AIDS Treatment Information - Supplementary Appendix · 2020-03-26 · On-treatment Adverse Events...

Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Swindells S, Andrade-Villanueva J-F, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med 2020;382:1112-23. DOI: 10.1056/NEJMoa1904398

(PDF updated March 26, 2020)

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Susan Swindells, et al.

Long-Acting Cabotegravir and Rilpivirine for HIV-1 (ATLAS Trial)

SUPPLEMENTARY APPENDIX

Contents

Study Sites and Lead Investigators ............................................................................................................... 2

Eligibility Criteria ........................................................................................................................................... 6

Figure S1. Timeliness of Injections Relative to Target. ............................................................................... 14

Figure S2. Unadjusted Difference (LA Arm Minus CAR Arm) in Percentage Proportion

with HIV-1 RNA ≥50 copies/mL at Week 48 (Snapshot) ± 95% CI. ............................................. 15

Figure S3. Incidence of Injection Site Reaction Adverse Events, LA Arm.................................................... 16

Table S1. Summary of Antiretroviral Agents Taken at Baseline. ................................................................ 17

Table S2. Reasons for Exclusion From the Per-Protocol Population .......................................................... 18

Table S3. Additional Secondary Endpoints ................................................................................................. 19

Table S4. Confirmed Virologic Failure. ........................................................................................................ 20

Table S5. On-treatment Adverse Events by System Organ Class and Maximum

Toxicity Grade – Maintenance Phase ......................................................................................... 21

Table S6. Serious Adverse Events – Maintenance Phase. ........................................................................... 37

Table S7. Adverse Events Leading to Withdrawal – Maintenance Phase. .................................................. 38

Table S8. On-treatment Laboratory Abnormalities by Maximum Toxicity

Grade – Maintenance Phase ....................................................................................................... 39

Table S9. Cabotegravir and Rilpivirine Plasma Concentrations in LA Recipients

with Confirmed Virologic Failure. ............................................................................................... 40

Table S10. Change from Baseline in Total Treatment Satisfaction Score by Visit – Adjusted,

Last Observation Carried Forward. ............................................................................................. 41

References .................................................................................................................................................. 42

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Study Sites and Lead Investigators

Lead Investigator Site

USA

1 Judith Aberg Icahn School of Medicine at Mount Sinai, New York, NY

2 U Fritz Bredeek Metropolis Medical, San Francisco, CA

3 Robert Brennan Infectious Diseases Assoc of Central VA, Lynchburg, VA

4 Cynthia Brinson Central Texas Clinical Research, Austin, TX

5 Indira Brar Henry Ford Hospital, Detroit, MI

6 Douglas Cunningham Pueblo Family Physicians, Phoenix, AZ

7 Franco Felizarta Bakersfield, CA

8 Deborah Goldstein Whitman Walker Clinic, Washington, D.C.

9 Harold Katner Mercer University School of Medicine, Macon, GA

10 Rachel Presti Washington University School of Medicine, St. Louis, MO

11 Edgar Overton University of Alabama 1917 Clinic, Birmingham, AL

12 Alyssa Shon Evergreen Health, University of Buffalo, Buffalo, NY

13 Chris Bettacchi North Texas Infectious Disease Consultants, Dallas, TX

14 Princy Kumar Georgetown University Hospital, Washington, D.C.

15 Christopher Polk Infectious Disease Consultants, Charlotte, NC

16 Gary Simon Medical Faculty Associates, George Washington University,

Washington, D.C.

17 David Wohl Medical Faculty Associates, George Washington University,

Washington, D.C.

18 Mia Scott Apex Research, Denver, CO

19 Susan Swindells University of Nebraska Medical Center, Omaha, NE

20 Babafemi Taiwo Northwestern University, Chicago, IL

21 Anthony Mills Kaiser Permanente Medical Center, Los Angeles, CA

22 Peter Ruane Los Angeles, CA

23 Jerome De Vente Living Hope Clinical Foundation, Long Beach, CA

24 Margaret Hoffman-Terry Lehigh Valley Hospital, Allentown, PA

25 Chiu-Bin Hsiao Allegheny General Hospital, Pittsburgh, PA

26 Annie Luetkemeyer San Francisco General Hospital, San Francisco, CA

27 Martin Markowitz Aaron Diamond AIDS Research Center, New York, NY

28 Gerald Pierone AIDS Research & Treatment Center of the Treasure Coast,

Vero Beach, FL

29 Gary Richmond Fort Lauderdale, FL

30 David Wheeler Clinical Alliance for Research & Education - Infectious

Diseases, Annandale, VA

31 Carl Fichtenbaum University of Cincinnati College of Medicine, Cincinnati, OH

32 Gordon Crofoot Houston, TX

33 Hannah Olivet Community Research Initiative of New England, Boston, MA

34 Tanya Schreibman Comprehensive Care Clinic, Sarasota, FL

35 Kenneth Lichtenstein Eisenhower Medical Associates, Palm Springs, CA

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36 Moti Ramgopal Fort Pierce, FL

Canada

37 Jean-Guy Baril Clinique Medicale Quartier Latin, Montreal, Québec

38 Sylvie Trottier CHU de Québec Hôpital CHUL, Québec, Québec

39 Jonathan Angel The Ottawa Hospital-General Campus, Ottawa, Ontario

40 Alexander Wong Regina Qu’Appelle Health Region, Regina, Saskatchewan

41 Alexandra de Pokomandy Royal Victoria Hospital/McGill University Health Centre

(MUHC), Montreal, Québec

42 Graham Smith Maple Leaf Research, Toronto, Ontario

Mexico

43 Jaime-Federico Andrade-

Villanueva

Hospital Civil de Guadalajara Fray Antonio Alcalde,

Guadalajara, Jalisco

Argentina

44 Pedro Cahn Fundación Huésped, Buenos Aires

45 Isabel Cassetti Helios Salud, Buenos Aires

46 Norma Porteiro Fundación IDEAA, Buenos Aires

47 Sergio Lupo Instituto Caici, Rosario, Santa Fe

France

48 Jean-Michel Molina Hôpital Saint Louis, Paris

49 Pierre Delobel Hôpital Purpan, Toulouse

50 Faïza Ajana Hôpital Gustave Dron, Tourcoing

51 Marie-Aude Khuong-Josses Hôpital Delafontaine, Saint Denis

52 Christine Katlama Hôpital de la Pitié-Salpêtrière, Paris

53 Pierre-Marie Girard Hôpital Saint Antoine, Paris

54 Yazdan Yazdanpanah Hôpital Bichat-Claude Bernard, Paris

55 Jacques Reynes Hôpital Gui de Chauliac, Montpellier

Germany

56 Axel Baumgarten Zentrum für Infektiologie Berlin Prenzlauer Berg, Berlin

57 Matthias Stoll Medizinische Hochschule Hannover, Hannover

58 Juergen Rockstroh Rheinische Friedrich-Wilhelms Universitaet, Bonn

59 Christoph Stephan Klinikum der J-W-Goethe-Universitaet, Frankfurt am Main

60 Stefan Esser Universitaetsklinikum Essen, Essen

61 Thomas Lutz Infektio Research, Frankfurt

62 Hans Jaeger MUC Research GmbH, Muenchen

63 Olaf Degen Universitaetsklinikum Eppendorf, Hamburg

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64 Keikawus Arasteh Epimed GmbH, Berlin

65 Hans-Juergen Stellbrink ICH Study Center, Hamburg

Italy

66 Francesco Castelli Azienda Ospedaliera Spedali Civili, Brescia

67 Giuliano Rizzardini PO Ospedale Luigi Sacco - Polo Universitario, Milano

Spain

68 Rafael Rubio Hospital 12 de Octubre, Madrid

69 Marisa Montes Hospital la Paz, Madrid

70 Pompeyo Viciana

Fernández

Hospital Universitario Virgen del Rocío, Sevilla

71 Maria Del Mar Masia

Canuto

Hospital General de Elche, Elche

72 Miguel Garcia Deltoro Hospital General Universitario, Valencia

73 Antonio Ocampo Hermida Complejo Hospitalario Universitario de Vigo–Hospital Álvaro

Cunqueiro, Vigo

74 Manuel Castaño Hospital Carlos Haya, Malaga

75 Antonio Antela Complejo Hospitalario Universitario de Santiago de

Compostela, Santiago de Compostela

76 Eugenia Negredo Puigmal Hospital Germans Trias i Pujol, Badalona

77 Josep Mallolas Hospital Clinic I Provincial De Barcelona, Barcelona

78 Hernando Knobel Hospital del Mar, Barcelona

79 Vicens Falcó Ferrer Hospital Valle d’Hebrón, Barcelona

80 Antonio Rivero Román Hospital Reina Sofía, Córdoba

81 Santiago Moreno Guillen Hospital Ramón Y Cajal, Madrid

Sweden

82 Anders Thalme Karolinska Universitetssjukhuset, Huddinge, Stockholm

83 Carl Johan Treutiger Karolinska Universitetssjukhuset, Huddinge, Stockholm

84 Magnus Gisslén Sahlgrenska Universitetssjukhuset/Östra, Göteborg

Russian Federation

85 Vadim Pokrovsky Central Research Institute of Epidemiology, Moscow

86 Denis Gusev St. Petersburg City AIDS Centre, St. Petersburg

87 Olga Tsybakova Smolensk Regional AIDS Centre, Smolensk

88 Svetlana Volkova Sverdlovsk Regional AIDS Center, Ekaterinburg

89 Valery Kulagin Krasnodar’s Area AIDS Centre, Krasnodar

90 Oksana Chernova Tolyatti City AIDS Centre, Tolyatti

91 Olga Borodkina Kemerovo Regional AIDS Centre, Kemerovo

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92 Firaya Nagimova Tatarstan Republican AIDS Centre, Kazan

93 Olga Tonkikh Lipetsk Regional AIDS Centre, Lipetsk

94 Alexey Yakovlev City Hospital of Infectious Diseases, St. Petersburg

95 Elena Belonosova Orel Regional AIDS Centre, Orel

96 Eugene Voronin Republican Hospital of Infectious Diseases, St. Petersburg

97 Andrey Shuldyakov Saratov Regional AIDS Centre, Saratov

South Africa

98 Mohammed Tayob Mzansi Ethical Research Centre, Middelburg

99 Monja-Marie Nortje Moriana Clinical Research, Brandfort

100 Johannes Jurgens

Lombaard

Josha Research, Bloemfontein

101 Lelanie van Zyl Syzygy Clinical Research Services, Pretoria

102 Catherine Orrell Desmond Tutu HIV Foundation, Groote Schuur Hospital,

Cape Town

103 Essack Mitha Newtown Clinical Research Centre, Johannesburg

104 Farzana Hoosen Synapta Clinical Research Centre, Durban

105 Rosie Mngqibisa Wentworth Hospital, Enhancing Care Foundation,

Wentworth

106 Gulam Latiff Durban

Republic of Korea

107 Shin-Woo Kim Kyungpook National University Hospital, Daegu

108 Sang-Il Kim The Catholic University of Korea Seoul St. Mary’s Hospital,

Seoul

109 YeonSook Kim Chungnam National University Hospital, Daejeon

110 Jun Yong Choi Severance Hospital, Seoul

111 Sun Hee Lee Pusan National University Hospital, Busan

Australia

112 Mark Bloch Holdsworth House Medical Practice, Sydney

113 David Baker East Sydney Doctors, Darlinghurst

114 Matthew Shields Taylor Square Private Clinic, Darlinghurst

115 Norman Roth Prahran Market Clinic, Prahran

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Eligibility Criteria

Inclusion Criteria

A participant will be eligible for inclusion in this study only if all of the following criteria apply:

• Be able to understand and comply with protocol requirements, instructions, and restrictions

• Understand the long-term commitment to the study and be likely to complete the study as planned

• Be considered an appropriate candidate for participation in an investigative clinical trial with oral

and intramuscularly injectable medications (e.g., no active substance use disorder, acute major

organ disease, or planned long-term work assignments out of the country, etc.)

The following are study-specific eligibility criteria unless stated otherwise. In addition to these criteria,

Investigators must exercise clinical discretion regarding selection of appropriate study participants,

taking into consideration any local treatment practices or guidelines and Good Clinical Practice (GCP). All

participants must be considered appropriate candidates for antiretroviral therapy (ART) in accordance

with local treatment guidelines.

Laboratory results from the central laboratory services provided by this trial will be used to assess

eligibility. In exceptional circumstances only, if a repeat lab is required because a central lab result

cannot be generated, local labs can be reviewed and approved by the medical monitor for consideration

of participant eligibility. A repeat central lab will be submitted concurrently or at the next planned visit.

Source documentation to verify entry criteria must be reviewed by the Principal Investigator or designee

prior to randomization. Source documents from other medical facilities must be located/received during

the 14-day screening phase (or up to 35 days) and under no circumstances may the participant be

randomized in the absence of source documentation.

Participants eligible for enrollment in the study must meet all of the following criteria:

Age

1. Aged 18 years or older (or ≥19 where required by local regulatory agencies) at the time of

signing the informed consent.

Type of Participant and Diagnosis, Including Disease Severity

2. Must be on uninterrupted current regimen (either the initial or second antiretroviral [ARV]

regimen) for at least 6 months prior to screening. Any prior switch, defined as a change of a

single drug or multiple drugs simultaneously, must have occurred due to tolerability/safety,

access to medications, or convenience/simplification, and must NOT have been done for

treatment failure (HIV-1 RNA ≥400 copies/mL).

Acceptable stable (initial or second) ARV regimens prior to screening include two nucleos(t)ide

reverse transcriptase inhibitors (NRTIs) plus:

• Integrase inhibitor with the exception of abacavir/dolutegravir/lamivudine

(ABC/DTG/3TC) (either the initial or second combination antiretroviral therapy [CAR]

regimen)

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• Non-nucleoside reverse transcriptase inhibitor (NNRTI) (either the initial or second CAR

regimen)

• Boosted protease inhibitor or atazanavir unboosted (must be either the initial CAR

regimen or one historical within class switch is permitted due to safety/tolerability)

The addition, removal, or switch of a drug(s) that has been used to treat HIV based on

antiretroviral properties of the drug constitutes a change in ART with the following limited

exceptions:

• Historical changes in formulations of ART drugs or booster drugs will not constitute a

change in ART regimen if the data support similar exposures and efficacy, and the

change must have been at least 3 months prior to screening

• Historical perinatal use of an NRTI when given in addition to an ongoing highly active

ART will not be considered a change in ART regimen

• A change in dosing scheme of the same drug from twice daily to once daily will not be

considered a change in ART regimen if data support similar exposures and efficacy

3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 copies/mL in the 12

months prior to screening: one within the 6- to 12-month window, and one within 6 months

prior to screening.

4. Plasma HIV-1 RNA <50 copies/mL at screening.

Sex

5. A female participant is eligible to participate if she is not pregnant (as confirmed by a negative

serum human chorionic gonadotrophin (hCG) test at screening and a negative urine hCG test at

randomization), not lactating, and at least one of the following conditions applies:

a. Non-reproductive potential defined as:

• Pre-menopausal females with one of the following:

– Documented tubal ligation

– Documented hysteroscopic tubal occlusion procedure with follow-up confirmation

of bilateral tubal occlusion

– Hysterectomy

– Documented bilateral oophorectomy

• Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable

cases a blood sample with simultaneous follicle-stimulating hormone and estradiol

levels consistent with menopause [refer to laboratory reference ranges for confirmatory

levels]). Females on hormone replacement therapy (HRT) and whose menopausal status

is in doubt will be required to use one of the highly effective contraception methods if

they wish to continue their HRT during the study. Otherwise, they must discontinue HRT

to allow confirmation of post-menopausal status prior to study enrollment.

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b. Reproductive potential and agrees to follow one of the options listed in the modified list of

highly effective methods for avoiding pregnancy in females of reproductive potential (not

shown) from 30 days prior to the first dose of study medication, and until from 30 days prior to

the first dose of study medication throughout the study, and for at least 30 days after

discontinuation of all oral study medications and for at least 52 weeks after discontinuation of

long-acting cabotegravir (CAB LA) and long-acting rilpivirine (RPV LA).

The investigator is responsible for ensuring that participants understand how to properly use these

methods of contraception.

Informed Consent

Capable of giving signed informed consent, which includes compliance with the requirements and

restrictions listed in the consent form and in this protocol. Eligible participants or their legal guardians

(and next of kin when locally required), must sign a written informed consent form before any protocol-

specified assessments are conducted. Enrollment of participants who are unable to provide direct

informed consent is optional and will be based on local legal/regulatory requirements and site feasibility

to conduct protocol procedures.

Other

Participants enrolled in France must be affiliated to, or a beneficiary of, a social security category.

All participants in the study should be counselled on safer sexual practices, including the use and

benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to an

uninfected partner.

Exclusion Criteria

Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific

integrity of the study, regulatory acceptability, or participant safety. Therefore, adherence to the criteria

as specified in the protocol is essential. A participant will not be eligible for inclusion in this study if any

of the following criteria apply:

Exclusionary criteria prior to screening or day 1

1. Within 6 months prior to screening and after confirmed suppression to <50 copies/mL on

current ART regimen, any plasma HIV-1 RNA measurement 50 copies/mL.

2. Within the 6- to 12-month window prior to screening and after confirmed suppression to <50

copies/mL, any plasma HIV-1 RNA measurement >200 copies/mL, or two or more plasma HIV-1

RNA measurements 50 copies/mL.

3. Any drug holiday during the window between initiating first HIV ART and 6 months prior to

screening, except for brief periods (less than 1 month) where all ART was stopped due to

tolerability and/or safety concerns.

4. Any switch to a second-line regimen, defined as change of a single drug or multiple drugs

simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV-1 RNA

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measurement 400 copies/mL after initial suppression to <50 copies/mL while on first-line HIV

therapy regimen).

5. ABC/DTG/3TC as current ART regimen.

6. A history of use of any regimen consisting of only single NNRTI therapy (even if only for

peripartum treatment), or only single or dual NRTI therapy prior to starting CAR.

7. Participants who are currently participating in, or anticipate being selected for, any other

interventional study.

Exclusionary medical conditions

8. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the

study.

9. Any evidence of an active Center for Disease Control and Prevention (CDC) Stage 3 disease,1

except cutaneous Kaposi’s sarcoma not requiring systemic therapy and historical or current

CD4 cell counts less than 200 cells/mm3.

10. Participants with moderate-to-severe hepatic impairment.

11. Any pre-existing physical or mental condition (including substance use disorder) which, in the

opinion of the Investigator, may interfere with the participant’s ability to comply with the

dosing schedule and/or protocol evaluations or which may compromise the safety of the

participant.

12. Participants determined by the Investigator to have a high risk of seizures, including

participants with an unstable or poorly controlled seizure disorder. A participant with a prior

history of seizures may be considered for enrollment if the Investigator believes the risk of

seizure recurrence is low. All cases of prior seizure history should be discussed with the

medical monitor prior to enrollment.

13. All participants will be screened for syphilis (rapid plasma reagin [RPR]). Participants with

untreated syphilis infection, defined as a positive RPR without clear documentation of

treatment, are excluded. Participants with a serofast RPR result (persistence of a reactive

nontreponemal syphilis test) despite history of adequate therapy and no evidence of re-

exposure may enroll after consultation with the medical monitor. Participants with a positive

RPR test who have not been treated may be rescreened at least 30 days after completion of

antibiotic treatment for syphilis.

14. Participants who, in the investigator’s judgment, pose a significant suicide risk. Participants’

recent history of suicidal behavior and/or suicidal ideation should be considered when

evaluating for suicide risk.

15. The participant has a tattoo or other dermatological condition overlying the gluteus region

which may interfere with interpretation of injection site reactions.

16. Evidence of hepatitis B virus (HBV) infection based on the results of testing at screening for

hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), hepatitis B surface

antibody (anti-HBs), and HBV DNA as follows:

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• Participants positive for HBsAg are excluded

• Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and

positive for HBV DNA are excluded

Note: Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past

and/or current evidence) are immune to HBV and are not excluded.

17. Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded,

however, Investigators must carefully assess if therapy specific for HCV infection is required;

participants who are anticipated to require HCV treatment within 12 months must be excluded.

(HCV treatment on study may be permitted post week 48, following consultation with the

medical monitor.)

Participants with HCV co-infection will be allowed entry into phase 3 studies if:

• Liver enzymes meet entry criteria

• HCV disease has undergone appropriate work-up, and is not advanced, and will not

require treatment prior to the week 48 visit. Additional information (where available) on

participants with HCV co-infection at screening should include results from any liver

biopsy, Fibroscan, ultrasound, or other fibrosis evaluation, history of cirrhosis or other

decompensated liver disease, prior treatment, and timing/plan for HCV treatment

• In the event that recent biopsy or imaging data are not available or inconclusive, the Fib-4

score will be used to verify eligibility

– Fib-4 score >3.25 is exclusionary

– Fib-4 scores 1.45–3.25 require medical monitor consultation

Fibrosis 4 Score Formula: (age x AST) / (platelets x (sqr [ALT])

18. Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy,

coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or

cirrhosis), known biliary abnormalities (with the exception of Gilbert's syndrome or

asymptomatic gallstones or otherwise stable chronic liver disease per investigator

assessment).

19. History of liver cirrhosis with or without hepatitis viral co-infection.

20. Ongoing or clinically relevant pancreatitis.

21. Clinically significant cardiovascular disease, as defined by history/evidence of congestive heart

failure, symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG)

surgery or percutaneous transluminal coronary angioplasty, (PTCA) or any clinically significant

cardiac disease.

22. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected,

non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other

localized malignancies require agreement between the investigator and the Study medical

monitor for inclusion of the participant prior to randomization.

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23. Any condition which, in the opinion of the Investigator, may interfere with the absorption,

distribution, metabolism, or excretion of the study drugs, or render the participant unable to

receive study medication.

24. History or presence of allergy or intolerance to the study drugs or their components or drugs

of their class. In addition, if heparin is used during PK sampling, participants with a history of

sensitivity to heparin or heparin-induced thrombocytopenia must not be enrolled.

25. Current or anticipated need for chronic anti-coagulation with the exception of the use of

low-dose acetylsalicylic acid (≤325 mg).

Exclusionary laboratory values or clinical assessments at screening (a single repeat to determine

eligibility is allowed):

26. Any evidence of primary resistance based on the presence of any major known INSTI or NNRTI

resistance-associated mutation, except for K103N, by any historical resistance test result.2

Note: Prior genotypic resistance testing is not required but if available it must be provided to

GSK after screening and before randomization, according to guidance in the SPM, to provide

direct evidence of no pre-existing exclusionary resistance mutations. You must wait for the

study virologists to confirm the lack of exclusionary resistance mutations, which will be

provided before the screening window closes. Details regarding baseline or prior resistance

data must be noted in the source documentation.

27. Any verified grade 4 laboratory abnormality. A single repeat test is allowed during the

Screening phase to verify a result.

28. Any acute laboratory abnormality at screening, which, in the opinion of the investigator, would

preclude the participant’s participation in the study of an investigational compound.

29. Participant has estimated creatine clearance <50 mL/min per 1.73 m2 via CKD-EPI method.

30. Alanine aminotransferase (ALT) 3 × ULN.

Concomitant Medications

31. Exposure to an experimental drug or experimental vaccine within either 30 days, five half-lives

of the test agent, or twice the duration of the biological effect of the test agent, whichever is

longer, prior to day 1 of this study.

32. Treatment with any of the following agents within 28 days of screening:

• Radiation therapy

• Cytotoxic chemotherapeutic agents

• Tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazide, INH)

• Anti-coagulation agents

• Immunomodulators that alter immune responses such as chronic systemic corticosteroids,

interleukins, or interferons. Note: Participants using short-term (e.g., ≤21 days) systemic

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corticosteroid treatment; topical, inhaled, and intranasal corticosteroids are eligible for

enrollment

33. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening.

34. Treatment with any agent, except recognized ART as allowed above, with documented activity

against HIV-1 within 28 days of study day 1.

35. Use of medications which are associated with Torsade de Pointes. (See SPM for a list of

relevant medications.)

36. Current or prior history of etravirine (ETR) use.

37. Current use of tipranavir/ritonavir or fosamprenavir/ritonavir.

38. Participants receiving any prohibited medication listed below, and who are unwilling or unable

to switch to an alternate medication. Note: Any prohibited medications listed below that

decrease CAB or RPV concentrations should be discontinued for a minimum of 4 weeks or a

minimum of three half-lives (whichever is longer) prior to the first dose and any other

prohibited medications should be discontinued for a minimum of 2 weeks or a minimum of

three half-lives (whichever is longer) prior to the first dose.

Prohibited Medications and Non-Drug Therapies

The following concomitant medications or therapies are not permitted at any time during the study:

• HIV immunotherapeutic vaccines are not permitted at any time during the study.

• Other experimental agents, antiretroviral drugs not otherwise specified in the protocol,

cytotoxic chemotherapy, or radiation therapy may not be administered

• Systemically administered immunomodulators (such as interleukin and interferon agents) are

prohibited (a list of examples is provided in the SPM). This includes topical agents with

substantial systemic exposure and systemic effects. Use of topical imiquimod is permitted

• Acetaminophen (paracetamol) cannot be used in patients with acute viral hepatitis

• Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided due to their

immunosuppressive effect and potential decreases in RPV plasma concentrations; however,

short treatment courses with oral prednisone/ prednisolone/methylprednisolone (e.g.,

adjunctive treatment of Pneumocystis pneumonia with ≤21 days of tapering prednisone) are

allowed. A single dose of systemic dexamethasone is permitted (more than a single dose in a

treatment course may cause significant decrease in RPV plasma concentration and is

prohibited). Topical, inhaled, or intranasal use of glucocorticoids will be allowed

• Hepatitis C infection therapy is prohibited during the maintenance phase before the week 48

primary endpoint, and interferon-based HCV therapy or use of any drugs that have a potential

for adverse drug:drug interactions with study treatment is prohibited throughout the entire

study

For information on concurrent therapies and interactions suspected to be relevant to other

antiretroviral therapy in the regimen, please consult the local prescribing information.

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Concurrent with CAB and/or RPV

For participants receiving either formulation of CAB and/or RPV, the following medications could

significantly decrease the levels of CAB and/or RPV due to enzyme induction and therefore must not be

administered concurrently:

• Carbamazepine

• Oxcarbazepine

• Phenobarbital

• Phenytoin

• Rifabutin

• Rifampicin/rifampin

• Rifapentine

• St. John’s wort (Hypericum perforatum)

Concurrent with RPV

In addition, participants must discontinue the following (or change to an allowable alternative) while

receiving treatment with oral RPV:

• Proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and

rabeprazole

• Systemic dexamethasone (more than a single dose, for both oral RPV and RPV LA)

If the participant cannot discontinue use or change to an allowable alternative while receiving treatment

with RPV, the participant should not be randomized into the study.

Concurrent with either CAB LA or RPV LA

In addition, for participants receiving CAB LA and RPV LA, use of anticoagulation agents for greater than

14 days is prohibited, with the exception of the use of anticoagulation for DVT prophylaxis (e.g.,

postoperative DVT prophylaxis) or the use of low-dose acetylsalicylic acid (≤325 mg). Systemic

anticoagulation (including prophylaxis doses) on the day of an IM injection should be avoided.

Note: Any prohibited medications that decrease cabotegravir or rilpivirine concentrations should be

discontinued for a minimum of 4 weeks or a minimum of three half-lives (whichever is longer) prior to

the first dose and any other prohibited medications should be discontinued for a minimum of 2 weeks

or a minimum of three half-lives (whichever is longer) prior to the first dose.

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Figure S1. Timeliness of Injections Relative to Target.

The number of injections received by participants in the LA arm during the maintenance phase is plotted

according to proximity to the target day, which was set according to the protocol-defined injection

schedule. LA denotes long-acting.

8 20

296

195

353

1567

267 242332

545

0

200

400

600

800

1000

1200

1400

1600

1800

< -14 -14 to -8 -7 to -4 -3 to -2 -1 0 1 2 to 3 4 to 7 8 to 14 >14

Nu

mb

er o

f In

ject

ion

Vis

its

Days From Target Date

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Figure S2. Unadjusted Difference (LA Arm Minus CAR Arm) in Percentage Proportion with

HIV-1 RNA ≥50 copies/mL at Week 48 (Snapshot) ± 95% CI.

The proportion of participants in the LA arm who met the primary endpoint (HIV-1 RNA ≥50 copies/mL

at week 48 [snapshot]) minus the corresponding proportion in the CAR arm, ± the 95% confidence

interval, was determined according to population subgroups pertaining to randomization strata (sex at

birth, third agent in baseline antiretroviral regimen) and baseline characteristics including age, race, and

CD4+ cell counts. Covariates included plasma concentrations at weeks 8 and 48, age, weight, body mass

index, sex, race, CDC classification, and CD4+ cell count.

CAR denotes current antiretroviral therapy, CDC United States Centers for Disease Control and

Prevention, CI confidence interval, INSTI integrase strand transfer inhibitor, LA long-acting, NNRTI non-

nucleoside reverse transcriptase inhibitor, and PI protease inhibitor.

LA, n/N CAR, n/N

All patients 5/308 3/308

Sex at birthFemale 2/99 0/104

Male 3/209 3/204

Third agent in baseline regimen

NNRTI 4/155 1/155

INSTI 0/102 2/99

PI 1/51 0/54

Age, years

<35 0/80 1/80

35-49 4/162 1/132

≥50 1/66 1/96

Race

White 3/214 2/207

Non-white 2/94 1/101

Black/Afr Amer 2/62 1/77

Non-black/AfrAmer 3/246 2/231

CD4+ cell count

<350 0/23 1/27

350-499 2/56 0/57

≥500 3/229 2/224

Unadjusted Difference in Proportion ± 95% CI

0.4

3.6

-3.7

0.4

1.9

1.1

0.4

0.5

1.7

-1.3

2.0

-2.0

1.9

0.0

2.0

0.6

-10.0 -5.0 0.0 5.0 10.0 15.0

−19

Favors LA Favors CAR

16

Figure S3. Incidence of Injection Site Reaction Adverse Events, LA Arm.

A Any Injection Site Reaction

B Pain

C Nodule

D Induration

E Swelling

The proportions of participants in the LA arm who experienced any injection site reaction are shown by study week, beginning at week 4B when the first injections were administered. Week 4 is the visit at which the first LA injections were administered.

ISR denotes injection site reaction, and LA long-acting. N values at each time point are the same as shown for overall ISRs (panel A) and for each ISR subcategory.

64

35

23 2218 18 17

13 14 15 12 10

0

20

40

60

80

100

4 8 12 16 20 24 28 32 36 40 44 48

Part

icip

ants

wit

h IS

Rs

(%)

Study Week

64

35

23 2218 18 17

13 14 15 12 10

0

20

40

60

80

100

4 8 12 16 20 24 28 32 36 40 44 48

Part

icip

ants

wit

h IS

Rs

(%)

Study Week

3 2 1 3 0.6 1 0.7 0.3 0.7 2 0.4 0.80

20

40

60

80

100

4 8 12 16 20 24 28 32 36 40 44 48

Part

icip

ants

wit

h IS

Rs

(%)

Study Week

5 2 1 2 1 1 1 0.7 1 1 1 0.40

20

40

60

80

100

4 8 12 16 20 24 28 32 36 40 44 48

Part

icip

ants

wit

h IS

Rs

(%)

Study Week

3 2 0 1 0.3 1 0.7 0.7 1 0.4 1 0.40

20

40

60

80

100

4 8 12 16 20 24 28 32 36 40 44 48

Part

icip

ants

wit

h IS

Rs

(%)

Study Week

17

Table S1. Summary of Antiretroviral Agents Taken at Baseline.

ART, n (%)

LA Arm

N=308

CAR Arm

N=308

ART, n (%)

LA Arm

N=308

CAR Arm

N=308

PI + NRTIs 51 (17) 54 (18) NNRTI + NRTIs 155 (50) 155 (50)

ATV ± RTV 18 (6) 16 (5) EFV 100 (32) 105 (34)

3TC, ABC 10 (3) 5 (2) FTC, TDF 74 (24) 75 (24)

3TC, ABC, AZT 0 1 (<1) 3TC, ABC 15 (5) 13 (4)

3TC, AZT 2 (1) 3 (1) 3TC, AZT 5 (2) 13 (4)

3TC, TDF 1 (<1) 1 (<1) 3TC, TDF 5 (2) 3 (1)

ABC, TDF 0 1 (<1) 3TC, ddl 1 (<1) 1 (<1)

FTC, TDF 5 (2) 4 (1) NVP 15 (5) 15 (5)

FTC, TAF 0 1 (<1) 3TC, ABC 6 (2) 7 (2)

DRV + RTV or COBI 14 (5) 12 (4) 3TC, AZT 1 (<1) 0

FTC, TAF 1 (<1) 0 3TC, TDF 0 1 (<1)

FTC, TDF 7 (2) 9 (3) FTC, TAF 1 (<1) 1 (<1)

3TC, ABC 2 (1) 2 (1) FTC, TDF 7 (2) 6 (2)

3TC, AZT 2 (1) 1 (<1) RPV 40 (13) 35 (11)

3TC, TDF 2 (1) 0 FTC, TAF 2 (<1) 1 (<1)

LPV + RTV 19 (6) 26 (8) FTC, TDF 37 (12) 32 (10)

3TC, ABC 3 (1) 7 (2) 3TC, ABC 1 (<1) 2 (1)

3TC, AZT 9 (3) 14 (5) INSTI + NRTIs 102 (33) 99 (32)

3TC, PSZ 2 (1) 0 RAL 24 (8) 18 (6)

3TC, TDF 2 (1) 2 (1) 3TC, ABC 4 (1) 4 (1)

FTC, TDF 3 (1) 2 (1) 3TC, AZT 0 1 (<1)

TDF 0 1 (<1) FTC, TAF 2 (1) 1 (<1)

FTC, TDF 18 (6) 12 (4)

DTG 8 (3) 6 (2)

FTC, TAF 3 (1) 0

FTC, TDF 5 (2) 6 (2)

EVG + COBI 70 (23) 75 (24)

FTC, TAF 40 (13) 49 (16)

FTC, TDF 30 (10) 26 (8)

3TC denotes lamivudine, ABC abacavir, ART antiretroviral therapy, ATV atazanavir, AZT zidovudine,

CAR current ART, COBI cobicistat, ddI didanosine, DRV darunavir, DTG dolutegravir, EFV efavirenz,

EVG elvitegravir, FTC emtricitabine, INSTI integrase strand transfer inhibitor, LA long-acting, LPV

lopinavir, NNRTI, non-nucleoside reverse transcriptase inhibitor, NRTI nucleoside reverse

transcriptase inhibitor, NVP nevirapine, PI protease inhibitor, PSZ phosphazide, RTV ritonavir, RAL

raltegravir, RPV rilpivirine, TAF tenofovir alafenamide, and TDF tenofovir disoproxil fumarate.

18

Table S2. Reasons for Exclusion From the Per-Protocol Population.

LA Arm

N=308

CAR Arm

N=308

Total number of participants excluded from per-protocol population 14 (5%) 16 (5%)

Study treatment not administered per protocol 3 (<1%) 0

Eligibility criteria not met* 10 (3%) 15 (5%)

A history of use of any regimen consisting of only single NNRTI

therapy (even if only for peri-partum treatment), or only single or

dual NRTI therapy prior to starting combination antiretroviral therapy

1 0

Evidence of hepatitis B virus infection based on the results of testing

at screening for hepatitis B surface antigen

1 0

Any drug holiday during the window between initiating first

antiretroviral therapy and 6 months prior to screening except for brief

periods (<1 month) where all antiretroviral therapy was stopped due

to tolerability and/or safety concerns

0 2

Uninterrupted antiretroviral therapy for ≥6 months prior to screening.

Any prior switch must have occurred due to tolerability/safety, access

to medications or simplification and must NOT have been done for

virologic failure

8 12

Females of non-childbearing potential, or if childbearing potential,

has a negative serum hCG test at screening and agrees to use an

acceptable birth control method

1 1

Other deviation from study procedures 1 (<1%) 2 (<1%)

hCG denotes human chorionic gonadotropin, NNRTI nonnucleoside reverse transcriptase inhibitor,

NRTI nucleoside reverse transcriptase inhibitor.

*A participant may have more than one important deviation leading to exclusion.

19

Table S3. Additional Secondary Endpoints.

A. HIV-1 RNA Plasma RNA at Week 48

Assessment N LA Arm N CAR Arm

HIV-1 RNA, mean (SD) log10 copies/mL

Baseline 308 1.52 (0.17) 308 1.51 (0.04)

Week 48 265 1.51 (0.05) 292 1.52 (0.11)

HIV-1 RNA change from baseline, mean (SD) log10 copies/mL

Week 48 265 -0.013 (0.19)

292 0.012 (0.12)

CAR denotes current antiretroviral therapy, LA long acting.

B. Post-Baseline HIV-1 Disease Progression

Parameter, n (%)

LA Arm

N=308

CAR Arm

N=308

Did participant experience disease progression to CDC Stage III or death?

Yes 8 (3) 8 (3)

No 300 (97) 300 (97)

Progression

n 89 66

From CDC Stage I to CDC Stage II 81 (26) 58 (19)

From CDC Stage I to CDC Stage III 4 (1) 3 (1)

From CDC Stage II to CDC Stage III 4 (1) 4 (1)

From CDC Stage III to new CDC Stage III 0 0

From CDC Stage I, II or III to death 0 1 (<1)

CDC denotes Centers for Disease Control.

20

Table S4. Confirmed Virologic Failure.

Treatment Arm

HIV-1

Subtype

On-Treatment RAMs (HIV-1 RNA)

SVF Timepoint

Drug Sensitivity (Fold Change) at

SVF Timepoint*

Baseline RAMs

(PBMC/HIV-1 DNA on Day 1)

NRTI NNRTI PI INSTI NRTI NNRTI INSTI RT INSTI

1 LA A/A1 none E138A none none none RPV (2.4) none E138E/A none

2 LA A1/A none E138E/K none N155H none

DLV (30)

EFV (3.3)

ETR (5.2)

NVP (11)

RPV (6.5)

RAL (16)

EVG (33)

CAB (2.7)

none none

3 LA AG none V108I

E138K N88N/S none none

DLV (15)

EFV (4.2)

ETR (5.8)

NVP (16)

RPV (3.7)

none V108V/I

E138K none

4 CAR

(EFV+3TC+AZT) A1 M184V G190S none none Phenotypic assay failed for RT/PR none M184M/I none

5 CAR

(EVG/c+FTC+TDF) B M184I none none none

3TC (>97.2)

FTC (>97.2) none none none none

6 CAR

(EVG/c+FTC+TAF) B none none none none none none none none none

7 CAR

EVG/c+FTC+TDF B none M230M/I none none none none none none none

3TC denotes lamivudine; AZT, zidovudine; c, cobicistat; CAB, cabotegravir; CAR, current antiretroviral therapy; DLV, delavirdine; EFV, efavirenz; ETR, etravirine; EVG, elvitegravir; FTC, emtricitabine; LA, long acting; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NPV, nevirapine; NRTI, nucleoside reverse-transcriptase inhibitor; PBMC, peripheral blood mononuclear cell; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; RAM, resistance-associated mutation; RPV, rilpivirine; RT, reverse transcriptase; SVF, suspected virologic failure; TAF, tenofovir alafenamide; and TDF, tenofovir.

*Fold change in sensitivity data are provided for compounds with values above the biological cut-off or the lower clinical cut-off; cut-off values are from Monogram Biosciences. The INSTI bictegravir was not available at the time of testing.

Genotypic and phenotypic resistance was assessed using GenoSure Archive®, Phenosense GT®, GenoSeq® Integrase, and PhenoSeq® Integrase (Monogram Biosciences).

21

Table S5. Participants With On-treatment Adverse Events by System Organ Class and Maximum Toxicity Grade – Maintenance Phase

Maximum Toxicity Grade*

LA Arm, N=308 CAR Arm, N=308

System Organ Class and Event

no. participants (%) no. participants (%)

1 2 3 4 5 Total 1 2 3 4 5 Total

Participants with any event 100 (32) 158 (51) 27 (9) 8 (3) 0 293 (95) 115 (37) 81 (26) 19 (6) 4 (1) 1 (<1) 220 (71)

General disorders and administration site conditions Any event 135 (44) 106 (34) 11 (4) 0 0 252 (82) 17 (6) 5 (2) 0 0 0 22 (7) Injection site pain 130 (42) 91 (30) 10 (3) 0 0 231 (75) 0 0 0 0 0 0 Injection site nodule 33 (11) 4 (1) 0 0 0 37 (12) 0 0 0 0 0 0 Injection site induration 20 (6) 9 (3) 1 (<1) 0 0 30 (10) 0 0 0 0 0 0 Injection site swelling 16 (5) 7 (2) 0 0 0 23 (7) 0 0 0 0 0 0

Fatigue 20 (6) 2 (<1) 0 0 0 22 (7) 5 (2) 1 (<1) 0 0 0 6 (2) Pyrexia 17 (6) 3 (<1) 1 (<1) 0 0 21 (7) 8 (3) 1 (<1) 0 0 0 9 (3) Injection site erythema 12 (4) 1 (<1) 0 0 0 13 (4) 0 0 0 0 0 0 Influenza-like illness 6 (2) 5 (2) 0 0 0 11 (4) 3 (<1) 0 0 0 0 3 (<1) Injection site bruising 8 (3) 2 (<1) 0 0 0 10 (3) 0 0 0 0 0 0 Chills 5 (2) 3 (<1) 0 0 0 8 (3) 0 0 0 0 0 0

Pain 6 (2) 2 (<1) 0 0 0 8 (3) 0 1 (<1) 0 0 0 1 (<1) Injection site hematoma 5 (2) 2 (<1) 0 0 0 7 (2) 0 0 0 0 0 0 Injection site pruritus 7 (2) 0 0 0 0 7 (2) 0 0 0 0 0 0 Asthenia 6 (2) 0 0 0 0 6 (2) 0 0 0 0 0 0 Injection site warmth 6 (2) 0 0 0 0 6 (2) 0 0 0 0 0 0 Injection site reaction 3 (<1) 1 (<1) 0 0 0 4 (1) 0 0 0 0 0 0

Discomfort 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Feeling hot 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Malaise 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Chest pain 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Cyst 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Feeling of body temp change 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Injection site anesthesia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Injection site discomfort 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Injection site discoloration 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Peripheral edema 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Vessel puncture site pain 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Chest discomfort 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Non-cardiac chest pain 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Peripheral swelling 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

22





1 2 3 4 5 Total 1 2 3 4 5 Total

Infections and infestations Any event 125 (41) 58 (19) 3 (<1) 3 (<1) 0 189 (61) 111 (36) 50 (16) 2 (<1) 1 (<1) 0 164 (53) Nasopharyngitis 40 (13) 12 (4) 0 0 0 52 (17) 39 (13) 3 (<1) 0 0 0 42 (14) Upper respiratory tract infection 25 (8) 7 (2) 0 0 0 32 (10) 23 (7) 2 (<1) 0 0 0 25 (8) Influenza 16 (5) 1 (<1) 0 0 0 17 (6) 9 (3) 5 (2) 0 0 0 14 (5) Bronchitis 9 (3) 4 (1) 0 0 0 13 (4) 7 (2) 5 (2) 0 0 0 12 (4)

Viral respiratory tract infection 7 (2) 4 (1) 0 0 0 11 (4) 13 (4) 4 (1) 0 0 0 17 (6) Urinary tract infection 10 (3) 1 (<1) 0 0 0 11 (4) 6 (2) 2 (<1) 0 0 0 8 (3) Respiratory tract infection 10 (3) 0 0 0 0 10 (3) 11 (4) 1 (<1) 0 0 0 12 (4) Pharyngitis 5 (2) 3 (<1) 0 0 0 8 (3) 9 (3) 3 (<1) 0 0 0 12 (4) Sinusitis 7 (2) 1 (<1) 0 0 0 8 (3) 2 (<1) 3 (<1) 0 0 0 5 (2) Tonsillitis 4 (1) 4 (1) 0 0 0 8 (3) 2 (<1) 2 (<1) 0 0 0 4 (1)

Conjunctivitis 6 (2) 1 (<1) 0 0 0 7 (2) 3 (<1) 0 0 0 0 3 (<1) Gonorrhea 6 (2) 0 0 0 0 6 (2) 3 (<1) 1 (<1) 0 0 0 4 (1) Herpes zoster 1 (<1) 5 (2) 0 0 0 6 (2) 1 (<1) 2 (<1) 0 0 0 3 (<1) Lower respiratory tract infection 6 (2) 0 0 0 0 6 (2) 4 (1) 1 (<1) 0 0 0 5 (2) Viral upper respir tract infection 5 (2) 1 (<1) 0 0 0 6 (2) 3 (<1) 0 0 0 0 3 (<1) Chlamydial infection 5 (2) 0 0 0 0 5 (2) 2 (<1) 1 (<1) 0 0 0 3 (<1)

Gastroenteritis 5 (2) 0 0 0 0 5 (2) 9 (3) 1 (<1) 0 0 0 10 (3) Viral gastroenteritis 5 (2) 0 0 0 0 5 (2) 1 (<1) 0 0 0 0 1 (<1) Oral herpes 4 (1) 1 (<1) 0 0 0 5 (2) 5 (2) 0 0 0 0 5 (2) Furuncle 3 (<1) 1 (<1) 0 0 0 4 (1) 1 (<1) 0 0 0 0 1 (<1) Rhinitis 3 (<1) 1 (<1) 0 0 0 4 (1) 2 (<1) 3 (<1) 0 0 0 5 (2) Syphilis 2 (<1) 2 (<1) 0 0 0 4 (1) 7 (2) 2 (<1) 0 0 0 9 (3)

Acarodermatitis 1 (<1) 2 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0 Acute sinusitis 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0 Cellulitis 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0 Cystitis 0 3 (<1) 0 0 0 3 (<1) 1 (<1) 0 0 0 0 1 (<1) Injection site abscess 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0 Otitis media 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0

Tinea versicolor 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0 Tooth infection 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0 Candida infection 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Fungal infection 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Fungal skin infection 2 (<1) 0 0 0 0 2 (<1) 0 2 (<1) 0 0 0 2 (<1) Genital herpes 0 2 (<1) 0 0 0 2 (<1) 2 (<1) 2 (<1) 0 0 0 4 (1)

Genital herpes simplex 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0

23





1 2 3 4 5 Total 1 2 3 4 5 Total Hepatitis A 0 1 (<1) 1 (<1) 0 0 2 (<1) 0 0 0 1 (<1) 0 1 (<1) Herpes simplex 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 2 (<1) 0 0 0 3 (<1) Hordeolum 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Impetigo 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Injection site cellulitis 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Oropharyngeal gonococcal infection

1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0

Paronychia 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Gonococcal proctitis 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Secondary syphilis 0 2 (<1) 0 0 0 2 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Gonococcal urethritis 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Viral infection 1 (<1) 0 1 (<1) 0 0 2 (<1) 0 0 0 0 0 0 Abscess 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Acute hepatitis B 0 0 0 1 (<1) 0 1 (<1) 0 0 0 0 0 0 Acute hepatitis C 0 0 0 1 (<1) 0 1 (<1) 0 0 0 0 0 0 Amebiasis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Anal abscess 0 1 (<1) 0 0 0 1 (<1) 0 0 1 (<1) 0 0 1 (<1) Anal chlamydia infection 1 (<1) 0 0 0 0 1 (<1) 0 2 (<1) 0 0 0 2 (<1) Anal infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Anorectal human papillomavirus 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Cervicitis human papillomavirus 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Chronic tonsillitis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Clostridium difficile colitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Folliculitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Gastric infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Escherichia coli gastroenteritis 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Gastrointestinal viral infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Gingival abscess 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Herpesvirus infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Infected bite 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Liver abscess 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0

Localized infection 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Nasal herpes 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Onychomycosis 0 1 (<1) 0 0 0 1 (<1) 2 (<1) 1 (<1) 0 0 0 3 (<1) Periodontitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Pertussis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Pneumonia 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 3 (<1) 0 0 0 4 (1)

24





1 2 3 4 5 Total 1 2 3 4 5 Total

Postprocedural infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Chlamydial proctitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Pulpitis dental 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Acute pyelonephritis 0 0 0 1 (<1) 0 1 (<1) 0 0 0 0 0 0 Rotavirus infection 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Skin candida 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Staphylococcal infection 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Tinea cruris 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Tinea infection 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Tinea pedis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Tooth abscess 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Ureaplasma infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Urethritis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Chlamydial urethritis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vaginal infection 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Tracheitis 0 0 0 0 0 0 2 (<1) 1 (<1) 0 0 0 3 (<1) Body tinea 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1) Ear infection 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1)

Orchitis 0 0 0 0 0 0 0 2 (<1) 0 0 0 2 (<1) Acute otitis media 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1) Subcutaneous abscess 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1) Acute sinusitis 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1) Appendicitis 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) Bacterial conjunctivitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Infectious enteritis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Epididymitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Gastrointestinal infection 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Groin abscess 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Infection 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Angular cheilitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Gastrointestinal disorders Any event 48 (16) 23 (7) 3 (<1) 0 0 74 (24) 29 (9) 15 (5) 2 (<1) 0 0 46 (15) Diarrhea 14 (5) 7 (2) 1 (<1) 0 0 22 (7) 13 (4) 2 (<1) 0 0 0 15 (5) Nausea 10 (3) 3 (<1) 1 (<1) 0 0 14 (5) 1 (<1) 4 (1) 0 0 0 5 (2) Dyspepsia 4 (1) 2 (<1) 0 0 0 6 (2) 2 (<1) 0 0 0 0 2 (<1) Vomiting 4 (1) 1 (<1) 1 (<1) 0 0 6 (2) 1 (<1) 3 (<1) 0 0 0 4 (1)

Abdominal pain 2 (<1) 2 (<1) 1 (<1) 0 0 5 (2) 1 (<1) 0 0 0 0 1 (<1)

25





1 2 3 4 5 Total 1 2 3 4 5 Total Gastroesophageal reflux disease 4 (1) 1 (<1) 0 0 0 5 (2) 1 (<1) 1 (<1) 0 0 0 2 (<1) Toothache 3 (<1) 2 (<1) 0 0 0 5 (2) 4 (1) 2 (<1) 0 0 0 6 (2) Constipation 4 (1) 0 0 0 0 4 (1) 3 (<1) 0 0 0 0 3 (<1) Flatulence 3 (<1) 1 (<1) 0 0 0 4 (1) 0 0 0 0 0 0 Hemorrhoids 3 (<1) 1 (<1) 0 0 0 4 (1) 2 (<1) 0 0 0 0 2 (<1) Gastritis 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0

Lower abdominal pain 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Upper abdominal pain 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Anal fissure 0 2 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Aphthous ulcer 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Dental caries 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Abdominal discomfort 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1)

Abdominal distension 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Abdominal hernia 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Anorectal discomfort 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Chronic gastritis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Enteritis 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Eosinophilic esophagitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0

Inguinal hernia 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Dry lip 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Lip swelling 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Odynophagia 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Oral pain 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Pancreatitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0

Acute pancreatitis 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Proctitis 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 3 (<1) 0 0 0 4 (1) Ulcerative proctitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Impacted tooth 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Umbilical hernia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Colitis 0 0 0 0 0 0 0 0 2 (<1) 0 0 2 (<1)

Food poisoning 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1) Anal pruritus 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Anal skin tags 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Dysphagia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Epigastric discomfort 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Functional gastrointestinal disorder 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Gingival disorder 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

26





1 2 3 4 5 Total 1 2 3 4 5 Total Thrombosed hemorrhoids 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Irritable bowel syndrome 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Mouth ulceration 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Oral disorder 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Chronic pancreatitis 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Rectal hemorrhage 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Steatorrhea 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Tongue ulceration 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Musculoskeletal and connective tissue disorders Any event 47 (15) 21 (7) 1 (<1) 0 0 69 (22) 27 (9) 15 (5) 1 (<1) 0 0 43 (14) Back pain 11 (4) 10 (3) 0 0 0 21 (7) 9 (3) 1 (<1) 0 0 0 10 (3) Myalgia 8 (3) 2 (<1) 0 0 0 10 (3) 2 (<1) 1 (<1) 0 0 0 3 (<1) Arthralgia 5 (2) 0 1 (<1) 0 0 6 (2) 7 (2) 1 (<1) 0 0 0 8 (3) Pain in extremity 3 (<1) 3 (<1) 0 0 0 6 (2) 6 (2) 2 (<1) 0 0 0 8 (3)

Musculoskeletal pain 3 (<1) 2 (<1) 0 0 0 5 (2) 5 (2) 4 (1) 0 0 0 9 (3) Neck pain 3 (<1) 1 (<1) 0 0 0 4 (1) 0 0 0 0 0 0 Tendonitis 3 (<1) 1 (<1) 0 0 0 4 (1) 0 0 0 0 0 0 Musculoskeletal chest pain 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 1 (<1) 0 0 0 1 (<1) Spinal pain 3 (<1) 0 0 0 0 3 (<1) 0 0 0 0 0 0 Bursitis 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0

Intervertebral disc protrusion 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Joint swelling 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Muscle contracture 1 (<1) 1 (<1) 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Muscle spasms 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 2 (<1) 0 0 0 4 (1) Osteoarthritis 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Arthropathy 0 1 (<1) 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1)

Costochondritis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dupuytren's contracture 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Exostosis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Flank pain 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Foot deformity 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Myositis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0

Osteopenia 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Patellofemoral pain syndrome 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Polyarthritis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Scoliosis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Temporomandibular joint syndrome 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

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1 2 3 4 5 Total 1 2 3 4 5 Total Tenosynovitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Arthritis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Intervertebral disc disorder 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Joint effusion 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Muscle tightness 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Musculoskeletal discomfort 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Osteonecrosis 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Rhabdomyolysis 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) Spinal osteoarthritis 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Synovial cyst 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Nervous system disorders Any event 48 (16) 14 (5) 2 (<1) 0 0 64 (21) 24 (8) 10 (3) 1 (<1) 0 0 35 (11) Headache 26 (8) 6 (2) 2 (<1) 0 0 34 (11) 12 (4) 5 (2) 0 0 0 17 (6) Dizziness 9 (3) 0 0 0 0 9 (3) 4 (1) 1 (<1) 0 0 0 5 (2) Sciatica 5 (2) 2 (<1) 0 0 0 7 (2) 1 (<1) 0 0 0 0 1 (<1) Migraine 2 (<1) 2 (<1) 0 0 0 4 (1) 1 (<1) 0 0 0 0 1 (<1)

Paraesthesia 4 (1) 0 0 0 0 4 (1) 2 (<1) 0 0 0 0 2 (<1) Neuralgia 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Presyncope 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Syncope 0 2 (<1) 0 0 0 2 (<1) 0 1 (<1) 0 0 0 1 (<1) Anterograde amnesia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Autonomic nervous system imbalance

1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Burning sensation 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Cervicobrachial syndrome 0 1 (<1) 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Cognitive disorder 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Disturbance in attention 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dysesthesia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Essential tremor 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Intercostal neuralgia 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Loss of consciousness 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Memory impairment 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Involuntary muscle contractions 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Neuromuscular blockade 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Postherpetic neuralgia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Somnolence 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Tension headache 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

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1 2 3 4 5 Total 1 2 3 4 5 Total Hypoesthesia 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Peripheral neuropathy 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Cerebral cyst 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Cerebrovascular accident 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Dysgeusia 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Dystonia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Facial paralysis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Posttraumatic headache 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Seizure 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1)

Injury, poisoning and procedural complications Any event 19 (6) 18 (6) 0 0 0 37 (12) 19 (6) 9 (3) 2 (<1) 0 1 (<1) 31 (10) Ligament sprain 5 (2) 1 (<1) 0 0 0 6 (2) 1 (<1) 1 (<1) 0 0 0 2 (<1) Arthropod bite 2 (<1) 1 (<1) 0 0 0 3 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Contusion 2 (<1) 1 (<1) 0 0 0 3 (<1) 2 (<1) 1 (<1) 0 0 0 3 (<1) Muscle strain 2 (<1) 1 (<1) 0 0 0 3 (<1) 4 (1) 1 (<1) 0 0 0 5 (2)

Epicondylitis 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Exposure to communicable disease

1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1)

Injection-related reaction 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Road traffic accident 0 2 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Upper limb fracture 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Animal bite 1 (<1) 0 0 0 0 1 (<1) 0 0 1 (<1) 0 0 1 (<1)

Bone contusion 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Buttock injury 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Facial bones fracture 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Hand fracture 0 1 (<1) 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Humerus fracture 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Corneal injury 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0

Joint dislocation 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Limb injury 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Meniscus injury 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Procedural pain 0 1 (<1) 0 0 0 1 (<1) 2 (<1) 1 (<1) 0 0 0 3 (<1) Radius fracture 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Skin abrasion 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Skin injury 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Soft tissue injury 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Thermal burn 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1)

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1 2 3 4 5 Total 1 2 3 4 5 Total Tooth fracture 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Eye injury 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) Foot fracture 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Ligament rupture 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Overdose 0 0 0 0 0 0 0 0 0 0 1 (<1) 1 (<1) Postprocedural complication 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Rib fracture 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Skull fracture 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) Splinter 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Tendon rupture 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Investigations Any event 15 (5) 9 (3) 7 (2) 5 (2) 0 36 (12) 10 (3) 7 (2) 5 (2) 1 (<1) 0 23 (7) Blood creatine phosphokinase increased

2 (<1) 2 (<1) 1 (<1) 1 (<1) 0 6 (2) 2 (<1) 2 (<1) 0 0 0 4 (1)

Lipase increased 1 (<1) 0 3 (<1) 2 (<1) 0 6 (2) 1 (<1) 0 0 1 (<1) 0 2 (<1) Creatinine renal clearance decreased 2 (<1) 3 (<1) 0 0 0 5 (2) 1 (<1) 2 (<1) 0 0 0 3 (<1) Alanine aminotransferase increased 3 (<1) 1 (<1) 0 0 0 4 (1) 1 (<1) 0 0 0 0 1 (<1)

Body temperature increased 4 (1) 0 0 0 0 4 (1) 0 0 0 0 0 0 Aspartate aminotransferase increased 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 1 (<1) 0 0 0 1 (<1) Blood pressure increased 3 (<1) 0 0 0 0 3 (<1) 0 0 0 0 0 0 Electrocardiogram QT prolonged 2 (<1) 1 (<1) 0 0 0 3 (<1) 0 0 0 0 0 0 Activated partial thromboplastin time prolonged

1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Blood bilirubin increased 0 0 0 1 (<1) 0 1 (<1) 0 0 0 0 0 0

Blood glucose increased 0 1 (<1) 0 0 0 1 (<1) 0 0 2 (<1) 0 0 2 (<1) Blood phosphorus decreased 0 0 1 (<1) 0 0 1 (<1) 0 0 1 (<1) 0 0 1 (<1) Blood triglycerides 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Glycosylated hemoglobin increased 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Liver function test abnormal 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Neisseria test positive 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0

Free thyroxine decreased 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Transaminases increased 0 0 0 1 (<1) 0 1 (<1) 0 0 0 0 0 0 Vitamin D decreased 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Weight increased 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Blood cholesterol increased 0 0 0 0 0 0 1 (<1) 2 (<1) 1 (<1) 0 0 4 (1) Blood creatinine decreased 0 0 0 0 0 0 3 (<1) 0 0 0 0 3 (<1)

Low density lipoprotein increased 0 0 0 0 0 0 2 (<1) 1 (<1) 0 0 0 3 (<1)

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1 2 3 4 5 Total 1 2 3 4 5 Total Blood pressure increased 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Blood triglycerides increased 0 0 0 0 0 0 1 (<1) 0 1 (<1) 0 0 2 (<1) Weight decreased 0 0 0 0 0 0 1 (<1) 0 1 (<1) 0 0 2 (<1) Blood creatinine increased 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) ECG signs of ventricular hypertrophy 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Hepatic enzyme increased 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Lipids increased 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Pancreatic enzymes increased 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Respiratory, thoracic and mediastinal disorders Any event 30 (10) 6 (2) 0 0 0 36 (12) 24 (8) 12 (4) 0 0 0 36 (12) Cough 14 (5) 2 (<1) 0 0 0 16 (5) 11 (4) 3 (<1) 0 0 0 14 (5) Oropharyngeal pain 9 (3) 0 0 0 0 9 (3) 9 (3) 2 (<1) 0 0 0 11 (4) Sinus congestion 3 (<1) 1 (<1) 0 0 0 4 (1) 2 (<1) 0 0 0 0 2 (<1) Catarrh 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1)

Dysphonia 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Nasal congestion 2 (<1) 0 0 0 0 2 (<1) 4 (1) 0 0 0 0 4 (1) Productive cough 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Respiratory disorder 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 1 (<1) 0 0 0 3 (<1) Rhinorrhea 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Dyspnea 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1)

Emphysema 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Lower respiratory tract congestion 0 1 (<1) 0 0 0 1 (<1) 0 2 (<1) 0 0 0 2 (<1) Nasal obstruction 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Nasal septum deviation 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Pulmonary mass 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Reflux laryngitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Respiratory tract congestion 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Sinus pain 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Asthma 0 0 0 0 0 0 0 2 (<1) 0 0 0 2 (<1) Allergic rhinitis 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Bronchospasm 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Lung disorder 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Pneumonitis 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Respiratory distress 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Respiratory tract congestion 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Sleep apnea syndrome 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Wheezing 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

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1 2 3 4 5 Total 1 2 3 4 5 Total

Skin and subcutaneous tissue disorders Any event 31 (10) 5 (2) 0 0 0 36 (12) 20 (6) 2 (<1) 0 0 0 22 (7) Rash 10 (3) 1 (<1) 0 0 0 11 (4) 4 (1) 0 0 0 0 4 (1) Pruritus 5 (2) 1 (<1) 0 0 0 6 (2) 3 (<1) 0 0 0 0 3 (<1) Eczema 3 (<1) 1 (<1) 0 0 0 4 (1) 1 (<1) 0 0 0 0 1 (<1) Acne 3 (<1) 0 0 0 0 3 (<1) 1 (<1) 0 0 0 0 1 (<1)

Seborrheic dermatitis 3 (<1) 0 0 0 0 3 (<1) 0 0 0 0 0 0 Alopecia 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Dermal cyst 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Generalized rash 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Pruritic rash 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Acneiform dermatitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Contact dermatitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Ecchymosis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Nail bed bleeding 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Onychoclasis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Purpura 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Erythematous rash 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0

Maculopapular rash 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Skin mass 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Urticaria 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Decubitus ulcer 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Dermatitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Intertrigo 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Neurodermatitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Photosensitivity reaction 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Generalized pruritus 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Sebaceous hyperplasia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Seborrhea 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Skin fissures 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Skin lesion 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Stasis dermatitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Psychiatric disorders Any event 20 (6) 12 (4) 0 0 0 32 (10) 14 (5) 8 (3) 2 (<1) 0 0 24 (8) Insomnia 11 (4) 4 (1) 0 0 0 15 (5) 4 (1) 0 0 0 0 4 (1) Anxiety 6 (2) 2 (<1) 0 0 0 8 (3) 4 (1) 2 (<1) 1 (<1) 0 0 7 (2) Abnormal dreams 3 (<1) 0 0 0 0 3 (<1) 2 (<1) 0 0 0 0 2 (<1)

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1 2 3 4 5 Total 1 2 3 4 5 Total Depression 0 3 (<1) 0 0 0 3 (<1) 2 (<1) 3 (<1) 1 (<1) 0 0 6 (2) Sleep disorder 2 (<1) 1 (<1) 0 0 0 3 (<1) 2 (<1) 0 0 0 0 2 (<1) Depressed mood 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Drug abuse 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 1 (<1) 0 0 0 1 (<1)

Acute stress disorder 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Adjustment disorder 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Affect lability 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Depression suicidal 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Irritability 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Mood altered 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Mood swings 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Suicidal behavior 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Suicidal ideation 0 1 (<1) 0 0 0 1 (<1) 0 1 (<1) 1 (<1) 0 0 2 (<1) Stress 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Anxiety disorder 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) Drug dependence 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Panic disorder 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Suicide attempt 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Tension 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Thinking abnormal 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Reproductive system and breast disorders Any event 10 (3) 5 (2) 1 (<1) 0 0 16 (5) 4 (1) 3 (<1) 0 0 0 7 (2) Benign prostatic hyperplasia 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Cervical dysplasia 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Menorrhagia 2 (<1) 0 0 0 0 2 (<1) 0 1 (<1) 0 0 0 1 (<1) Adenomyosis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0

Balanoposthitis 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Dysfunctional uterine bleeding 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dysmenorrhea 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Genital erythema 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Menometrorrhagia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Menstrual disorder 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Metrorrhagia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Ovarian cyst ruptured 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Penile pain 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vaginal discharge 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vaginal hemorrhage 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

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1 2 3 4 5 Total 1 2 3 4 5 Total Breast cyst 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Breast mass 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Breast pain 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Scrotal mass 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Metabolism and nutrition disorders Any event 9 (3) 4 (1) 1 (<1) 0 0 14 (5) 18 (6) 7 (2) 2 (<1) 0 0 27 (9) Vitamin D deficiency 7 (2) 1 (<1) 0 0 0 8 (3) 11 (4) 1 (<1) 0 0 0 12 (4) Hypophosphatemia 0 1 (<1) 1 (<1) 0 0 2 (<1) 0 0 0 0 0 0 Increased appetite 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Decreased appetite 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1)

Dehydration 0 1 (<1) 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Hypercholesterolemia 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 3 (<1) 0 0 0 4 (1) Hypokalemia 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Vitamin B12 deficiency 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Gout 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Hyperglycemia 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1)

Hypertriglyceridemia 0 0 0 0 0 0 0 0 2 (<1) 0 0 2 (<1) Diabetes mellitus 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Diabetic ketoacidosis 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Impaired fasting glucose 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Type 2 diabetes mellitus 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vitamin B6 deficiency 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Vascular disorders Any event 9 (3) 4 (1) 0 0 0 13 (4) 4 (1) 3 (<1) 0 0 0 7 (2) Hypertension 5 (2) 4 (1) 0 0 0 9 (3) 1 (<1) 2 (<1) 0 0 0 3 (<1) Hot flush 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Orthostatic hypotension 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Phlebitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Varicose vein 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Deep vein thrombosis 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Hypertensive crisis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Varicophlebitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Venous thrombosis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Renal and urinary disorders Any event 8 (3) 3 (<1) 1 (<1) 0 0 12 (4) 3 (<1) 3 (<1) 0 0 0 6 (2) Dysuria 4 (1) 0 0 0 0 4 (1) 2 (<1) 0 0 0 0 2 (<1) Pollakiuria 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1)

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1 2 3 4 5 Total 1 2 3 4 5 Total Renal colic 0 2 (<1) 0 0 0 2 (<1) 0 1 (<1) 0 0 0 1 (<1) Chronic kidney disease 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Hematuria 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Proteinuria 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1)

Renal impairment 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Urethral discharge 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Micturition urgency 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Blood and lymphatic system disorders Any event 7 (2) 2 (<1) 0 0 0 9 (3) 7 (2) 3 (<1) 1 (<1) 1 (<1) 0 12 (4) Anemia 2 (<1) 2 (<1) 0 0 0 4 (1) 3 (<1) 1 (<1) 1 (<1) 0 0 5 (2) Lymphadenopathy 3 (<1) 0 0 0 0 3 (<1) 0 0 0 0 0 0 Iron deficiency anemia 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Microcytic anemia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Anemia folate deficiency 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Deficiency anemia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Eosinophilia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Leukocytosis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Neutropenia 0 0 0 0 0 0 0 0 0 1 (<1) 0 1 (<1) Thrombocytopenia 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Neoplasms benign, malignant and unspecified, including cysts and polyps Any event 4 (1) 4 (1) 1 (<1) 0 0 9 (3) 4 (1) 0 2 (<1) 1 (<1) 0 7 (2) Anogenital warts 2 (<1) 2 (<1) 0 0 0 4 (1) 2 (<1) 0 1 (<1) 0 0 3 (<1) Lipoma 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Basal cell carcinoma 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Melanocytic nevus 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Papillary thyroid cancer 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Skin papilloma 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Squamous cell carcinoma of skin 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Fibrous histiocytoma 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Knuckle pads 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Seminoma 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1)

Squamous cell carcinoma 0 0 0 0 0 0 0 0 0 1 (<1) 0 1 (<1)

Ear and labyrinth disorders Any event 7 (2) 0 0 0 0 7 (2) 2 (<1) 0 0 0 0 2 (<1) Vertigo 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Deafness 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Ear pain 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

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1 2 3 4 5 Total 1 2 3 4 5 Total Excessive cerumen production 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Tinnitus 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Positional vertigo 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Ear discomfort 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Eye disorders Any event 7 (2) 0 0 0 0 7 (2) 8 (3) 2 (<1) 0 0 0 10 (3) Blepharitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Cataract 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Conjunctival hemorrhage 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Allergic conjunctivitis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1)

Eye pruritus 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Eye swelling 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vision blurred 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Chalazion 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Eyelid edema 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Subcapsular cataract 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Dry eye 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Eye pain 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Lacrimation increased 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Ocular hyperemia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vitreous hematoma 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Immune system disorders Any event 3 (<1) 3 (<1) 0 0 0 6 (2) 2 (<1) 0 0 0 0 2 (<1) Allergy to animal 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Seasonal allergy 1 (<1) 1 (<1) 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Drug hypersensitivity 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Mycotic allergy 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

Cardiac disorders Any Event 4 (1) 0 0 0 0 4 (1) 1 (<1) 0 0 0 0 1 (<1) Bradycardia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Cardiovascular disorder 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Palpitations 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Ventricular extrasystoles 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Sinus tachycardia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Hepatobiliary disorders Any event 1 (<1) 1 (<1) 0 1 (<1) 0 3 (<1) 0 0 0 0 0 0 Biliary tract disorder 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

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1 2 3 4 5 Total 1 2 3 4 5 Total Acute cholecystitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Hepatocellular injury 0 0 0 1 (<1) 0 1 (<1) 0 0 0 0 0 0 Hyperbilirubinemia 0 0 0 1 (<1) 0 1 (<1) 0 0 0 0 0 0

Endocrine disorders Any event 1 (<1) 1 (<1) 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Hypothyroidism 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Thyroid mass 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hypogonadism 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Social circumstances Any event 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Menopause 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Stress at work 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

Pregnancy puerperium and perinatal conditions Any event 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Spontaneous abortion 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Surgical and medical procedures Any event 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Dental implantation 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

*Toxicity grades were assigned according to criteria developed by the Division of AIDS, US Department of Health and Human Services, National Institutes of Health.3 CAR denotes current antiretroviral therapy, and LA long-acting.

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Table S6. Serious Adverse Events – Maintenance Phase.

LA Arm

N=308

CAR Arm

N=308

Event no. participants (%)

Any serious adverse event 6 (2) 4 (1)

Hepatitis A 1 (<1) 1 (<1)

Acute hepatitis B 1 (<1) 0

Escherichia coli gastroenteritis 1 (<1) 0

Liver abscess 1 (<1) 0

Acute pyelonephritis 1 (<1) 0

Viral infection 1 (<1) 0

Acute pancreatitis 1 (<1) 0

Vomiting 1 (<1) 0

Papillary thyroid cancer 1 (<1) 0

Acute cholecystitis 1 (<1) 0

Hepatocellular injury 1 (<1) 0

Hyperbilirubinemia 1 (<1) 0

Missed abortion 1 (<1) 0

Abnormal liver function test 1 (<1) 0

Back pain 1 (<1) 0

Anal abscess 0 1 (<1)

Appendicitis 0 1 (<1)

Pneumonia 0 1 (<1)

Colitis 0 2 (<1)

Animal bite 0 1 (<1)

Eye injury 0 1 (<1)

Overdose 0 1 (<1)

Skull fracture 0 1 (<1)

Anogenital warts 0 1 (<1)

Seminoma 0 1 (<1)

Spontaneous abortion 0 1 (<1)

Chest discomfort 0 1 (<1)

Cerebrovascular accident 0 1 (<1)

Suicidal ideation 0 1 (<1)

Respiratory distress 0 1 (<1)

Some participants experienced multiple serious adverse events.

CAR denotes current antiretroviral therapy, and LA long-acting.

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Table S7. Adverse Events Leading to Withdrawal – Maintenance Phase.

Event

LA Arm

N=308

CAR Arm

N=308

no. participants (%)

Any event* 14 (5%) 5 (2%)

Injection site pain 4 (1%) 0

Hepatitis A 2 (<1%) 0

Headache 2 (<1%) 0

Asthenia 1 (<1%) 0

Injection site nodule 1 (<1%) 0

Injection site swelling 1 (<1%) 0

Acute hepatitis B 1 (<1%) 0

Memory impairment 1 (<1%) 0

Anxiety 1 (<1%) 0

Anxiety disorder 0 1 (<1%)

Depression 0 1 (<1%)

Depression suicidal 1 (<1%) 0

Suicidal ideation 0 1 (<1%)

Colitis 0 1 (<1%)

Diarrhea 1 (<1%) 0

Nausea 1 (<1%) 0

Blood creatinine increased 0 1 (<1%)

Liver function test abnormal 1 (<1%) 0

Hepatocellular injury 1 (<1%) 0

Hyperbilirubinemia 1 (<1%) 0

Overdose 0 1 (<1%)

Myalgia 1 (<1%) 0

Renal impairment 0 1 (<1%)

Some participants discontinued due to multiple adverse events.


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Table S8. On-treatment Laboratory Abnormalities by Maximum Toxicity Grade – Maintenance Phase

Maximum Toxicity Grade LA Arm, N=308 CAR Arm, N=308


Event 1 2 3 4 Total 1 2 3 4 Total

Chemistry

Alanine aminotransferase (IU/L) 38 (12) 4 (1) 1 (<1) 3 (<1) 46 (15) 28 (9) 4 (1) 0 1 (<1) 33 (11)

Albumin (g/L) 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

Alkaline phosphatase (IU/L) 3 (<1) 1 (<1) 0 0 4 (1) 6 (2) 1 (<1) 0 0 7 (2)

Aspartate aminotransferase (IU/L) 30 (10) 10 (3) 6 (2) 1 (<1) 47 (15) 26 (8) 5 (2) 0 0 31 (10)

Bilirubin (µmol/L) 19 (6) 2 (<1) 0 1 (<1) 22 (7) 9 (3) 6 (2) 0 2 (<1) 17 (6)

Carbon dioxide (mmol/L) 71 (23) 5 (2) 0 0 76 (25) 76 (25) 4 (1) 0 0 80 (26)

Cholesterol (mmol/L) 39 (13) 10 (3) 0 0 49 (16) 14 (5) 17 (6) 1 (<1) 0 32 (10)

Creatine kinase (IU/L) 23 (7) 6 (2) 9 (3) 15 (5) 53 (17) 18 (6) 12 (4) 9 (3) 3 (<1) 42 (14)

Creatinine (µmol/L) 5 (2) 0 1 (<1) 0 6 (2) 6 (2) 1 (<1) 0 0 7 (2)

Direct bilirubin (µmol/L) 0 0 6 (2) 0 6 (2) 0 0 8 (3) 0 8 (3)

Estimated GFR† (mL/sec/1.73 m2) 0 84 (27) 7 (2) 1 (<1) 92 (30) 0 82 (27) 8 (3) 0 90 (29)

Glucose (mmol/L) 41 (13) 37 (12) 2 (<1) 0 80 (26) 59 (19) 27 (9) 4 (1) 1 (<1) 91 (30)

Hyperglycemia (mmol/L) 33 (11) 34 (11) 1 (<1) 0 68 (22) 52 (17) 27 (9) 4 (1) 0 83 (27)

Hyperkalemia (mmol/L) 3 (<1) 0 1 (<1) 1 (<1) 5 (2) 6 (2) 0 0 2 (<1) 8 (3)

Hypernatremia (mmol/L) 4 (1) 0 0 0 4 (1) 8 (3) 0 0 0 8 (3)

Hypoglycemia (mmol/L) 10 (3) 4 (1) 1 (<1) 0 15 (5) 12 (4) 0 0 1 (<1) 13 (4)

Hypokalemia (mmol/L) 3 (<1) 1 (<1) 0 0 4 (1) 10 (3) 1 (<1) 0 0 11 (4)

Hyponatremia (mmol/L) 18 (6) 0 0 0 18 (6) 18 (6( 0 0 1 (<1) 19 (6)

LDL cholesterol calculation (mmol/L) 26 (8) 10 (3) 3 (<1) 0 39 (13) 19 (6) 10 (3) 3 (<1) 0 32 (10)

Lipase (U/L) 30 (10) 22 (7) 9 (3) 6 (2) 67 (22) 25 (8) 20 (6) 3 (<1) 5 (2) 53 (17)

Phosphate (mmol/L) 27 (9) 42 (14) 10 (3) 0 79 (26) 37 (12) 43 (14) 14 (5) 0 94 (31)

Potassium (mmol/L) 6 (2) 1 (<1) 1 (<1) 1 (<1) 9 (3) 16 (5) 1 (<1) 0 2 (<1) 19 (6)

Sodium (mmol/L) 22 (7) 0 0 0 22 (7) 26 (8) 0 0 1 (<1) 27 (9)

Triglycerides (mmol/L) 20 (6) 6 (2) 1 (<1) 0 27 (9) 25 (8) 6 (2) 0 0 31 (10)

Hematology

Hemoglobin (g/L) 8 (3) 5 (2) 1 (<1) 0 14 (5) 10 (3) 4 (1) 1 (<1) 0 15 (5)

Leukocytes (109/L) 3 (<1) 1 (<1) 0 0 4 (1) 4 (1) 1 (<1) 0 0 5 (2)

Neutrophils (109/L) 8 (3) 5 (2) 1 (<1) 1 (<1) 15 (5) 5 (2) 4 (1) 1 (<1) 0 10 (3)

Platelets (109/L) 7 (2) 1 (<1) 0 0 8 (3) 4 (1) 2 (<1) 0 0 6 (2)

*Toxicity grades were assigned according to criteria developed by the Division of AIDS, US Department of Health and Human Services, National Institutes of Health.3 †Glomerular filtration rate (GFR) estimated from serum creatinine concentration using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.


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Table S9. Cabotegravir and Rilpivirine Plasma Concentrations in LA Recipients with Confirmed

Virologic Failure.

Cabotegravir Concentration (µg/mL) Rilpivirine Concentration (ng/mL)

Visit Week At SVF Visit,

Participants

with CVF

Overall LA Population,

Geometric Mean

(CVb%) [min, max]

At SVF Visit,

Participants

with CVF

Overall LA Population,

Geometric Mean

(CVb%) [min, max] CVF SVF

1 12 8 0.322 1.23 (77) [0.156, 5.88] 12.5 38.4 (59) [1.9, 180]

2 16 12 0.438 1.70 (50) [0.29, 6.22] 34.1 47.4 (48) [7.7, 189]

3 24 retest 24 2.04 2.26 (49) [0.025, 11.8] 30.6 55.4 (47) [10.6, 255]

Data indicate cabotegravir and rilpivirine plasma concentrations at the visit week at which SVF was

detected in the three LA recipients with CVF. Data for the overall LA population are values at the visit

week corresponding to the time of SVF for each participant.

CVF denotes confirmed virologic failure, LA long-acting, and SVF suspected virologic failure.

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Table S10. Change from Baseline in Total Treatment Satisfaction Score by Visit – Adjusted,

Last Observation Carried Forward.

Treatment

Arm

Study

Week

N

(Observed)

N

(LOCF)

Mean

Score* (SD)

Adjusted Mean

Change from

Baseline (95% CI)

Adjusted Mean

Difference

(95% CI), LA − CAR

LA

Baseline 302 302 55.25 (9.14) - -

24 285 300 61.67 (6.64) 6.43 (5.59, 7.28) 5.39 (4.17, 6.60)

44 277 300 61.31 (6.63) 6.12 (5.21, 7.03) 5.68 (4.37, 6.98)

CAR

Baseline 298 298 55.40 (8.68) - -

24 284 288 56.35 (9.54) 1.05 (0.18, 1.91) -

44 285 294 56.03 (9.83) 0.44 (−0.48, 1.37) -

A statistical comparison between the two treatment groups was performed at each visit for HIVTSQs

using an analysis of covariance model with covariates in the model that included treatment, age,

baseline third agent class, sex at birth, and race and baseline score value. Treatment by baseline

interaction was significant (P<.1), with greater treatment effect for LA vs. CAR with lower baseline levels

of satisfaction.

* The range of possible scores for this analysis was 0 to 66.

CAR denotes current antiretroviral therapy, CI confidence interval, HIVTSQs HIV Treatment Satisfaction

Questionnaire status version, LA long-acting, LOCF last observation carried forward, and SD standard

deviation.

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References

1. Centers for Disease Control and Prevention (CDC). Revised surveillance case definition for HIV

infection-United States, 2014. MMWR Recomm Rep 2014;63(RR-03):1-10.

2. Wensing AM, Calvez V, Günthard HF, et al. 2015 update of the drug resistance mutations in HIV-1.

Top Antivir Med 2015;23:132-41.

3. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0.

Bethesda, MD: 2014. U.S. Department of Health and Human Services, National Institutes of Health,

National Institute of Allergy and Infectious Diseases, Division of AIDS. (Accessed October 21, 2019,

at https://rsc.niaid.nih.gov/sites/default/files/table-for-grading-severity-of-adult-pediatric-adverse-

events.pdf).

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