possible risks and benefits of the trial by an informed consent
form approved by the EC. The original version of signed consent forms will be retained by the
investigators as a trial record, and a copy will be kept by the participants’ parents/legally
responsible representatives.
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Confidentiality
To assure confidentiality, all participants will be allotted a unique subject number throughout the
trial. Personal information will be collected with standardized paper forms by face to face
interviews. Paper-based data will be stored in locked cabinets with limited access at each site,
and the electronic data will be saved on password protected computers.
Access to data
The final dataset will be under the custody of the sponsor together with the CRO selected
beforehand. The data managers will be permitted to access the full analyzed final dataset. Access
to the final or identifiable data by others is subject to the sponsor's approval.
Dissemination policy
The trial will be reported in accordance with the CONSORT guidance.
Discussion
To date, the efficacy and safety of PCV13 among the Chinese population is still largely unknown.
Hence, this study intends to characterize the PCV13 among Chinese infants and develop a safety
profile for the vaccine. To fulfill these objectives, we calculated sample sizes under different
hypothetical conditions and determined the optimal sample size to use to take all of all factors
into consideration. In study design, we adopted the sequential test method to inspect the
non-inferiority of each of the 7 common pneumococcal serotypes and the efficacy of each of the
6 additional pneumococcal serotypes step by step to avoid false positive error inflation. To be
more discreet and conservative, instead of setting pneumococcal serotype 6B in PCV7 as a
baseline when verifying the immunogenicity of each of the 6 additional serotypes in PCV13, as
many other researchers have done, we defined 70% as the lower limit of the 2-sided 95% CI for
the percentage of responders that reach the serotype-specific IgG concentration threshold of
0.35μg/ml and supposed that the corresponding percentages in PCV7 are less than 50%.[29]
Allowing for the cross-reactivation between 6A and 6B as well as 19A and 19B in PCV7, we will
select a subgroup of which to obtain the OPA results for each of the 13 serotypes to correct for
potential bias.
Given the main focus of the research, this study is not designed to involve the assessment of
concomitant immunization with other vaccines specified in pediatric vaccination schedules such
as diphtheria, tetanus and acellular pertussis vaccine (DTaP), which might be regarded as a
potential limitation. Because the feasibility of PCV7 administered concomitantly with DTaP in
mainland Chinese infants has been shown in the research reported by Li RC et al.,[30] and the
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immunogenicity of PCV13 co-administered with DTaP was demonstrated by Togashi T et al.,[7]
we will not prohibit the usage of vaccines listed in the expanded program on immunization (EPI),
but we will compulsively demand at least a fortnight interval between two kinds of vaccination.
Footnotes
Author affiliations:
1 DHSFMMU, Department of Health Statistics of Fourth Military Medical University, Xi’an, Shanxi, China
2 Walvax, Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China
3 Beijing Chaoyang CDC, Beijing Chaoyang District Centre for Disease Control and Prevention, Beijing, China
4 Hebei CDC, Heibei Province Centre for Disease Control and Prevention, Shijiazhuang, Heibei, China
5 Henan CDC, Henan Province Centre for Disease Control and Prevention, Zhengzhou, Henan, China
6 Shanxi CDC, Shanxi Province Centre for Disease Control and Prevention, Taiyuan, Shanxi, China
7 Guangxi CDC, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, Guangxi,
China
Contributors
JLX provided statistical expertise and created the study design together with JJC. ZH and LY conceived the study and
participated in study design. JJC drafted the manuscript and calculated the sample size. NMS, YLZ, SLX and GHL are
the primary investigators and helped with protocol revise. RCL and YPL are the senior consultants and contributed to
protocol development. SYY compiled the original protocol in Chinese and participated in study design discussion. All
authors read and proved the final manuscript.
Funding The study is supported by a grant from Bio-pharmaceutical Major Scientific & Technological Project
(biological product development section) of Yunnan Province (project number 2015ZJ005). The funding source has no
role in the trial design and will have no role in the trial conduct, data analysis and interpretation, or writing or reporting.
Disclaimer The views expressed are those of the author(s) and not necessarily those of the DHSFMMU, Walvax or
CDCs which involved.
Competing interests We have read and understood BMJ policy on declaration of interests and declare the following
interests: This trial is sponsored by Walvax Biotechnology Co., Ltd.. Walvax, as the sponsor, is responsible for
organizing and managing the study to support the pre-licensing evaluation of the investigational PCV13. The new
PCV13 was researched and developed by Walvax and manufactured by an affiliate of Walvax. JJC, LY, ZH and SYY
work at Walvax and belong to the clinical research team of PCV13.
Ethics approval The trial is approved by: the Beijing Chaoyang District Centre for Disease Control and Prevention
Ethics Committee (the lead institution), the Heibei Province Centre for Disease Control and Prevention Ethics
Committee, the Henan Province Centre for Disease Control and Prevention Ethics Committee, and the Shanxi
Province Centre for Disease Control and Prevention Ethics Committee.
Provenance and peer review Not commissioned; internally peer reviewed.
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Figure 1 The study flow diagram
Figure 2 The sequential test flow chart
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Figure 1 The study flow diagram
281x174mm (300 x 300 DPI)
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Figure 2 The sequential test flow chart
281x182mm (300 x 300 DPI)
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1
SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*
Section/item Item No
Description Addressed on page number
Administrative information
Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______1 _____
Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ______2______
2b All items from the World Health Organization Trial Registration Data Set _____N/A_ ___
Protocol version 3 Date and version identifier _____N/A_____
Funding 4 Sources and types of financial, material, and other support ______13_____
Roles and
responsibilities
5a Names, affiliations, and roles of protocol contributors _____1,13 ____
5b Name and contact information for the trial sponsor _____N/A_ ___
5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and
interpretation of data; writing of the report; and the decision to submit the report for publication, including
whether they will have ultimate authority over any of these activities
_____N/A_ ___
5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint
adjudication committee, data management team, and other individuals or groups overseeing the trial, if
applicable (see Item 21a for data monitoring committee)
_____N/A_ ___
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Introduction
Background and
rationale
6a Description of research question and justification for undertaking the trial, including summary of relevant
studies (published and unpublished) examining benefits and harms for each intervention
______3______
6b Explanation for choice of comparators ______3______
Objectives 7 Specific objectives or hypotheses ______4______
Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),
allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
______4______
Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will
be collected. Reference to where list of study sites can be obtained
______4______
Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and
individuals who will perform the interventions (eg, surgeons, psychotherapists)
______4______
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be
administered
______5______
11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose
change in response to harms, participant request, or improving/worsening disease)
_____N/A_ ___
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence
(eg, drug tablet return, laboratory tests)
______6______
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _____N/A_ ___
Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood
pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,
median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen
efficacy and harm outcomes is strongly recommended
______7______
Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for
participants. A schematic diagram is highly recommended (see Figure)
______6______
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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including
clinical and statistical assumptions supporting any sample size calculations
______6______
Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size _____N/A_ ___
Methods: Assignment of interventions (for controlled trials)
Allocation:
Sequence
generation
16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any
factors for stratification. To reduce predictability of a random sequence, details of any planned restriction
(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants
or assign interventions
______8______
Allocation
concealment
mechanism
16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,
opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned
______8______
Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to
interventions
______8______
Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome
assessors, data analysts), and how
______8______
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s
allocated intervention during the trial
______8______
Methods: Data collection, management, and analysis
Data collection
methods
18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related
processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of
study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.
Reference to where data collection forms can be found, if not in the protocol
______9______
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be
collected for participants who discontinue or deviate from intervention protocols
_____N/A_ ___
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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality
(eg, double data entry; range checks for data values). Reference to where details of data management
procedures can be found, if not in the protocol
______9______
Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the
statistical analysis plan can be found, if not in the protocol
______9______
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _____ 10 _____
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any
statistical methods to handle missing data (eg, multiple imputation)
______9______
Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of
whether it is independent from the sponsor and competing interests; and reference to where further details
about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not
needed
_____N/A_ ___
21b Description of any interim analyses and stopping guidelines, including who will have access to these interim
results and make the final decision to terminate the trial
_____N/A_ ___
Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse
events and other unintended effects of trial interventions or trial conduct
_____ 11 _____
Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent
from investigators and the sponsor
_____ 11 _____
Ethics and dissemination
Research ethics
approval
24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _____ 11 _____
Protocol
amendments
25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,
analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,
regulators)
_____N/A_ ___
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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and
how (see Item 32)
_____ 11 _____
26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
_____N/A_ ___
Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained
in order to protect confidentiality before, during, and after the trial
_____ 12 _____
Declaration of
interests
28 Financial and other competing interests for principal investigators for the overall trial and each study site _____ 12 _____
Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that
limit such access for investigators
_____ 12 _____
Ancillary and post-
trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial
participation
_____N/A_ ___
Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,
the public, and other relevant groups (eg, via publication, reporting in results databases, or other data
sharing arrangements), including any publication restrictions
_____ 12 _____
31b Authorship eligibility guidelines and any intended use of professional writers _____ 13 _____
31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _____N/A_ ___
Appendices
Informed consent
materials
32 Model consent form and other related documentation given to participants and authorised surrogates _____N/A_ ___
Biological
specimens
33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular
analysis in the current trial and for future use in ancillary studies, if applicable
_____N/A_ ___
*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.
Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons
“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.
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