Protocol Concept Sheet Ver3.0surveygizmolibrary.s3.amazonaws.com/library/55348/Anifro... · Web...

MedImmune/AstraZeneca Protocol Concept Sheet- Sjögren’s syndrome Ph2aAnifrolumab (MEDI-546) draft Feb 2016

Protocol Concept SheetTITLE: A Multicenter Randomized Double-Blind Placebo Controlled

Phase 2a Proof of Concept Study to Evaluate the Efficacy and Safety of Anifrolumab in Adult Subjects Sjögren’s Syndrome

INDICATION: Sjögren’s Syndrome

SPONSOR: MedImmune/AstraZeneca

TYPE OF STUDY: [ ] First-Time-In-Humans (FTIH) [ ] Phase 0[X] Proof of Concept/Proof of Principle [ ] Supportive[ ] Dose Ranging [ ] Open Label Extension (OLE)[ ] Registration (Pivotal) [ ] Observational[X] Life Cycle Management/Supplemental Indication or New Indication [ ] Other, specify:

BACKGROUND & RATIONALE

Sjögren’s syndrome (SS) is a rheumatic, autoimmune disease characterized by chronic, inflammation and dysfunction of exocrine glands. The salivary and lacrimal glands are predominantly affected leading to dry mouth and dry eyes (sicca symptoms). SS is one of the most common rheumatic diseases, affecting 1-4 million Americans, with a female to male ratio of 9:1. The disease may occur alone, traditionally referred to as primary SS, or coexist with other rheumatic diseases (secondary SS). About 20-25% of patients develop severe disease with extra-glandular manifestations, such as arthritis, vasculitis, lung disease, peripheral or central neuropathy, and autonomic nervous system dysfunction. Immunological abnormalities, e.g. cryoglobulinemia, low complement levels, autoantibodies and hypergammaglobulinemia are more common in SS patients with extra-glandular disease and can be used to identify this subpopulation with worse prognosis (Brito-Zeron P et al, 2014; ; Error: Reference source not found). Patients with extra-glandular disease are at higher risk of lymphoma, with a 4- to 14-fold increased incidence (Error: Reference source not found; Error:Reference source not found; Error: Reference source not found).

Several classification criteria have been proposed for SS. The American European Consensus Group (AECG) criteria are the most commonly used in clinical trials (Vitali C, et al, 2002). The American College of Rheumatology (ACR) recently endorsed the new ACR criteria (Shiboski SC et al, 2012) which does not distinguish between primary and secondary SS. The AECG criteria require the combination of an immunological criterion (anti-SSA/SSB antibodies) or a histological criterion (focus score ≥1), an objective criterion of dry eyes or

CONFIDENTIAL AND PROPRIETARY 1 of 27


mouth and subjective signs of dryness whereas the ACR criteria require the combination of an immunological criterion (anti-SSA/SSB or ANA + RF), a histological criterion and/ or an objective criterion of dry eyes (OSS ≥3) for SS diagnosis (Fazaa et al, 2014).

The statistical comparison between the AECG criteria and the proposed ACR criteria showed a strong agreement between them (Error: Reference source not found), which was confirmed in an independent cohort study (Error: Reference source not found).

The treatment of sicca symptoms is mainly symptomatic. The current clinical management of extra-glandular disease manifestations is unsatisfactory and there are no evidence-based therapy or treatment guidelines. Standard of care (SOC) therapy is empirical and treatment recommendations are based on expert opinions. Recommendations for the treatment of extra-glandular manifestations include therapy with Disease Modifying Anti-Rheumatic Drugs (DMARD) commonly used and approved for other rheumatic diseases.

SS and SLE share many disease manifestations (e.g arthritis, skin symptoms, pulmonary, CNS, PNS, and renal involvement) and immunological abnormalities. Among the recently identified immunopathological mechanisms shared by the two diseases is the overexpression of type 1 IFN activated genes, the so called “interferon signature”. Increased type 1 IFN activity and type 1 IFN signature has been demonstrated in peripheral blood and increased expression of IFN regulated genes and proteins have been found in biopsies from affected salivary glands of pSS patients (Emamian ES et al 2009, Bave U et al 2005, Hjelmervik TU et al 2005). A marked infiltration of IFN-producing dendritic cells (DC) capable of producing large amounts of IFN in response to anti-RNA antibodies have been found in salivary glands (Brkic Z et al 2013, Gottenberg JE et al 2006). Furthermore, the type 1 IFN gene expression is seen primarily in the subset of patients with systemic extraglandular disease manifestations (Emamian ES et al 2009, Brkic Z et al 2013), is strongly associated with the presence of anti-ribonucleoprotein antibodies (SSA, SSB) and correlates with disease activity.

Data on the prevalence of increased Type I IFN signature in SS with extraglandular manifestations are scarce. Using the 4 gene IFN test proposed for stratification in this protocol, the Sponsor evaluated the distribution of IFN test-high versus IFN test-low patients in a small cohort of US SS patients with extraglandular disease. The frequency of IFN test-high patients was around 60%, similar to those observed in US patients in the Phase 2 SLE study (Study CD-IA-MEDI-546-1013). The IFN distribution in SS overlapped with the entire population of the Phase 2 SLE study, which had an approximately 75% IFN-test high population (Error: Reference source not found).



Anifrolumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab inhibits binding of type I interferon (IFN) to IFNAR and inhibits the biologic activity of all type I IFNs. In a Phase 2b study anifrolumab was more effective than placebo when added to SOC in patients with moderate to severe systemic lupus erythematosus (SLE). The beneficial effect was observed in patients with an elevated IFN signature whereas such effect was not seen in the IFN test low patients. Based on the similarities of the immunopathology and the overlapping clinical disease manifestations between SS and SLE and the preliminary clinical efficacy demonstrated in SLE we hypothesize that anifrolumab treatment will decrease disease activity in Sjögren’s syndrome patients with extraglandular manifestation.

PURPOSE & HYPOTHESES The purpose of this randomized, placebo-controlled and double-blind multinational study is to evaluate the efficacy and safety of anifrolumab in combination with SOC therapy in adult subjects with active SS with extraglandular disease manifestations.



Hypotheses Primary hypothesis

Treatment with anifrolumab will result in improvement of objective disease activity measures in subjects with active SS with extra-glandular disease manifestations.

Secondary hypotheses Subjects treated with anifrolumab will improve in subjective measures of disease

activity. Anifrolumab will have an acceptable safety profile in patients with active SS with

extra-glandular disease. Treatment with anifrolumab will suppress the IFN signature in both peripheral blood

INVESTIGATIONAL PRODUCT, DOSE AND REGIMEN, ROUTE OF ADMINISTRATION: Anifrolumab 150 mg or 300 mg IV every 4 weeks (q4W) in addition to background SOC Placebo IV administration every 4 weeks in addition to background SOC

STUDY OBJECTIVESPrimary ObjectiveTo evaluate the efficacy of anifrolumab compared to placebo, when given in addition to background SOC therapy, in reducing objective measures of overall disease activity as assessed by

The mean change in European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI) score from baseline at Week 24

Secondary ObjectivesTo assess the efficacy of anifrolumab compared to placebo on;

The proportion of subjects achieving ESSDAI response criteria at Week 52 defined as

o A decrease from baseline in ESSDAI score ≥ 3points AND

o no discontinuation of investigational product or use of rescue treatment beyond allowed threshold

The proportion of subjects achieving ESSPRI response criteria at Week 52 defined as

o ≥1 point or 15% reduction from baseline in European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index (ESSPRI) score at Week 52



o no discontinuation of investigational product or use of rescue treatment beyond allowed threshold

Exploratory ObjectivesTo assess the efficacy of anifrolumab compared to placebo on;

Mean change from baseline in ESSDAI score at Week 52 Changes of the individual subcomponents of ESSDAI from baseline The proportion of subjects achieving a decrease of ≥1 point or 15% from baseline in

the ESSPRI score at Week 24 The mean change from baseline ESSPRI score over time

Change from baseline in stimulated whole salivary flow

Change from baseline in tear flow measured by Schirmer’s test

Change from baseline in conjunctival damage measured by either the van Bijsterveld score or the ocular severity score (OSS)

Changes of the individual subcomponents of ESSPRI from baseline

Changes in interferon gene signature in salivary gland tissue

Changes of immunological biomarkers in peripheral blood and salivary glands

PK, PD, and immunogenicity (IM) of anifrolumab SS symptoms as measured by the Profile of Fatigue and Discomfort-Sicca Symptoms

Inventory-Short Form (PROFAD-SSI-SF) Health Status as measured by the Short Form-36 version 2 (SF-36v2) Health Survey

[acute recall] Patient Global Impression of Severity (PGI-S) Patient Global Impression of Change (PGI-C)

Safety Objectives

To assess the safety and tolerability of anifrolumab when combined with SOC therapy in active SS with extra-glandular manifestations by assessing:

Adverse events (AEs) and serious adverse events (SAEs)

Adverse events of special interest (AESIs) including herpes zoster, influenza, opportunistic infections, tuberculosis (TB), malignancies, non-SS related vasculitis, anaphylaxis, and major adverse cardiovascular events (MACE)



Depression and suicidal risk will be assessed at baseline and at regular intervals during the study by the Personal Health Questionnaire Depression Scale (PHQ-8) and Colombia Suicide Severity Rating Scale (C-SSRS) questionnaires.

Laboratory variables

Physical examinations

Vital signs

ECG

STUDY DESIGN: This is a Phase 2a, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the clinical and biological effects, as well as the safety of intravenous anifrolumab in adult subjects with active SS with extra-glandular disease despite SOC therapy.

Approximately 60 international sites will participate in the study. A total of 168 patients (56 subjects per treatment group) will be randomized in a 1:1:1 ratio to receive intravenous anifrolumab 150 mg or 300 mg or placebo every 4 weeks for 48 weeks. All subjects will be followed for 12 weeks after the last dose of investigational product. The primary endpoint will be evaluated at Week 24. Both subjects with high and low IFN tests will be enrolled with a maximum of 25% of enrolled subjects belonging to the IFN low subset. A schema of the study is provided in Figure 1.

Investigational product will be administered as an IV infusion via an infusion pump over a minimum 30 minutes. Randomization will be stratified by ESSDAI scores at baseline: ESSDAI <10 vs ESSDAI ≥ 10 and a 4 gene IFN test (IFN test high vs IFN test low).



Figure 1- Study Schema

Standard of Care Therapy Stable background SOC therapy for SS including treatment with stable doses of the most commonly used DMARDs, e.g hydroxychloroquine, chloroquine, methotrexate, azathioprine, and leflunomide will be allowed. Stable doses will be required before screening for periods pre-defined for each drug. Although it is expected that most patients will have received at least one of these treatments prior to or concurrent to enrollment, the concurrent use of any of these at enrollment is not necessary for eligibility. Other immunosuppressants and biologics will not be allowed. Subjects taking OCS must be on a stable dose for at least 4 weeks of oral prednisone at a dose of ≤40 mg/day (or equivalent). Tapering of OCS dose with the goal to achieve ≤7.5 mg/day by Week 24 and maintain this dose until Week 52 will be encouraged but not mandatory. One OCS burst and taper (max dose prednisone 40 mg/day, max duration 14 days) or one episode of intra-articular injection (max 40 mg) is allowed except between Week 16 – 24 and Week 44 – 52. Stable symptomatic pharmacologic treatment for sicca symptoms with sialogogues and cyclosporine eye drops will be allowed. Artificial tears and saliva and other physical measures can be freely used during the study except immediately before assessment of saliva and tear production.

The current study design allows estimation of treatment effects of anifrolumab combined with SOC therapy compared with placebo in combination with SOC therapy on overall disease activity over a 1 year period in active SS patients with extraglandular disease. By including



subjects with both high and low IFN tests the relative efficacy of anifrolumab can be explored in the entire SS population. It will also provide data of potential use for Phase 3 study design.

Rationale for anifrolumab dosesIn Phase 1 and Phase 2 SLE studies doses of anifrolumab in the range of 100 mg IV every 4 weeks (Q4W) to 1000 mg IV Q4W were tested.

In study CD-1013 in SLE at Week 52, analysis of the concentration- IFN signature response relationship indicated that the 300 mg and 1000 mg doses resulted in similar degree of IFN signature suppression. The 100-mg dose of anifrolumab displayed limited impact on the IFNGS at any timepoint examined in a Phase 1 open label study in Japanese patients. Consistent with the PD effects, the efficacy results were similar between the 300 mg the 1000 mg doses with a higher number of herpes zoster infections with the 1000 mg dose. Based on these data, the 300-mg dose was chosen as the Phase 3 dose in SLE patients. Considering that the IFNGS in SS and SLE are similar it is reasonable to assume that the degree of suppression of peripheral blood IFNGS obtained with anifrolumab will be similar in both diseases. PK/PD modelling in SLE predicts that lowering the anifrolumab dose below 300 mg will lead to a very rapid clearance and negligible exposure to anifrolumab. Based on these assumptions the 300 mg dose is considered to potentially provide the best benefit:risk profile in SS patients with extraglandular manifestations. A 150 mg dose is included to assess if the 300 mg dose may be considered as the minimally effective dose and to provide sufficient data to characterize the exposure interferon gene suppression response relationship of anifrolumab and to identify the pharmacodynamically optimal dose in this population. For an effective dose the selected dosing schedule is expected to ensure sufficient suppression of Type-1 interferon mediated gene signature through Week 52 to adequately test the impact of IFNAR blockade on the PD and clinical endpoints. Therefore, the 150 mg and 300 mg doses will be evaluated in this proof of concept study to identify the minimally clinically effective dose for future studies.

The 150 mg and 300 mg doses and dosing duration chosen for this study are expected to be well tolerated in subjects with SS based on the experience in SLE patients (Study CD1013).

Rationale for Endpoints

Primary endpoint:

There are no validated or uniformly accepted efficacy endpoints for SS and there have been no successful studies with immunomodulating agents in this disease. The efficacy measures in previous treatment studies have either been selected measures of glandular function, such as salivary flow, or composite outcome measures combining visual analog scales of physician



and patient assessments of various aspects of disease activity. Recently, an international panel of Sjögren’s experts developed and validated two indices to capture both the objective (ESSDAI) and the subjective (ESSPRI) measures of SS activity (Seror et al, 2009; Seror et al, 2011) in observational cohorts. Although, neither of these has been used as primary efficacy measure in any completed clinical trial yet, retrospective application of the ESSDAI to treatment studies with Benlysta (Mariette et al, 2013) and rituximab (Meiners et al, 2012; Moerman et al, 2013) supports its use as a primary outcome measure in populations very similar to this study. Data from the ESSDAI development group identified an ESSDAI score ≥5 as the cutoff between mild and moderate to severe disease and recommended it as the lower threshold for entry in clinical studies. The same group also identified a decrease of ≥3 in ESSDAI as a clinically meaningful improvement in SS patients (Error: Reference source not found).

Secondary and exploratory endpoints: The ESSPRI will be used to allow measurement of subjective symptoms of SS. A

decrease of ≥1 point or ≥15% on the ESSPRI score has been validated as a minimum clinically meaningful improvement (Error: Reference source not found).

The chronic nature of SS requires sustained treatment effects. Therefore, changes in both ESSDAI and ESSPRI will be evaluated throughout the entire study period. The proportions of subjects reaching an ESSDAI decrease of ≥3 points from baseline as well as the proportion of subjects with ≥1 point or ≥15% reduction from baseline in ESSPRI score at Week 52 will be analyzed.

The impact of anifrolumab on exocrine gland function will be assessed by comparing the change from baseline in salivary flow (stimulated salivary flow) and tear production (Schirmer’s I test) and ocular surface damage (van Bijsterveldt score or ocular severity score)

The efficacy of the two doses of anifrolumab in suppressing the IFN signature will be analysed in IFN high and low test subjects and the relation between suppression of IFN signature and clinical effects will be investigated.

STATISTICAL ASSESSMENTSData will be provided in listings and tabular summaries. Categorical data will be summarized by the number and percentage of subjects in each category. Continuous variables will be summarized by descriptive statistics, including mean, standard deviation, median, minimum, and maximum. Baseline values will be defined as the last assessment prior to the first administration of investigational product. Additional details will be described in the statistical analysis plan (SAP).

Analysis Population



The full analysis set will be used as the primary population for reporting efficacy and safety data. This comprises all subjects randomised into the study who receive at least 1 dose of investigational product and will be analysed according to randomised treatment (modified Intention-To-Treat principle). Any major deviations from randomised treatment will be listed and considered when interpreting the safety data.

Sample Size CalculationsThe sample size of 168 subjects (56 subjects per treatment group) will provide 80% power to detect a difference in mean change in ESSDAI of 2.7 (assumed standard deviation of 5, Meiners et al, 2012) between the 300 mg and placebo treatment groups at a two-sided alpha level of 0.05 using 2-sample t-test.

Analysis

Primary analysisThe primary estimand evaluates the effect on disease activity of anifrolumab relative to placebo in subjects with active SS, reflecting the effect of initially randomized treatment and all subsequent treatments that subjects may take as a result of, for example, intolerance or lack of efficacy, and includes data collected after discontinuation of study treatment. This is measured by the difference in mean change from baseline in ESSDAI score at Week 24. Patients who discontinue the investigational product will be encouraged to continue in the study and will be analyzed as randomized.

The primary estimand will be analyzed using an MMRM model that includes the fixed effects of treatment, visit (categorical covariate), treatment-by-visit interaction, IFN test at screening (low or high), ESSDAI stratification category (ESSDAI <10 vs ESSDAI ≥ 10) and baseline ESSDAI score (continuous covariate). An unstructured variance-covariance matrix will be used. For each of the 2 anifrolumab treatment groups, the null hypothesis is that the change from baseline in ESSDAI score at Week 24 is equal to the change from baseline in ESSDAI score at Week 24 for the placebo treatment group. The alternative hypothesis is that the change from baseline in ESSDAI score at Week 24 for an anifrolumab treatment group is not equal to the change from baseline in ESSDAI score at Week 24 for the placebo treatment group.

The primary analysis will evaluate whether there is a difference between treatment groups in the mean change from baseline in ESSDAI score at Week 24 and will be based on the treatment difference at Week 24 using least-squares means. This will be accomplished by using appropriate linear contrasts of the parameters in the model described above. Changes from baseline at Weeks 4, 8, 12, 16, and 20 will be assessed using the output from the MMRM analyses.



Strong control of family wise error rate (FWER) will be achieved by sequentially testing each anifrolumab treatment group against placebo. The higher dose will be tested first, and if statistically significant then the lower dose will be then tested.

The literature proposes 3 points as the minimum clinically important difference (MCID) in ESSDAI (Seror et al, 2014). Because an observed treatment difference has variability associated with it, the statistical test can be statistically significant if the observed treatment difference is as low as 1.87 points when the true (unobserved) treatment difference is 2.7 points. An effect size lower than the MCID was assumed for sample size calculation to account for dropouts, given that a treatment policy estimand will be used and the effect size in such subjects will be reduced during the analysis. Also, a different effect size might be seen in IFN test-high and IFN test-low subjects.

As a sensitivity analysis, a method for missing value imputation based on pattern mixture models might be implemented. It assumes that after discontinuation from the study, patients receiving anifrolumab will exhibit the same future disease activity as patients on the placebo treatment group. This method uses sequential regression and multiple imputation methodology to impute missing values for visits after a patient’s discontinuation from the study. Based on the available data from placebo-treated patients, the missing values from the placebo and anifrolumab treatment groups will be imputed sequentially using a procedure for monotone missing data patterns until all visits are imputed.

Secondary analysesWhen a comparison between an anifrolumab dose group and the placebo group is statistically significant on the primary efficacy endpoint, the secondary efficacy endpoints for the anifrolumab dose group will be tested through a step-down approach in the following order: ESSDAI responder index, ESSPRI responder index. Each of the endpoints will be analyzed using stratified CMH for the difference in proportions, stratified by IFN test at screening (low or high) and the ESSDAI category at screening (: ESSDAI <10 vs ESSDAI ≥ 10).

Exploratory Analyses:The exploratory analyses will be described in the SAP.

Safety Analysis:Adverse events (including AE of special interest) will be summarised by means of counts summaries by MedDRA System Organ Class and Preferred Term separately for the study periods (treatment period and follow-up period). All AEs will be listed.

Laboratory data for haematology and clinical chemistry will be summarised. The frequency of changes with respect to normal ranges between baseline and each post-treatment time point



will be tabulated. Frequencies of clinically noteworthy values (defined in the SAP) occurring during the clinical study will also be given.

The incidence of markedly abnormal values and changes from baseline in the ECG parameters will be summarised by treatment group.

Other safety variables will be summarised as appropriate. Further details will be provided in the SAP.

Planned analysis

Two formal analyses are planned – Stage I and Final analyses.

The Stage I analysis will be conducted after the last subject has completed the week 24 visit or discontinues from study treatment early. This is the primary analysis of the study (primary objective).

The Final analysis will be conducted after the last subject has completed or discontinued the study (48 weeks treatment period plus 12 weeks safety follow up).

DURATION OF TREATMENT AND DURATION OF STUDYSubjects will be in the study for approximately 64 weeks, including up to 4 weeks for Screening and 12 weeks of safety follow up after the last dose.

PLAN FOR SPECIFIC FOLLOW-UP: Subjects will enter a 12-week safety follow-up after the last dose of investigational product.

SUBJECT POPULATIONThe target population is adults between 18 and 75 years of age with active SS with extraglandular manifestations despite SOC.

Rationale for Population The study population is representative of the subset of SS patients with more severe disease with systemic involvement. Several lines of evidence support a role for type I IFN in the pathogenesis of SS and the increased type 1 IFN activity is seen primarily in the subset of patients with extraglandular manifestations.Based on the sex distribution of Sjögren’s we anticipate a predominantly (>80%) female population. Children and vulnerable populations are not included in the study.

PATIENT ELIGIBILITY CRITERIA

Inclusion criteria



Subjects must meet all of the following criteria:1) Written informed consent for study participation must be obtained prior to any study

related procedures being performed2) Adult subjects aged 18 to 75 years of age at the time of signing informed consent 3) Body weight ≥ 40 kg 4) Fulfill American European Consensus Group (AECG) or American College of

Rheumatology (ACR) criteria for SS 5) ESSDAI score ≥ 56) Disease duration ≤ 5 years since diagnosis7) Measurable amount of whole stimulated salivary flow8) A salivary gland biopsy obtained within 5 years showing a focus score of at least 1 9) Willingness to undergo protocol-required end of treatment minor salivary gland biopsy10) Negative serum pregnancy test11) Females of childbearing potential who are sexually active with a nonsterilized male

partner must use a highly effective method of contraception from signing informed consent, and must agree to continue using such precautions through the end of the follow up of the study; cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.

12) Non-sterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from Day 1 through the end of the follow up.

13) Females with an intact cervix must have documentation of a Pap smear with no documented malignancy within 2 years prior to Day 1

14) Meets all of the following tuberculosis (TB) criteria: (a) No history of latent or active TB prior to screening, with the exception

of latent TB with documented completion of appropriate treatment or currently receiving prophylactic treatment for latent TB and the subject commits to completing the full duration of prophylaxis

(b) No signs or symptoms suggestive of active TB from medical history or physical examination

(c) No recent close contact with a person with active TB or if there has been such contact, referral to a physician specialising in TB to undergo additional evaluation prior to randomisation (documented appropriately in source), and, if warranted, receipt of appropriate treatment for latent TB at or before the first administration of investigational product



(d) Must meet one of the following criteria:

(i) Negative QuantiFERON-TB Gold [QFT-G] test result for TB obtained from central laboratory within 12 weeks prior to randomisation or

(ii) Positive QFT-G test result for TB obtained during the screening period from central laboratory for which active TB has been ruled out and appropriate treatment for latent TB has been initiated prior to the first investigational product administration and the subject commits to completing the full duration of prophylaxis, which may mean completing prophylaxis during the study; or

(iii) Indeterminate (confirmed as indeterminate on retest during screening) QFT-G test for TB obtained during the screening period from central laboratory with ongoing QFT-G testing for TB to the Study Plan (Error: Reference source not found)

(e) A chest radiograph with no evidence of current active TB or other infection, or old active TB, malignancy, or clinically significant abnormalities (unless due to SLE) obtained during the screening period or anytime within 12 weeks prior to signing of the ICF

Exclusion criteriaAny of the following would exclude the subject from participation in the study:

1) Exclusion criteria of the American-European Classification Criteria or the ACR criteria:

a. Past head and neck irradiationb. Hepatitis B, C, or human immunodeficiency virus infectionc. Immunoglobulin G4-mediated diseased. History of lymphoma, preceding the diagnosis of pSSe. Sarcoidosisf. Graft-versus-host disease

2) Documented history of systemic sclerosis, SLE or RA

3) History of, or current diagnosis of, a clinically significant non SS related vasculitis syndrome. Patients who have experienced vasculitis as a feature of their SS can be recruited to the study



4) Active severe or unstable neuropsychiatric manifestation of SS that a. would make the subject unable to fully understand the informed consent ORb. In the opinion of the Investigator, protocol specified SOC is insufficient to

control neurologic features of SS and utilisation of a more aggressive therapeutic approach, such as adding IV cyclophosphamide and/or high dose IV pulse corticosteroid therapy or other treatments not permitted in the protocol, is indicated or anticipated

5) Active severe extraglandular SS with e.g. pulmonary, renal, vasculitic, peripheral neurological, ongoing involvement requiring treatment with cyclophosphamide, high dose corticosteroids, plasmapheresis, or intravenous immunoglobulins (IVIG)6) History of any non-SS disease that has required treatment with oral or parenteral corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF

7) History or evidence of suicidal ideation (severity of 4 [active: method and intent, but no plan] or 5 [active: method, intent, and plan]) within the past 6 months; or any suicidal behaviour within the past 12 months based on an assessment with the C-SSRS at screening or at baseline

8) Evidence of significant renal insufficiency, defined by estimated Glomerular Filtration Rate (eGFR) < 35 mL/min/1.73m2.

9) Abnormal ECG findings that in the opinion of the investigator would put the subject at risk, if participated in this study

10) At screening (within 4 weeks before Day 1 [Week 0 visit]), any of the following:

a. Aspartate transaminase (AST) > 2.0 × upper limit of normal (ULN). Subjects with AST > 2.0 × ULN may be allowed if, in the opinion of the investigator, is caused by SS and discussed with the medical monitor.

b. Alanine transaminase (ALT) > 2.0 × ULN. Subjects with ALT > 2.0 × ULN may be allowed if, in the opinion of the investigator, is caused by SS and discussed with the medical monitor.

c. Total bilirubin > ULN (unless due to Gilbert’s syndrome)d. Glycosylated hemoglobin (HbA1c) > 8% (or > 0.08) at screening (diabetic

subjects only)e. Neutrophil count < 1,000/μL (or < 1.0 × 109/L) f. Platelet count < 50,000/μL (or < 50 × 109/L) g. Hemoglobin < 8 g/dL (or < 80 g/L)

(Note: Abnormal laboratory results may be repeated one time on a separate sample

before subject is declared a screen failure)

11) History of ethanol or drug abuse within 1 year prior to signing informed consent.



12) Participation in an investigational drug or device trial within 30 days or 5 half-lives,

whichever time period is longer, prior to randomization (Day 1).

13) Planned or ongoing pregnancy (a negative pregnancy test is required during Screening

and at study visits specified in the schedule of assessments) or lactation.

Exclusion Criteria Related to Concomitant Medications14) Receipt of any experimental or commercially available biologic agent within 5 half-lives

(Refer to Appendix X) prior to loss of pharmacodynamic and/or clinical effect, whichever is longer, prior to signing of the ICF

15) Receipt of B cell depleting therapy (BCDT) in the past 6 months or CD19+ B cells <LLN or pre-BCDT if treatment was more than 6 months prior to randomization

16) Subjects receiving any of the following will be excluded for:a. Corticosteroids:

i. > 40 mg/day oral prednisone (or equivalent);ii. Any change or initiation of new dose within 4 weeks prior to signing the

ICF through randomization (Day 1);iii. Intramuscular, IV, or intra-articular corticosteroids within 4 weeks prior to

signing the ICF through randomization (Day 1);iv. Any change or initiation of new dose of topical corticosteroids within 2

weeks prior to signing the ICF through randomization (Day 1);

b. Increase in the dose of antimalarials (eg, chloroquine, hydroxychloroquine, quinacrine) within 8 weeks prior to signing informed consent through randomization (Day 1).



c. Methotrexate i. > 25 mg/week

ii. A change in the dose of route of administration within 4 weeks prior to signing informed consent through randomization (Day 1).

d. Azathioprine i. > 200 mg/day


e. Leflunomide i. > 20 mg/day


f. Change in the dose of regularly scheduled nonsteroidal anti-inflammatory drugs (NSAIDs) at anti-inflammatory doses within 2 weeks of signing informed consent

g. Cevimeline, pilocarpine or cyclosporine eye drops (Restasis): change in the dose within 2 weeks prior to signing informed consent through randomization (Day 1).

17) A known history of allergy or reaction to any component of the investigational product formulation or history of anaphylaxis to any human gamma globulin therapy

18) Receipt of any of the following:a. Any live or attenuated vaccine within 4 weeks prior to signing the ICF (administration

of killed vaccines is acceptable, the sponsor recommends investigators ensure all subjects are up to date on required vaccinations prior to study entry)

b. Plasmapheresisc. Bacillus of Calmette and Guerin (BCG) vaccine within 1 year of signing consent formd. Blood transfusion within 4 weeks prior to signing the ICF

Exclusion Criteria Related to Infection and Malignancy Risk Factors will be based on the criteria used in the SLE anifrolumab studies19) Known history of a primary immunodeficiency (eg, common variable immunodeficiency

syndrome) or an underlying condition such as splenectomy that predisposes the subject to infection

20) Confirmed positive test for hepatitis B serology for:

(a) Hepatitis B surface antigen, or

(b) Hepatitis B core antibody (HBcAb) and hepatitis B virus (HBV) DNA detected above the lower level of quantification (LLQ by reflex



testing by the central laboratory at screening

Note: Subjects who are HBcAb positive at screening will be tested monthly for HBV DNA. To remain eligible for the study, subject HBV DNA levels must remain below the LLQ as per central laboratory.

21) Positive test for hepatitis C antibody

22) Confirmed positive HIV test

23) Any severe herpes infection at any time prior to Day 1 (Week 0 visit), including but not limited to, disseminated herpes, herpes encephalitis, or ophthalmic herpes

24) Recurrent herpes zoster (defined as 2 episodes within 2 years) within 5 years prior to Day 1

25) Any herpes zoster infection that has not completely resolved within 12 weeks prior to Day 1

26) History of systemic opportunistic infection requiring hospitalisation or parenteral anti-infective treatment within 3 years prior to Day 1 (oral, vaginal and skin candidiasis is allowed)

27) Cytomegalovirus and/or Epstein–Barr virus infection not completely resolved within the 12 weeks prior signing the ICF

28) Either of the following:

(a) Clinically significant chronic infection (ie, osteomyelitis, bronchiectasis, etc.) which is not resolved within 8 weeks prior to signing the ICF (chronic nail infections are allowed)

(c) Any infection requiring hospitalisation or treatment with parenteral anti-infectives not completed at least 8 weeks prior to Day 1

29) Any infection requiring oral anti-infectives (including antivirals) within 2 weeks prior to Day 1, except chronic suppressive antiviral treatment for herpes simplex virus in the absence of active lesions within 2 weeks prior to Day 1

30) History of cancer, apart from:

(a) Squamous or basal cell carcinoma of the skin treated with documented success of curative therapy ≥12 weeks prior to Day 1 (Week 0 visit)

(d) Cervical carcinoma in situ (cervical intraepithelial neoplasia grade III [CIN III], carcinoma in situ [CIS]) treated with apparent success with curative therapy ≥1 year prior to Day 1 (Week 0 visit)



Table 1- Schedule of Screening Visit Procedures

Visit Number V1

Procedure / Study Day Day -28 to Day -1

Written informed consent / assign SID number X

Subject Global Assessment of Disease Activity X

ESSPRI X

C-SSRS X

PHQ-8 X

Medical history X

Physical examination, weight and height X

Vital signs (BP, HR, RR and temp) X

Sjogren’s Classification Worksheet X

28 joint assessment X

ESSDAI X



Physician Global Assessment of Disease Activity X

Safety Laboratory Tests a X

ESSDAI-required labs b X

Coagulation Tests X

Hemoglobin A1c c X

Serum β-hCG pregnancy test d X

Follicle-stimulating hormone e X

Autoantibody panel f X

Exploratory autoantibody panel g X

Infectious Disease panel h X

Inflammatory marker panel i X

Exploratory biomarker sample (serum) X

Optional biomarker repository sample (serum) X

Optional biomarker repository sample (plasma) X

IFN test X

QuantiFERON-TB Gold test X

PK sample X

PAXgene RNA X

Chest X-ray j X

ECG k X

Pap smear l X

Minor salivary gland biopsy m X

Assessment of AEs/SAEs X

Concomitant medications X

Verify eligibility criteria X

Stimulated and unstimulated salivary measurement X

Abbreviations: AE adverse event; ANA anti-nuclear antibody; AP anteroposterior; B-2 microglobulin



beta-2 microglobulin; βhCG beta-human chorionic gonadotropin; BP blood pressure; CRP C-reactive protein; C-SSRS Columbia Suicide Severity Rating Scale; PHQ-8 Personal Health Questionnaire Depression Scale; ECG electrocardiogram; ENA extractable nuclear antigens; ESR erythrocyte sedimentation rate; ESSDAI European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index; ESSPRI European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index; FSH Follicle stimulating hormone; HIV human immunodeficiency virus; HR heart rate; IFN Interferon; IgG immunoglobulin G; IgM immunoglobulin M; LIPS Luciferase Immunoprecipitation Systems; PK Pharmacokinetics; RNA ribonucleic acid; RR respiratory rate; SAE serious adverse event

Footnotes:

a: Serum chemistry, hematology and urinalysis

b: Diabetic subjects only

c:Complements C3, C4, CH50; cryoglobulins; quantitative immunoglobulins; and immunofixation electrophoresis

d: Female subjects, unless surgically sterile or 1 year postmenopausal

e: Post-menopausal females

f:Autoantibody panel: ANA, ENA (anti-SS-A, anti-SS-B, anti-Smith, anti-ribonuclear protein), rheumatoid factor (at minimum, IgG and IgM)

g: Exploratory autoantibody panel: assessment of anti-SS-A and anti-SS-B by LIPS assay

h: Infectious disease panel: HIV, Hepatitis B and C

i:Inflammatory markers include plasma immunoglobulin levels (IgM, IgG, IgA), B-2 microglobulin, ESR, and CRP

j:AP and lateral chest x-ray will be performed at screening, if not performed within the previous 3 months

k: Standard 12-lead ECG

l: In females who have not had a Pap smear the last 2 years

m: Assess when taken and availability



Table 2- Schedule of Treatment Visit Procedures

Visit number V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15

Study day Procedure 1 Baseline

29 ±7d 57 ±7d 85 ±7d 113 ±7d 141 ±7d 169 ±7d 197 ±7d 225 ±7d 253 ±7d 281 ±7d 309 ±7d 337 ±7d 365 ±7d

Randomization XSubject Global Assessment of Disease Activity

X X X X X X X X X X X X X X

ESSPRI X X X X X X X X X X X X X XSF-36v2 X X X X XPGI-S X X X X X

PGI-C X X X X X

PROFAD-SSI-SF X X X X X

C-SSRS X X X X X X X X X X X X X XPHQ-8 X X X X X X X X X X X X X XAssessment of AEs/SAEs


Concomitant medications


Full physical examination

X X X

Symptom driven physical exam


Vital Signs (BP, HR, RR and temp)


Weight X X X X X X X X X X X X X X28-joint assessment X X X X X X X X X X X X X XESSDAI X X X X X X X X X X X X X XPhysician Global Assessment of Disease Activity




Safety lab tests a X X X X X X X X X X X X X X

Urine pregnancy test b X X X X X X X X X X X X X XCoagulation tests X X XHemoglobin A1c c X X XESSDAI labs d X X X X X X X X X X X X X XAutoantibody panel e X X X X X

Inflammatory markers f X X X X X X X X X X X X X X

IFN test X X XQuantiFERON-TB Gold X XQuantiFERON-TB Gold (for pts with indterminate at baseline)

X X X X

TB questionnaire X X XExploratory biomarker sample (serum)

X X X

Optional biomarker repository sample (serum)

X X X

Optional biomarker repository sample (plasma)

X X X

Anti-anifrolumab

antibodies

X X X X X

Stimulated and unstimulated salivary measurement

X X X X X

Complete dry eye evaluation

X X X

PK pre-dose sample X X X X XPK post-dose sample X XMinor salivary gland biopsy g

X



Administration of study drug

X X X X X X X X X X X X X

Abbreviations: AE adverse event; ANA anti-nuclear antibody; AP anteroposterior; B-2 microglobulin beta-2 microglobulin; BP blood pressure; CRP C-reactive protein; C-SSRS Columbia Suicide Severity Rating Scale; ECG electrocardiogram; ENA extractable nuclear antigens; ESR erythrocyte sedimentation rate; ESSDAI European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index; ESSPRI European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index; HR heart rate; IFN Interferon; PGI-C Patient Global Impression of Change; PGI-S Patient Global Impression of Severity; PHQ-8 Personal Health Questionnaire Depression Scale; PK Pharmacokinetics; PROFAD-SSI-SF Profile of Fatigue and Discomfort--Sicca Symptoms Inventory Short Form; RR respiratory rate; SAE serious adverse event; SF-36v2 Short Form Health Survey 36, Version 2Footnotes:a: Safety labs: Serum chemistry, hematology and urinalysisb: Diabetic subjects onlyc: Female subjects, unless surgically sterile or 1 year postmenopausald: ESSDAI labs: Complements C3, C4, CH50; cryoglobulins; quantitative immunoglobulins; and immunofixation electrophoresise: Autoantibody panel: ANA, ENA (anti-SS-A, anti-SS-B, anti-Smith/anti-ribonuclear protein), rheumatoid factor (at minimum, IgG and IgM)f: Inflammatory markers: B-2 microglobulin, ESR, and CRPg: Assess when taken and availability



Table 3- Schedule of Follow-Up Visit Procedures

Visit NumberV16

(8 Wks post treatment)V17

(12 Wks post treatment)Procedure / Study Day 421±7d 449±7d

Subject Global Assessment of Disease Activity X X

ESSPRI X X

SF-36v2 X

PGI-S X

PGI-C X

PROFAD-SSI-SF X

C-SSRS X X

PHQ-8 X X

Assessment of AEs/SAEs X X

Concomitant medications X X

Full physical examination X X

Vital Signs (BP, HR, RR and temp) X X

ESSDAI X X

Physician Global Assessment of Disease Activity X X

Safety labs a X X

Urine pregnancy test b X X

Coagulation tests X X

ESSDAI labs c X X

Autoantibody panel d X

Anti-anifrolumab antibodies X

Inflammatory markers e X

IFN test X

QuantiFERON-TB Gold (only for indeterminate at baseline) X

TB questionnaire X

Pharmacokinetics blood sample X XBiomarker blood sample X XChest X-ray f XECG g XStimulated and unstimulated salivary measurement X

Ophthalmological evaluation X

Abbreviations: AE adverse event; ANA anti-nuclear antibody; AP anteroposterior; B-2 microglobulin



beta-2 microglobulin; BP blood pressure; CRP C-reactive protein; C-SSRS Columbia Suicide Severity Rating Scale; ECG electrocardiogram; ENA extractable nuclear antigens; ESR erythrocyte sedimentation rate; ESSDAI European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index; ESSPRI European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index; HIV human immunodeficiency virus; HR heart rate; IFN Interferon; IgG immunoglobulin G; IgM immunoglobulin M; LIPS Luciferase Immunoprecipitation Systems; PHQ-8 Personal Health Questionnaire Depression Scale; PK Pharmacokinetics; RNA ribonucleic acid; RR respiratory rate; SAE serious adverse event

Footnotes:

a: Safety labs: Serum chemistry, hematology and urinalysis

b: Female subjects, unless surgically sterile or 1 year postmenopausal

c:ESSDAI labs: Complements C3, C4, CH50; cryoglobulins; quantitative immunoglobulins; and immunofixation electrophoresis

d:Autoantibody panel: ANA, ENA (anti-SS-A, anti-SS-B, anti-Smith/anti-ribonuclear protein), rheumatoid factor (at minimum, IgG and IgM)

e: Inflammatory markers: B-2 microglobulin, ESR, and CRP

f:AP and lateral chest x-ray will be performed at screening, if not performed within the previous 3 months

g: Standard 12-lead ECG


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