Supplementary Appendix

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

Supplement to: Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med 2020;382:1124-35. DOI: 10.1056/NEJMoa1909512

Chloe Orkin, et al. Long-acting Cabotegravir and Rilpivirine After Oral Induction for HIV-1 Infection

Contents

Principal Investigators and Study Sites ...... 2 Eligibility criteria ...... 6 Induction and Maintenance Phase Time and Events Schedule ...... 11 Study Endpoints ...... 13 Figure S1. Adherence to LA Dosing Schedule, Maintenance Phase ...... 15 Figure S2. Effects of Baseline Parameters and Stratification Criteria on HIV-1 RNA ≥50 copies/mL at Week 48 (Snapshot)...... 16 Figure S3. Frequency of Injection Site Reactions by Study Week, LA Arm, Safety Population...... 17 Figure S4. Plasma Pharmacokinetic Profiles of Cabotegravir and Rilpivirine for Participants with Confirmed Virologic Failure...... 18 Table S1. Confirmed Virologic Failure (CVF) Through Week 48 ...... 19 Table S2. Prevalence of HIV-1 Subtypes and L74I at Baseline (ITT-E Population) ...... 20 Table S3. Participants With Adverse Events by System Organ Class and Maximum Toxicity Grade – Maintenance Phase ...... 22 Table S4. Serious Adverse Events – Maintenance Phase ...... 42 Table S5. Adverse Events Leading to Withdrawal – Maintenance Phase ...... 43 Table S6. Emergent Laboratory Abnormalities by Maximum Toxicity Grade – Maintenance Phase ...... 44 Table S7. Patient-Reported Outcomes ...... 45 References ...... 46

Principal Investigators and Study Sites

Lead Investigator Site USA 1 Judith Aberg Icahn School of Medicine at Mount Sinai, New York, NY 2 John Baxter Cooper Health System, Camden, NJ 3 Chris Bettacchi North Texas Infectious Disease Consultants, Dallas, TX 4 Robert Brennan Infectious Diseases Assoc of Central VA, Lynchburg, VA 5 Cynthia Brinson Central Texas Clinical Research, Austin, TX 6 Thomas Campbell University of Colorado, Denver, CO 7 Jerome De Vente Living Hope Clinical Foundation, Long Beach, CA 8 Franco Felizarta Bakersfield, CA 9 Deborah Goldstein Whitman Walker Clinic, Washington, D.C. 10 William Keith Henry Hennepin County Medical Center, Minneapolis, MN 11 Harold Katner Mercer University School of Medicine, Macon, GA 12 Cheryl McDonald Tarrant County Infectious Disease Assoc, Fort Worth, TX 13 Cheryl Newman Georgia Regents University, Augusta, GA 14 Roberto Ortiz Bliss Health System, Orlando, FL 15 Edgar Overton University of Alabama 1917 Clinic, Birmingham, AL 16 Gary Richmond Fort Lauderdale, FL 17 Peter Ruane Los Angeles, CA 18 Natasha Rybak The Miriam Hospital, Providence, RI 19 Anita Scribner Longview, TX 20 James Sims III St. Hope Foundation, Bellaire, TX 21 Susan Swindells University of Nebraska Medical Center, Omaha, NE 22 William Towner Kaiser Permanente Medical Center, Los Angeles, CA

Canada 23 Jonathan Angel The Ottawa Hospital-General Campus, Ottawa, ON 24 Brian Conway Vancouver ID Research and Care Centre Society, Vancouver, BC 25 Graham Smith Maple Leaf Research, Toronto, ON 26 Jason Szabo Clinique Medicale L'Actuel, Montreal, QC 27 Darrell Tan St. Michael's Hospital, Toronto, ON 28 Sharon Walmsley University Health Network, Toronto, ON

France 29 Olivier Bouchaud Hôpital Avicenne, Bobigny 30 Pierre-Marie Girard Hôpital Saint Antoine, Paris 31 Christine Katlama Hôpital de la Pitié-Salpêtrière, Paris 32 Jean-Michel Livrozet Hôpital Edouard Herriot, Lyon 33 Jean-Michel Molina Hôpital Saint Louis, Paris

Lead Investigator Site 34 Patrick Philibert Hôpital Européen, Marseille 35 Gilles Pialoux Hôpital Tenon, Paris 36 Yazdan Yazdanpanah Hôpital Bichat-Claude Bernard, Paris

Germany

37 Keikawus Arasteh Epimed GmbH, Berlin 38 Axel Baumgarten Zentrum für Infektiologie Berlin Prenzlauer Berg, Berlin 39 Johannes Bogner Klinikum Innenstadt, München 40 Olaf Degen Universitaetsklinikum Eppendorf, Hamburg 41 Stefan Esser Universitaetsklinikum Essen, Essen 42 Hans Jaeger MUC Research GmbH, München 43 Thomas Lutz Infektio Research, Frankfurt 44 Juergen Rockstroh Rheinische Friedrich-Wilhelms Universitaet, Bonn 45 Hans-Jürgen Stellbrink ICH Study Center, Hamburg 46 Christoph Stephan Klinikum der J-W-Goethe-Universitaet, Frankfurt am Main 47 Matthias Stoll Medizinische Hochschule Hannover, Hannover

Italy 48 Andrea Antinori Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, IRCCS, Roma 49 Francesco Castelli Azienda Ospedaliera Spedali Civili, Brescia 50 Adriano Lazzarin IRCCS Ospedale San Raffaele, Milano 51 Guglielmo Migliorino Nuovo Ospedale San Gerardo, Monza 52 Giuliano Rizzardini PO Ospedale Luigi Sacco - Polo Universitario, Milano

Netherlands 53 Wouter F.W. Bierman UMC Groningen, Groningen 54 Ilja M. Hoepelman UMC Utrecht, Utrecht 55 Jan G. den Hollander Maasstad Ziekenhuis, Rotterdam

Spain 56 Enrique Bernal Morell Hospital Reina Sofía, Murcia 57 Mª Angeles Castro Iglesias Complejo Hospitalario Universitario A Coruña, La Coruña 58 María del Carmen Fariñas Hospital Marques de Valdecilla, Santander Álvarez 59 Carlos Enrique Galera Hospital Virgen de la Arrixaca, Murcia Peñaranda 60 Mercedes García Gasalla Hospital Son LlatzerPalma de Mallorca 61 Juan Luis Gomez Sirvent Hospital Universitario de Canarias, La Laguna-Tenerife 62 Juan González García Hospital La Paz, Madrid

Lead Investigator Site 63 Miguel Górgolas Fundacion Jimenez Diaz, Madrid Hernández-Mora 64 José Hernandez-Quero Complejo Hospitalario Universitario de Granada, Granada 65 Sofía Ibarra Ugarte Hospital de Basurto, Bilbao 66 Ana Isabel Marino Callejo Hospital Arquitecto Marcide, Ferrol (A Coruña) 67 Maria Del Mar Masiá Hospital General de Elche, Elche (Alicante) 68 Gracia Mateo García Hospital Santa Cruz y San Pablo, Barceloa 69 Máximo Miguelez Hospital Universitario Nuestra Señora de Candelaria, Santa Morales Cruz de Tenerife 70 Daniel Podzamczer Palter Ciudad Sanitaria y Universitaria de Bellvitge, Barcelona 71 Federico Pulido Ortega Hospital 12 Octubre, Madrid 72 Mª Angeles Ribas del Hospital de Son Espases, Palma de Mallorca Blanco 73 Inés María Suárez García Hospital Infanta Sofia, San Sebastian de los Reyes

Russian Federation 74 Elena Belonosova Orel Regional AIDS Centre, Orel 75 Olga Borodkina Kemerovo Regional AIDS Centre, Kemerovo 76 Oksana Chernova Tolyatti City AIDS Centre, Tolyatti 77 Denis Gusev St. Petersburg City AIDS Centre, St. Petersburg 78 Valery Kulagin Krasnodar’s Area AIDS Centre, Krasnodar 79 Firaya Nagimova Tatarstan Republican AIDS Centre AIDS, Kazan 80 Vadim Pokrovsky Central Research Institute of Epidemiology, Moscow 81 Andrey Shuldyakov Saratov Regional AIDS Centre, Saratov 82 Olga Tonkikh Lipetsk Regional AIDS Centre, Lipetsk 83 Olga Tsybakova Smolensk Regional AIDS Centre, Smolensk 84 Svetlana Volkova Sverdlovsk Regional AIDS Center, Ekaterinburg 85 Eugene Voronin Republican Hospital of Infectious Diseases, St. Petersburg 86 Alexey Yakovlev City Hospital of Infectious Diseases, St. Petersburg

United Kingdom 87 Sris Allan City of Coventry Health Centre, Coventry 88 Margaret Johnson Royal Free Hospital, London 89 Chloe Orkin Queen Mary University, London 90 Sarah Pett Central and North West London NHS Trust, London 91 Steve Taylor Heartlands Hospital, Birmingham 92 Janet Wilson Leeds General Infirmary, Leeds 93 Alan Winston St Mary's Hospital London

South Africa 94 Ayesha Bassa Mzansi Ethical Research Centre, Middelburg

Lead Investigator Site 95 Gulam Latiff Durban 96 Johannes Jurgens Josha Research, Bloemfontein Lombaard 97 Essack Mitha Newtown Clinical Research Centre, Johannesburg 98 Rosie Mngqibisa Enhancing Care Foundation, Wentworth 99 Monja-Marie Nortje Moriana Clinical Research, Brandfort 100 Yashna Singh Groote Schur Hospital, Cape Town 101 Lelanie van Zyl Syzygy Clinical Research Services, Pretoria

Japan 102 Shinichi Oka National Center for Global Health and Medicine, Tokyo 103 Takuma Shirasaka National Hospital Organization Osaka National Hospital, Osaka 104 Yoshiyuki Yokomaku National Hospital Organization Nagoya Medical Center, Aichi

Eligibility criteria

INCLUSION CRITERIA AGE 1. HIV-1 infected, ART-naive men or women aged 18 years or greater at the time of signing the informed consent. TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 2. HIV-1 infection as documented by Screening plasma HIV-1 RNA 1000 c/mL; 3. Antiretroviral-naive ( 10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection). Any previous exposure to an HIV integrase inhibitor or non- nucleoside reverse transcriptase inhibitor will be exclusionary. SEX 4. Female Participants: A female participant is eligible to participate if she is not pregnant at Screening and first day of Induction Phase (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the following conditions applies:

a. Nonreproductive 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 (FSH) 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 enrolment. 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 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 CAB LA and RPV LA. The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception.

ALL participants in the study should be counseled 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.

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. OTHER French participants: In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

EXCLUSION CRITERIA Exclusionary Medical Conditions 1. Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed during the study. 2. Any evidence at Screening of an active Centers for Disease and Prevention Control (CDC) Stage 3 disease,1 except cutaneous Kaposi’s sarcoma not requiring systemic therapy or historic or current CD4+ cell count <200 cells/mm3 are not exclusionary (local guidelines dictate). 3. Participants with known moderate to severe hepatic impairment. 4. Any pre-existing physical or mental condition (including substance abuse 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. 5. 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 seizure may be considered for enrolment 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 enrolment. 6. Participant who, in the investigator's judgment, poses a significant suicide risk. Participant’s recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk. 7. The participant has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions. 8. 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: • 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. 9. 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 prior to Week 48 of the Maintenance Phase 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, HCV 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 is not available or is inconclusive, the Fib-4 score will be used to verify eligibility.

• A Fib-4 score > 3.25 is exclusionary

• Fib-4 scores 1.45 – 3.25 requires Medical Monitor consultation.

Fibrosis 4 Score Formula: (Age x AST) / (Platelets x (√ALT)) 10. Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). 11. History of liver cirrhosis with or without hepatitis viral co-infection. 12. Ongoing or clinically relevant pancreatitis. 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 positive RPR test who have not been treated may be rescreened at least 30 days after completion of antibiotic treatment for syphilis. 14. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non- invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the study Medical Monitor for inclusion of the participant prior to enrolment. 15. Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug or render the participant unable to receive study medication.

16. 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. 17. Current or anticipated need for chronic anti-coagulation. 18. Alanine aminotransferase (ALT) 3 times ULN. 19. 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.

CONCOMITANT MEDICATIONS 20. Exposure to an experimental drug and/or experimental vaccine within 28 days or 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP. 21. Treatment with any of the following agents within 28 days of Screening: • radiation therapy • cytotoxic chemotherapeutic agents • tuberculosis (TB) therapy, with the exception of treatment of latent TB with isoniazid • Immunomodulators that alter immune responses (such as chronic systemic corticosteroids, interleukins, or interferons). Note: Participants using short-term (e.g. 21 day) systemic corticosteroid treatment; topical, inhaled or intranasal corticosteroids are eligible for enrolment. 22. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening. 23. Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 within 28 days of the first dose of IP. 24. Use of medications which are associated with Torsades de Pointes (See SPM for a list of relevant medications). DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA 25. Any evidence of primary resistance to NNRTIs (except for K103N which is allowed), or any known resistance to INIs from historical resistance test results.2 Note: re-tests of Screening genotypes are allowed only at the discretion of the study virologist. 26. Participants who are HLA-B*5701 positive and are unable to use an NRTI backbone that does not contain abacavir (participants who are HLA-B*5701 positive may be enrolled if they use a NRTI backbone that does not contain abacavir; HLA-B*5701 positive participants may be excluded from the study if local provision of an alternate NRTI backbone is not possible). 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 creatinine clearance <50 mL/min/1.73m2 via the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.3

30. Participants who are currently participating in or anticipate to be selected for any other interventional study.

Eligibility for the Maintenance Phase

• Participants with an undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) visit are eligible to enter the Maintenance Phase. • A single repeat HIV-1 RNA test to determine eligibility may be allowed ONLY after consultation with the medical monitor. • Participants with HIV-1 RNA 400 c/mL at Week (-4) are not eligible to enter the Maintenance Phase, will not be allowed a repeat to determine eligibility, and will therefore be withdrawn from the study.

Result of HIV-1 RNA at Week (-4) Action <50 c/mL Begin maintenance phase at day 1.

50 c/mL but <400 c/mL Single repeat allowed only after consultation and approval from medical monitor. Single repeat <50 c/mL Begin maintenance phase at day 1.

Single repeat 50 c/mL Cannot begin maintenance phase and must be withdrawn from study; complete withdrawal visit instead of day 1.

400 c/mL Cannot begin maintenance phase and must be withdrawn from study; complete withdrawal visit instead of day 1.

Induction and Maintenance Phase Time and Events Schedule

Induction Phase by Week Maintenance Phase by Week

20)

LA arm LA

LA arm LA Arm LA

Arm LA

LA arm LA

–

– –

Procedures -

–

16) 12, 4)

- - - Arm LA

Screening Screening

Baseline ( Baseline ( ( ( WD 1 Day 4a 4b 5 12, 20 16, 8, 24 36 32, 28, 44 40, 41 48 52 56 60 88 80, 72, 64, 92 84, 68,76, 96 100

Written informed consent X Eligibility verification (inclusion / exclusion X X Xb Xb criteria) Randomization X Demography X Medical historyc X Medication history / prior ART history X Symptom directed physical exam & medical X X X X X X X X X X X X X X X X X X X X X X X assessmentd Weight, BMI, and height e X X X X Cardiovascular risk assessment X X Vital signs (BP, HR, temperature) f X X X X X X 12-lead ECG g X X pre- X X Xg Xg X dose x3 CDC classification X X HIV associated conditions X X X X X X X X X X X X X X X X X X X X X AE and SAE assessment, con meds X h X X X X X X X X X X X X X X X X X X X X X X ISR assessment (LA arm only) X X X X X X X X X X X X X X X Columbia suicide severity rating scale (eC- X X X X X X X X X X X X W72 W84 X SSRS) i Clinical chemistry and hematology X X X X X X X X X X X X X X X X X X X Rapid plasma reagin (RPR) X X Pregnancy testingj S U S S S S U S U S S S S S S S S S S S S HIV-1 RNA and sample for storagek Xk X X X X X X X X X X X X Sk X X X X Sk CD4+ X X X X X X X X X X X X X X X X X CD8+ X X X X X X X Urinalysisl X X X X X X Fasting lab assessments: glucose, cholesterol X X X X (total, HDL, LDL) & triglycerides m 11

Induction Phase by Week Maintenance Phase by Week

20)

LA arm LA

LA arm LA Arm LA

Arm LA

LA arm LA

–

– –

Procedures -

–

16) 12, 4)

- - - Arm LA

Screening Screening

( ( ( WD 1 Day 4a 4b 5 12, 20 16, 8, 24 36 32, 28, 44 40, 41 48 52 56 60 88 80, 72, 64, 92 84, 68,76, 96 100

( Baseline

- Hepatitis B (HBsAg, anti-HBc, and anti- X HBsAg); hepatitis C (anti-HCV Ab) HLA-B*5701 X PT/PTT/INR X X Renal and bone marker analytes X X X (blood/urine)n Peripheral blood mononuclear cells o X X Genetic samplep X PK sample; (S)= storage sample Xv w Xt v X X X X Xv Xv X X X S Xv X Oral CAB and oral RPV dispensation X X Xx ABC/DTG/3TC dispensation (or DTG alt) X X X Xq r X X X X X X X X X X Study treatment accountability (pill counts) X X Xr X X X Xu X X X X X X X X X IM study treatment administration – Q4W X X X X X X X X X X X X X throughout maintenance and extension phase HAT-QoL (short form) X X X X SF-12 X X X X ACCEPT X W8 X X X HIVTSQ(s) X X X W44 X HIVTSQ(c) X PIN (LA arm only)aa X X X X NRS (LA arm only) X X W40 X X Preference (LA arm only) X 3TC, lamivudine; ABC, abacavir; ACCEPT, chronic treatment acceptance questionnaire; AE, adverse event; anti-HBc, hepatitis B core antibody; ART, antiretroviral; BMI, body mass index; BP, blood pressure; CAB, cabotegravir; CDC, Centers for Disease Control; DTG, dolutegravir; ECG, electrocardiogram; HAT-QoL, HIV/AIDS-targeted quality of life; HBsAg, hepatitis B surface antigen; HDL, high-density lipoprotein; HIVTSQ, HIV treatment satisfaction questionnaire; HR, heart rate; INR, international normalized ratio; ISR, injection site reaction; LDL, low-density lipoprotein; NRS, numeric rating scale; PIN, perception of injection questionnaire; PK, pharmacokinetic; PT, prothrombin time; PTT, partial thromboplastin time; Q4W, every 4 weeks; RPV, rilpivirine; SAE, serious adverse event; SF-12, short-form 12.

Table shows the schedule for study assessments through the end of the maintenance phase.

Study Endpoints

Primary Efficacy Endpoint • Proportion of participants with a ‘virologic failure’ endpoint as per FDA snapshot algorithm at week 48 (ITT-E population). Secondary Efficacy Endpoints • Proportion of participants with plasma HIV-1 RNA <50 copies/mL at week 48 using the FDA snapshot algorithm (ITT-E population). • Proportion of participants with plasma HIV 1 RNA <200 copies/mL at week 48 using the FDA snapshot algorithm (ITT-E population). • Proportion of participants with confirmed virologic failure at week 48.

• Absolute values and change from baseline in plasma HIV-1 RNA (log10 copies/mL) at week 48. • Absolute values and changes from baseline in CD4+ lymphocyte counts over time. • Incidence of disease progression (HIV-associated conditions, AIDS and death). Exploratory Efficacy Endpoints • Proportion of participants by subgroup(s) (e.g., by age, sex, body mass index, race, HIV-1 subtype, baseline CD4+) with virologic failure over time including week 48 using the snapshot algorithm for the ITT-E Population. • Proportion of participants by subgroup(s) (e.g. by age, sex, body mass index, race, HIV-1 subtype, baseline CD4+) with plasma HIV-1 RNA <50 copies/mL at week 48. • Change from baseline in CD4+ cell counts by subgroups at week 48. Safety assessments • Monitoring of adverse events • Clinical laboratory tests (hematology, blood chemistry, urinalysis and fasting glucose and lipids) • Vital signs • ECGs • Physical examinations • Past medical, family, social, and medication histories and targeted history on cardiovascular risk (smoking history, family and personal history) • HIV-associated conditions • Bone and renal markers • Pregnancy testing • Concomitant medications • Blood products

• Injection site reactions (pain, tenderness, pruritus, warmth, bruising, discoloration, infections, rash, erythema, swelling, induration, nodules granulomas or cysts, and DAIDS grading scale) • electronic Columbia-Suicide Severity Rating Scale (eC-SSRS)

Figure S1. Adherence to LA Dosing Schedule, Maintenance Phase

1800 1627 1600

1400

1200

1000

800

600

Number of Injection Number Visits 373 398 400 291 330 260 228 200 42 0 18 5 0 < -14 -14 to -8 -7 to -4 -3 to -2 -1 0 1 2 to 3 4 to 7 8 to 14 >14

Days From Target Date

The numbers of injections given in the LA arm in relation to the optimal (4-week) target date are shown. The recommended needle for injections was 23 gauge and 1.5 inches in length. Variable needle lengths and/or gauges (cabotegravir LA: 21 to 25 gauge; rilpivirine LA: 21 to 23 gauge) were permitted if needed to accommodate individual body types; longer needle lengths may have been required for participants with a body mass index >30 kg/m2 to enable intramuscular administration. Needles of 2 inches or longer were used for 4% and 5% of participants receiving cabotegravir LA and rilpivirine LA, respectively.

LA denotes long acting.

Figure S2. Effects of Baseline Parameters and Stratification Criteria on HIV-1 RNA ≥50 copies/mL at Week 48 (Snapshot).

LA, n/N (%) CAR, n/N (%) -0.4 All patients 6/283 (2.1) 7/283 (2.5)

3.2 Female 3/63 (4.8) 1/64 (1.6) Sex at birth -1.4 Male 3/220 (1.4) 6/219 (2.7)

-1.4 <35 3/143 (2.1) 5/145 (3.4) 1.0 Age, years 35-49 2/107 (1.9) 1/109 (0.9) -0.4 ≥50 1/33 (3.0) 1/29 (3.4)

7.5 ≥30 3/40 (7.5) 0/37 (0) BMI, kg/m2 -1.6 <30 3/243 (1.2) 7/246 (2.8)

0.3 White 6/216 (2.8) 5/201 (2.5) -2.5 Non-white 0/67 (0) 2/80 (2.5) Race -3.6 Black/Afr Amer 0/47 (0) 2/56 (3.6) 0.3 Non-black/AfrAmer 6/236 (2.5) 5/225 (2.2)

-1.8 W Europe/N Amera 2/206 (1.0) 6/225 (2.7) 4.8 Russian Federation 4/54 (7.4) 1/39 (2.6) Region 0 Japan 0/8 (0) 0/12 (0) 0 South Africa 0/15 (0) 0/17 (0)

-2.4 <200 1/16 (6.3) 2/23 (8.7) 1.3 Baseline CD4+ 200-349 2/71 (2.8) 1/64 (1.6) 3 3.4 cells/mm 350-499 3/88 (3.4) 0/88 (0) -3.7 ≥500 0/108 (0) 4/108 (3.7)

<350 0/19 (0) 1/27 (3.7) -3.7 Day 1 CD4+ 4.7 3 350-499 3/64 (4.7) 0/60 (0) cells/mm -1.6 ≥500 3/200 (1.5) 6/196

-0.4 <100,000 4/227 (1.8) 5/227 (2.2) Baseline HIV-1 0 RNA, c/mL ≥100,000 2/56 (3.6) 2/56 (3.6)

0 A 0/46 (0) 0/36 (0) 12.5 A1 3/8 (37.5) 1/4 (25.0) −50 61.6 0 AE 0/1 (0) 0/6 (0) 10.0 AG 1/10 (10) 0/16 (0) 44.5 HIV-1 subtype -2.3 B 2/174 (1.1) 6/174 (3.4) 0 C 0/18 (0) 0/20 (0) 0 Other 0/19 (0) 0/21 (0) 0 Missing 0/7 (0) 0/6 (0)

3.4 Yes 3/54 (5.6) 1/47 (2.1) Baseline L74I -1.5 present No 3/189 (1.6) 6/193 (3.1)

-25 -20 -15 -10 -5 0 5 10 15 20 25 Unadjusted Difference in Proportion 95% CI

Favors LA Favors CAR

BMI denotes body mass index, CAR current antiretroviral therapy, LA long acting. aW Europe/N Amer includes the USA, Canada, France, Germany, Italy, The Netherlands, Spain, and the UK. Differences in proportions of participants reaching the primary study endpoint (HIV-1 RNA ≥50 copies/mL at week 48 (snapshot) according to demographic and disease-related subgroups are shown. The 95% CIs for subgroup differences were calculated using an unconditional exact method with two inverted one-sided tests. Subgroup analyses according to presence of L74I at baseline and region, respectively, were performed post-hoc. 16

Figure S3. Frequency of Injection Site Reactions by Study Week, LA Arm, Safety Population.

A Any Injection Site Reaction 100

80 71

60 43 38 40 33 34 32 31 29 27 27 24 20

20 Participants with with Participants ISRs(%) N = 278 276 276 272 270 270 269 267 267 265 264 259 0 4B 8 12 16 20 24 28 32 36 40 44 48 Study Week

B Pain C Nodule

100 100

80 80 69

60 60

39 36 40 30 31 32 40 29 26 26 27 20 20

20 20 Participants with with Participants ISRs(%) Participants with with Participants ISRs(%) 3 3 2 3 1 2 2 1 1 3 2 1 0 0 4B 8 12 16 20 24 28 32 36 40 44 48 4B 8 12 16 20 24 28 32 36 40 44 48 Study Week Study Week D Induration E Swelling

100 100

80 80

60 60

40 40

20 20 Participants with with Participants ISRs(%) Participants with with Participants ISRs(%) 7 3 1 1 2 1 1 0 1 1 2 1 3 1 1 1 1 1 0 0 0 1 0 0 0 0 4B 8 12 16 20 24 28 32 36 40 44 48 4B 8 12 16 20 24 28 32 36 40 44 48 Study Week Study Week

The proportions of participants in the LA arm who experienced any injection site reaction are shown by study week, beginning at week 4 when the first injections were administered. N values at each time point are the same as shown for overall ISRs (panel A) and for each ISR subcategory. Bars represent incidence of onset ISRs relative to the most recent IM injection visit; n=number of participants who received injections at each visit. ISR denotes injection site reaction, and LA long-acting. ISR denotes injection site reaction, LA long acting.

Figure S4. Plasma Pharmacokinetic Profiles of Cabotegravir and Rilpivirine for Participants with Confirmed Virologic Failure.

A. Cabotegravir

10.0 (μg/mL)

1.0 Cabotegravir

Plasma 0.1 4B 8 12 16 20 24 28 32 36 40 44 48 Week

B. Rilpivirine

1000 (ng/mL)

100

Rilpivirine Plasma 10 4B 8 12 16 20 24 28 32 36 40 44 48 Week

Median success 5th percentile success 95th percentile success Participant 1 Participant 2 Participant 3

Plasma concentrations over time are shown for cabotegravir and rilpivirine, for each of the three LA participants with confirmed virologic failure. The arrows denote the study week when virologic failure was first detected (suspected virologic failure). The solid black, dotted and dashed lines indicate the median concentrations and 5th and 95th percentile concentrations, respectively, for LA participants without HIV-1 RNA >50 copies/mL at week 48. LA denotes long acting.

Table S1. Confirmed Virologic Failure (CVF) Through Week 48

On-Treatment RAMs Drug Sensitivity (HIV-1 RNA) (Fold Change) at HIV-1 SVF Timepoint SVF Timepoint* Baseline RAMs Arm† Subtype NNRTI INSTI NNRTI INSTI NNRTI INSTI CAB (6.7) 1 LA A1 K101E G140R RPV (2.63) none none DTG (2.2)

CAB (5.2) 2 LA A1 E138E/A/K/T Q148R RPV (7.1) none none DTG (1.0)

CAB (9.4) 3 LA A1 E138K Q148R RPV (1.0) none none DTG (1.1) CAB (0.7) 4 CAR A1 V179V/I none RPV (0.5) none none DTG (0.8) CAB (0.9) 5 CAR B none none RPV (0.3) none none DTG (0.8) CAB (0.7) 7 CAR B none none RPV (0.4) none none DTG (0.7)

CAB denotes cabotegravir, CAR current antiretroviral therapy, DTG dolutegravir, INSTI integrase strand transfer inhibitor, LA long acting, NNRTI non-nucleoside reverse transcriptase inhibitor, RAM resistance-associated mutation, RPV rilpivirine, SVF suspected virologic failure. *Genotypic and phenotypic resistance were assessed using Phenosense GT®, GenoSeq® Integrase, and PhenoSeq® Integrase (Monogram Biosciences). †One additional LA participant had oral CAB plus RPV dosing interrupted due to a false-positive pregnancy test; upon re- initiation of oral therapy, suspected VF was confirmed. This participant withdrew before initiating LA therapy; no NNRTI or INSTI RAMs were detected at baseline or withdrawal.

Table S2. Prevalence of HIV-1 Subtypes and L74I at Baseline (ITT-E Population)

A. HIV-1 Subtype Prevalence

LA Arm CAR Arm HIV-1 Subtype, n (%) N=283 N=283 A 46 (16) 36 (13) A/B 1 (<1) 0 A1 8 (3) 4 (1) AE 1 (<1) 6 (2) AG 10 (4) 16 (6) B 174 (61) 174 (61) B/C 1 (<1) 0 BC 0 3 (1) BF 2 (<1) 2 (<1) BG 1 (<1) 0 C 18 (6) 20 (7) Complex 1 (<1) 3 (1) CPX 3 (1) 3 (1) D 0 4 (1) F 5 (2) 5 (2) F2 3 (1) 0 G 2 (<1) 1 (<1) Missing 7 (2) 6 (2)

B. L74I Polymorphism Prevalence (post hoc analysis)

LA Arm CAR Arm HIV-1 Subtype N=283 N=283 A 32/38 (84) 28/32 (88) A1 5/8 (63) 3/4 (75) AG 3/10 (30) 3/13 (23) B 12/165 (7) 11/161 (7) C 0/2 0/4 Missing 0/5 0/5 Other 2/15 (13) 2/18 (11) Results pending 40 (14) 43 (15) CAR denotes current antiretroviral therapy, ITT-E intention-to-treat exposed, LA long acting.

C. Effect of L74I on Virologic Suppression at Week 48 in FLAIR Participants (post hoc analysis)

Number with Difference in L74I Polymorphism HIV-1 RNA <50 copies/mL Proportion* at Induction Baseline Treatment / Total Assessed (%) (95% CI)

LA 50/54 (93) Yes −1.0 (−12.7, 11.0) CAR 44/47 (94)

LA 177/189 (94) No 0.4 (−4.9, 5.6) CAR 180/193 (93)

*Difference (unadjusted): proportion on LA – proportion on CAR. CAR denotes current antiretroviral, CI confidence interval, LA long-acting, RPV rilpivirine.

Table S3. Participants With Adverse Events by System Organ Class and Maximum Toxicity Grade – Maintenance Phase

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Participants with any event 93 (33) 143 (51) 23 (8) 8 (3) 0 267 (94) 119 (42) 95 (34) 10 (4) 1 (<1) 0 225 (80) General disorders and administration site conditions Any event 136 (48) 96 (34) 11 (4) 0 0 243 (86) 21 (7) 4 (1) 1 (<1) 0 0 26 (9) Injection site pain 124 (44) 92 (33) 11 (4) 0 0 227 (80) 0 0 0 0 0 0 Injection site nodule 39 (14) 5 (2) 0 0 0 44 (16) 0 0 0 0 0 0 Injection site induration 29 (10) 8 (3) 1 (<1) 0 0 38 (13) 0 0 0 0 0 0 Injection site swelling 19 (7) 3 (1) 0 0 1 (<1) 23 (8) 0 0 0 0 0 0 Pyrexia 15 (5) 6 (2) 0 0 1 (<1) 22 (8) 2 (<1) 2 (<1) 0 0 0 4 (1) Injection site pruritus 16 (6) 0 0 0 0 16 (6) 0 0 0 0 0 0 Injection site erythema 10 (4) 3 (1) 0 0 0 13 (5) 0 0 0 0 0 0 Asthenia 10 (4) 2 (<1) 0 0 0 12 (4) 1 (<1) 0 0 0 0 1 (<1) Influenza-like illness 7 (2) 1 (<1) 0 0 0 8 (3) 7 (2) 0 0 0 0 7 (2) Injection site warmth 7 (2) 1 (<1) 0 0 0 8 (3) 0 0 0 0 0 0 Fatigue 5 (2) 2 (<1) 0 0 0 7 (2) 7 (2) 1 (<1) 0 0 0 8 (3) Injection site bruising 5 (2) 2 (<1) 0 0 0 7 (2) 0 0 0 0 0 0 Malaise 5 (2) 2 (<1) 0 0 0 7 (2) 1 (<1) 0 0 0 0 1 (<1) Injection site hematoma 3 (1) 1 (<1) 0 0 0 4 (1) 0 0 0 0 0 0 Discomfort 2 (<1) 1 (<1) 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Pain 3 (1) 0 0 0 0 3 (1) 0 0 0 0 0 0 Feeling hot 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Injection site discoloration 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Injection site hemorrhage 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Chest discomfort 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Chest pain 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Chills 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 cyst 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Injection site discomfort 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Injection site granuloma 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Injection site necrosis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Injection site scar 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Nodule 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Peripheral edema 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Swelling 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Catheter site erythema 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Noncardiac chest pain 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Systemic inflammatory 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) response syndrome Temperature regulation disorder 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vessel puncture site bruise 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Infections and infestations Any event 132 (47) 56 (20) 1 (<1) 2 (<1) 5 (2) 196 (69) 123 (43) 48 (17) 2 (<1) 0 0 173 (61) Nasopharyngitis 50 (18) 6 (2) 0 0 0 56 (20) 44 (16) 4 (1) 0 0 0 48 (17) Upper respiratory tract infection 32 (11) 6 (2) 0 0 0 38 (13) 23 (8) 5 (2) 0 0 0 28 (10) Influenza 18 (6) 4 (1) 0 0 3 (1) 25 (9) 17 (6) 3 (1) 0 0 0 20 (7) Pharyngitis 13 (5) 2 (<1) 0 0 0 15 (5) 9 (3) 0 0 0 0 9 (3) Viral respiratory tract infection 11 (4) 2 (<1) 0 0 0 13 (5) 7 (2) 4 (1) 0 0 1 (<1) 12 (4) Gastroenteritis 13 (5) 2 (<1) 0 0 0 15 (5) 9 (3) 2 (<1) 0 0 0 11 (4) Bronchitis 8 (3) 4 (1) 0 0 0 12 (4) 5 (2) 5 (2) 0 0 0 10 (4) Syphilis 8 (3) 4 (1) 0 0 0 12 (4) 6 (2) 0 0 0 0 6 (2) Oral herpes 6 (2) 3 (1) 0 0 2 (<1) 11 (4) 4 (1) 0 0 0 0 4 (1) Rhinitis 9 (3) 1 (<1) 0 0 0 10 (4) 9 (3) 1 (<1) 0 0 0 10 (4) Folliculitis 8 (3) 0 0 0 0 8 (3) 5 (2) 1 (<1) 0 0 0 6 (2) Gonorrhea 5 (2) 3 (1) 0 0 0 8 (3) 5 (2) 1 (<1) 0 0 0 6 (2) Herpes zoster 6 (2) 2 (<1) 0 0 0 8 (3) 0 1 (<1) 0 0 0 1 (<1) Tonsillitis 6 (2) 2 (<1) 0 0 0 8 (3) 5 (2) 1 (<1) 0 0 0 6 (2) Conjunctivitis 5 (2) 2 (<1) 0 0 0 7 (2) 3 (1) 0 0 0 0 3 (1) Viral gastroenteritis 5 (2) 1 (<1) 0 0 0 6 (2) 3 (1) 1 (<1) 0 0 0 4 (1) Herpes simplex 4 (1) 2 (<1) 0 0 0 6 (2) 5 (2) 0 0 0 0 5 (2) Tooth infection 6 (2) 0 0 0 0 6 (2) 2 (<1) 1 (<1) 0 0 0 3 (1) Anal chlamydia infection 3 (1) 2 (<1) 0 0 0 5 (2) 2 (<1) 1 (<1) 0 0 0 3 (1) Hordeolum 5 (2) 0 0 0 0 5 (2) 2 (<1) 0 0 0 0 2 (<1) Papillomavirus infection 5 (2) 0 0 0 0 5 (2) 0 0 0 0 0 0 Respiratory tract infection 4 (1) 1 (<1) 0 0 0 5 (2) 0 0 0 0 0 0 Body tinea 4 (1) 0 0 0 0 4 (1) 0 0 0 0 0 0 Cellulitis 4 (1) 0 0 0 0 4 (1) 1 (<1) 0 0 0 0 1 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Chlamydial infection 3 (1) 1 (<1) 0 0 0 4 (1) 0 1 (<1) 0 0 0 1 (<1) Cystitis 3 (1) 1 (<1) 0 0 0 4 (1) 0 2 (<1) 0 0 0 2 (<1) Genital herpes 3 (1) 1 (<1) 0 0 0 4 (1) 3 (1) 0 0 0 0 3 (1) Laryngitis 3 (1) 1 (<1) 0 0 0 4 (1) 3 (1) 0 0 0 0 3 (1) Lower respiratory tract infection 4 (1) 0 0 0 0 4 (1) 1 (<1) 0 0 0 0 1 (<1) Sinusitis 4 (1) 0 0 0 0 4 (1) 1 (<1) 3 (1) 0 0 0 4 (1) Urethritis 3 (1) 1 (<1) 0 0 0 4 (1) 3 (1) 0 0 0 0 3 (1) Gonococcal urethritis 2 (<1) 2 (<1) 0 0 0 4 (1) 1 (<1) 2 (<1) 0 0 0 3 (1) Fungal skin infection 3 (1) 0 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Furuncle 2 (<1) 1 (<1) 0 0 0 3 (1) 6 (2) 1 (<1) 0 0 0 7 (2) Genital herpes simplex 1 (<1) 2 (<1) 0 0 0 3 (1) 2 (<1) 0 0 0 0 2 (<1) Hepatitis A 0 1 (<1) 0 2 (<1) 0 3 (1) 0 0 1 (<1) 0 0 1 (<1) Infection 3 (1) 0 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Pharyngotonsillitis 3 (1) 0 0 0 0 3 (1) 0 0 0 0 0 0 Chlamydial proctitis 2 (<1) 1 (<1) 0 0 0 3 (1) 0 0 0 0 0 0 Gonococcal proctitis 1 (<1) 2 (<1) 0 0 0 3 (1) 2 (<1) 2 (<1) 0 0 0 4 (1) Secondary syphilis 3 (1) 0 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Tinea versicolor 3 (1) 0 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Ureaplasma infection 3 (1) 0 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Acute hepatitis B 0 1 (<1) 1 (<1) 0 0 2 (<1) 0 0 0 0 0 0 Acute hepatitis C 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Anal infection 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Candidal balanitis 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Candida infection 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Ear infection 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 2 (<1) 0 0 0 4 (1) Onychomycosis 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Oropharyngeal gonococcal 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 infection Otitis externa 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Subcutaneous abscess 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Tinea infection 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Tinea pedis 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Urinary tract infection 1 (<1) 1 (<1) 0 0 0 2 (<1) 7 (2) 3 (1) 0 0 0 10 (4) Viral infection 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 1 (<1) 0 0 0 3 (1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Viral upper respiratory tract 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) infection Abscess 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Acarodermatitis 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Anal abscess 1 (<1) 0 0 0 0 1 (<1) 0 0 1 (<1) 0 0 1 (<1) Bacterial vulvovaginitis 1 (<1) 0 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) Bacterial conjunctivitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dacryocystitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Epididymitis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Escherichia urinary tract 0 1 (<1) 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) infection Fungal infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Shigella gastroenteritis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Gastrointestinal infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Genital candidiasis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Genital infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Genitourinary chlamydia infection 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Gonococcal genitourinary tract 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 infection Helicobacter infection 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Herpesvirus infection 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Injection site abscess 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Lice infestation 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Mycoplasma genitalium infection 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Mycoplasma infection 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Oophoritis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Orchitis 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Otitis media 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Pertussis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Streptococcal pharyngitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Pneumonia 0 1 (<1) 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Postprocedural infection 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Pyelonephritis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Sexually transmitted disease 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Staphylococcal abscess 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Strongyloidiasis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Bacterial tonsillitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Tooth abscess 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 1 (<1) 0 0 0 3 (1) Tracheitis 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Tracheobronchitis 0 1 (<1) 0 0 0 1 (<1) 3 (1) 0 0 0 0 3 (1) Bacterial upper respiratory tract 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 infection Mycoplasmal urethritis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Varicella 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Viral pharyngitis 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Viral tonsillitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vulvovaginal candidiasis 0 1 (<1) 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Vulvovaginal mycotic infection 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Vulvovaginitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Staphylococcal skin infection 0 0 0 0 0 0 0 2 (<1) 0 0 0 2 (<1) Chlamydial urethritis 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Limb abscess 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Acute sinusitis 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) Anorectal human papillomavirus 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) infection Anorectal infection 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Pneumococcal bronchitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Cat scratch disease 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Erysipelas 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Eyelid infection 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Genitourinary tract infection 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Gingivitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Groin abscess 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Helicobacter gastritis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Hepatitis E 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Impetigo 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Infectious colitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Lymphogranuloma venereum 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Malaria 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Oral infection 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Paronychia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Pharyngeal chlamydial infection 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Mycoplasmal proctitis 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Chronic pyelonephritis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Bacterial respiratory tract infection 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Rotavirus infection 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Skin candida 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Tinea cruris 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vaginal infection 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Gastrointestinal disorders Any event 72 (25) 34 (12) 1 (<1) 0 0 107 (38) 62 (22) 12 (4) 0 1 (<1) 0 75 (27) Diarrhea 20 (7) 12 (4) 0 0 0 32 (11) 21 (7) 4 (1) 0 0 0 25 (9) Hemorrhoids 13 (5) 3 (1) 0 0 0 16 (6) 2 (<1) 1 (<1) 0 0 0 3 (1) Nausea 15 (5) 1 (<1) 0 0 0 16 (6) 9 (3) 2 (<1) 0 0 0 11 (4) Abdominal pain 8 (3) 4 (1) 0 0 0 12 (4) 7 (2) 1 (<1) 0 0 0 8 (3) Vomiting 6 (2) 2 (<1) 0 0 0 8 (3) 1 (<1) 2 (<1) 0 0 0 3 (1) Constipation 3 (1) 4 (1) 0 0 0 7 (2) 3 (1) 0 0 0 0 3 (1) Dyspepsia 6 (2) 1 (<1) 0 0 0 7 (2) 3 (1) 0 0 0 0 3 (1) Proctitis 3 (1) 4 (1) 0 0 0 7 (2) 2 (<1) 0 0 0 0 2 (<1) Toothache 6 (2) 1 (<1) 0 0 0 7 (2) 3 (1) 2 (<1) 0 0 0 5 (2) Upper abdominal pain 3 (1) 2 (<1) 0 0 0 5 (2) 2 (<1) 0 0 0 0 2 (<1) Anogenital dysplasia 4 (1) 0 0 0 0 4 (1) 2 (<1) 0 0 0 0 2 (<1) Food poisoning 3 (1) 1 (<1) 0 0 0 4 (1) 2 (<1) 0 0 0 0 2 (<1) Gastritis 2 (<1) 2 (<1) 0 0 0 4 (1) 3 (1) 0 0 0 0 3 (1) Dental caries 3 (1) 0 0 0 0 3 (1) 3 (1) 0 0 0 0 3 (1) Odynophagia 3 (1) 0 0 0 0 3 (1) 3 (1) 0 0 0 0 3 (1) Lower abdominal pain 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Anal fissure 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Anal inflammation 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Hemorrhagic diarrhea 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Dry mouth 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Flatulence 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 1 (<1) 0 0 0 3 (1) Gingival bleeding 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Hemorrhoidal hemorrhage 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Dry lip 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Proctalgia 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Rectal hemorrhage 1 (<1) 1 (<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 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Aerophagia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Anal fistula 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Anal pruritus 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Anal ulcer 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Aphthous ulcer 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Barrett's esophagus 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Bile acid malabsorption 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Bowel movement irregularity 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Colitis 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Microscopic colitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dysbacteriosis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Enteritis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Enterocolitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Epigastric discomfort 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Soft feces 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Gastroduodenitis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Gastrointestinal sounds abnormal 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Gastroesophageal reflux disease 1 (<1) 0 0 0 0 1 (<1) 3 (1) 0 0 0 0 3 (1) Gingival swelling 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hematochezia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Irritable bowel syndrome 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Oral leukoplakia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Oral pain 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Palatal ulcer 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 Tooth development disorder 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Umbilical hernia 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Inguinal hernia 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1) Stomatitis 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Gingival pain 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Large intestinal perforation 0 0 0 0 0 0 0 0 0 1 (<1) 0 1 (<1) Lymphoid hyperplasia of intestine 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Esophageal polyp 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Oral paresthesia 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Rectal discharge 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Rectal fissure 0 0 0 0 0 0 0 0 0 1 (<1) 0 1 (<1) Tongue eruption 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Musculoskeletal and connective tissue disorders Any event 46 (16) 16 (6) 2 (<1) 0 0 64 (23) 34 (12) 10 (4) 0 0 0 44 (16) Back pain 15 (5) 7 (2) 0 0 0 22 (8) 9 (3) 4 (1) 0 0 0 13 (5) Myalgia 12 (4) 2 (<1) 0 0 0 14 (5) 4 (1) 1 (<1) 0 0 0 5 (2) Arthralgia 6 (2) 3 (1) 0 0 0 9 (3) 6 (2) 1 (<1) 0 0 0 7 (2) Pain in extremity 5 (2) 1 (<1) 0 0 0 6 (2) 0 0 0 0 0 0 Muscle spasms 3 (1) 1 (<1) 0 0 0 4 (1) 2 (<1) 0 0 0 0 2 (<1) Musculoskeletal chest pain 4 (1) 0 0 0 0 4 (1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Osteochondrosis 1 (<1) 3 (1) 0 0 0 4 (1) 1 (<1) 0 0 0 0 1 (<1) Muscle contracture 3 (1) 0 0 0 0 3 (1) 3 (1) 0 0 0 0 3 (1) Musculoskeletal discomfort 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Musculoskeletal stiffness 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Neck pain 1 (<1) 1 (<1) 0 0 0 2 (<1) 3 (1) 0 0 0 0 3 (1) Plantar fasciitis 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Spinal disorder 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Tendonitis 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 0 0 0 0 2 (<1) Arthritis 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Bursitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Groin pain 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Musculoskeletal pain 1 (<1) 0 0 0 0 1 (<1) 5 (2) 0 0 0 0 5 (2) Osteoarthritis 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Osteonecrosis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Osteoporosis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Rotator cuff syndrome 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Vertebral foraminal stenosis 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Spinal osteoarthritis 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1) Intervertebral disc disorder 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Joint swelling 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Soft tissue mass 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Temporomandibular joint 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) syndrome Tendon pain 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Nervous system disorders Any event 47 (17) 16 (6) 1 (<1) 0 0 64 (23) 24 (8) 9 (3) 0 0 0 33 (12) Headache 28 (10) 11 (4) 0 0 0 39 (14) 17 (6) 4 (1) 0 0 0 21 (7) Dizziness 13 (5) 2 (<1) 0 0 0 15 (5) 3 (1) 0 0 0 0 3 (1) Paresthesia 3 (1) 0 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Sciatica 2 (<1) 1 (<1) 0 0 0 3 (1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Syncope 2 (<1) 1 (<1) 0 0 0 3 (1) 0 0 0 0 0 0 Migraine 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Amnesia 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Anosmia 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Autonomic nervous system 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 imbalance Cervical neuritis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Disturbance in attention 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Intercostal neuralgia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Lethargy 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Peripheral neuropathy 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Poor quality sleep 0 0 1 (<1) 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Postherpetic neuralgia 1 (<1) 0 0 0 0 1 (<1) 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 Tremor 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Trigeminal neuralgia 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Visual field defect 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dysarthria 0 0 0 0 0 0 0 2 (<1) 0 0 0 2 (<1) Presyncope 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Hypoesthesia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Nerve compression 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Peripheral neuropathy 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Brachial radiculitis 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Skin and subcutaneous tissue disorders Any event 39 (14) 7 (2) 1 (<1) 0 0 47 (17) 25 (9) 7 (2) 0 0 0 32 (11) Eczema 7 (2) 0 0 0 0 7 (2) 5 (2) 1 (<1) 0 0 0 6 (2) Rash 5 (2) 1 (<1) 0 0 0 6 (2) 5 (2) 3 (1) 0 0 0 8 (3) Acne 3 (1) 0 0 0 0 3 (1) 2 (<1) 0 0 0 0 2 (<1) Dermatitis 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Atopic dermatitis 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Dyshidrotic eczema 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Erythema 2 (<1) 0 0 0 0 2 (<1) 0 1 (<1) 0 0 0 1 (<1) Hyperhidrosis 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Night sweats 1 (<1) 0 1 (<1) 0 0 2 (<1) 0 0 0 0 0 0 Papule 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Pityriasis 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Generalized pruritus 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Skin lesion 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Urticaria 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Alopecia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dandruff 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Ephelides 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Granuloma annulare 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Intertrigo 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Acquired lipodystrophy 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Pityriasis alba 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Pruritus 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Generalized rash 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Macular rash 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Maculopapular rash 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Morbilliform rash 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Papular rash 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Pruritic rash 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Vesicular rash 1 (<1) 0 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Seborrheic dermatitis 1 (<1) 0 0 0 0 1 (<1) 3 (1) 0 0 0 0 3 (1) Skin disorder 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Skin erosion 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Skin hyperpigmentation 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Skin hypopigmentation 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Skin induration 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Skin mass 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Skin reaction 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Xeroderma 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dermal cyst 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Blood blister 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Allergic dermatitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Nail pigmentation 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Penile ulceration 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Psoriasis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Purpura 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Rosacea 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Respiratory, thoracic and mediastinal disorders Any event 29 (10) 13 (5) 0 0 1 (<1) 43 (15) 27 (10) 7 (2) 0 0 0 34 (12) Oropharyngeal pain 8 (3) 4 (1) 0 0 0 12 (4) 4 (1) 0 0 0 0 4 (1) Cough 5 (2) 5 (2) 0 0 0 10 (4) 9 (3) 3 (1) 0 0 0 12 (4) Allergic rhinitis 7 (2) 3 (1) 0 0 0 10 (4) 1 (<1) 0 0 0 0 1 (<1) Catarrh 3 (1) 2 (<1) 0 0 0 5 (2) 3 (1) 1 (<1) 0 0 0 4 (1) Nasal congestion 1 (<1) 1 (<1) 0 0 0 2 (<1) 4 (1) 1 (<1) 0 0 0 5 (2) Respiratory disorder 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Sinus congestion 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Asthma 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Bronchial obstruction 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Chronic bronchitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Epistaxis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Nasal dryness 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Nasal ulcer 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Throat irritation 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 0 0 Tonsillar hypertrophy 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Rhinorrhea 0 0 0 0 0 0 5 (2) 0 0 0 0 5 (2) Productive cough 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Bronchospasm 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Nasal obstruction 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Nasal turbinate hypertrophy 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Reflux laryngitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Upper respiratory tract 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) inflammation Wheezing 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Investigations Any event 20 (7) 11 (4) 5 (2) 4 (1) 1 (<1) 41 (14) 11 (4) 12 (4) 4 (1) 0 0 27 (10) Blood creatine phosphokinase 2 (<1) 3 (1) 1 (<1) 2 (<1) 1 (<1) 9 (3) 4 (1) 2 (<1) 0 0 0 6 (2) increased Body temperature increased 9 (3) 0 0 0 0 9 (3) 0 0 0 0 0 0 Lipase increased 2 (<1) 0 1 (<1) 1 (<1) 0 4 (1) 2 (<1) 0 2 (<1) 0 0 4 (1) Aspartate aminotransferase 0 2 (<1) 0 1 (<1) 0 3 (1) 0 1 (<1) 0 0 0 1 (<1) increased Creatinine renal clearance 0 3 (1) 0 0 0 3 (1) 1 (<1) 2 (<1) 1 (<1) 0 0 4 (1) decreased Alanine aminotransferase 0 2 (<1) 0 0 0 2 (<1) 0 0 1 (<1) 0 0 1 (<1) increased Blood glucose abnormal 2 (<1) 0 0 0 0 2 (<1) 0 0 0 0 0 0 Transaminases increased 0 1 (<1) 1 (<1) 0 0 2 (<1) 0 0 0 0 0 0 Vitamin D decreased 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Aortic bruit 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Blood cholesterol increased 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Blood creatinine increased 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Blood triglycerides increased 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Carbon dioxide decreased 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Electrocardiogram 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 repolarization abnormality Heart rate increased 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hepatic enzyme increased 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Low density lipoprotein 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 increased Mycoplasma test positive 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Platelet count decreased 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Protein urine present 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vitamin D increased 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Weight decreased 0 0 0 1 (<1) 0 1 (<1) 0 2 (<1) 0 0 0 2 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Weight increased 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Glomerular filtration rate 0 0 0 0 0 0 0 3 (1) 0 0 0 3 (1) decreased Blood folate decreased 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Electrocardiogram QT 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) prolonged Hemoglobin decreased 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Abnormal brain nuclear 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) magnetic resonance imaging Total lung capacity decreased 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Treponema test positive 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) White blood cell count 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) decreased Psychiatric disorders Any event 26 (9) 11 (4) 0 0 1 (<1) 38 (13) 17 (6) 9 (3) 1 (<1) 0 0 27 (10) Anxiety 9 (3) 3 (1) 0 0 1 (<1) 13 (5) 3 (1) 3 (1) 0 0 0 6 (2) Insomnia 6 (2) 1 (<1) 0 0 0 7 (2) 2 (<1) 2 (<1) 0 0 0 4 (1) Depression 3 (1) 3 (1) 0 0 0 6 (2) 2 (<1) 2 (<1) 0 0 0 4 (1) Abnormal dreams 5 (2) 0 0 0 0 5 (2) 1 (<1) 0 0 0 0 1 (<1) Depressed mood 3 (1) 0 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Decreased libido 2 (<1) 1 (<1) 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Panic attack 0 3 (1) 0 0 0 3 (1) 0 0 0 0 0 0 Adjustment disorder with 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 depressed mood Sleep disorder 2 (<1) 0 0 0 0 2 (<1) 3 (1) 0 0 0 0 3 (1) Adjustment disorder 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Affect lability 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Affective disorder 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Anxiety disorder 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Intentional self-injury 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Nervousness 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Nightmare 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Paranoia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Stress 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Suicidal ideation 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Acute stress disorder 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Drug abuse 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Major depression 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Suicide attempt 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) Metabolism and nutrition disorders Any event 26 (9) 5 (2) 1 (<1) 1 (<1) 0 33 (12) 15 (5) 7 (2) 1 (<1) 0 0 23 (8) Vitamin D deficiency 21 (7) 2 (<1) 0 0 0 23 (8) 10 (4) 3 (1) 0 0 0 13 (5) Hypovitaminosis 3 (1) 0 0 0 0 3 (1) 1 (<1) 0 0 0 0 1 (<1) Hypercholesterolemia 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Hyperlipasemia 1 (<1) 0 1 (<1) 0 0 2 (<1) 0 0 0 0 0 0 Diabetes mellitus 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Diabetic ketoacidosis 0 0 0 1 (<1) 0 1 (<1) 0 0 0 0 0 0 Impaired glucose tolerance 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hypertriglyceridemia 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Hypomagnesemia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Type 2 diabetes mellitus 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Hypophosphatemia 0 0 0 0 0 0 1 (<1) 2 (<1) 1 (<1) 0 0 4 (1) Gout 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Hypocalcemia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Hypokalemia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Increased appetite 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Iron deficiency 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Lactose intolerance 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Injury, poisoning and procedural complications Any event 18 (6) 11 (4) 0 1 (<1) 1 (<1) 31 (11) 23 (8) 12 (4) 1 (<1) 1 (<1) 0 37 (13) Contusion 5 (2) 2 (<1) 0 0 0 7 (2) 1 (<1) 1 (<1) 0 0 0 2 (<1) Laceration 2 (<1) 2 (<1) 0 1 (<1) 0 5 (2) 1 (<1) 1 (<1) 0 0 0 2 (<1) Arthropod bite 1 (<1) 2 (<1) 0 0 0 3 (1) 7 (2) 0 0 0 0 7 (2) Fall 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Multiple injuries 1 (<1) 0 1 (<1) 0 0 2 (<1) 0 0 0 0 0 0 Ankle fracture 0 1 (<1) 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Arthropod sting 0 0 0 0 1 (<1) 1 (<1) 2 (<1) 1 (<1) 0 0 0 3 (1) Foot fracture 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Heat stroke 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Injury 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Joint injury 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Ligament sprain 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Meniscus injury 0 1 (<1) 0 0 0 1 (<1) 0 1 (<1) 0 0 0 1 (<1) Muscle strain 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Neck injury 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Penile contusion 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Skin abrasion 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Skin injury 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Spinal column injury 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Tendon injury 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Thermal burn 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Traumatic hematoma 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Wound 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Limb injury 0 0 0 0 0 0 1 (<1) 1 (<1) 0 0 0 2 (<1) Penis injury 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Procedural pain 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Bone contusion 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Craniocerebral injury 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Epicondylitis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Exposure via inhalation 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Fracture 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Hand fracture 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Joint dislocation 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Postlumbar puncture syndrome 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) Postprocedural hemorrhage 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Rib fracture 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Road traffic accident 0 0 0 0 0 0 0 0 0 1 (<1) 0 1 (<1) Skin abrasion 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Soft tissue injury 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Sunburn 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Tibia fracture 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Urethral injury 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Wound 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Any event 17 (6) 4 (1) 2 (<1) 0 0 23 (8) 15 (5) 4 (1) 0 0 0 19 (7)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Anogenital warts 11 (4) 1 (<1) 0 0 0 12 (4) 4 (1) 2 (<1) 0 0 0 6 (2) Skin papilloma 3 (1) 0 0 0 0 3 (1) 2 (<1) 0 0 0 0 2 (<1) Acrochordon 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Adenocarcinoma of colon 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Anal neoplasm 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Benign spleen tumor 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Dysplastic nevus 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Kidney angiomyolipoma 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Lipoma 0 1 (<1) 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Skin cancer 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Uterine leiomyoma 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Melanocytic nevus 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Oral papilloma 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Breast cancer 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Kaposi’s sarcoma 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Skin neoplasm 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Oral fibroma 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Reproductive system and breast disorders Any event 13 (5) 6 (2) 0 0 0 19 (7) 13 (5) 5 (2) 0 0 0 18 (6) Cervical dysplasia 6 (2) 0 0 0 0 6 (2) 0 2 (<1) 0 0 0 2 (<1) Erectile dysfunction 2 (<1) 3 (1) 0 0 0 5 (2) 1 (<1) 0 0 0 0 1 (<1) Atrophic vulvovaginitis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Breast discharge 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Breast mass 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Cervix disorder 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Menopausal symptoms 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Menstruation irregular 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Ovarian cyst 0 1 (<1) 0 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 Polymenorrhea 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Priapism 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Prostatitis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Genital lesion 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Breast pain 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Dysfunctional uterine bleeding 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Dysmenorrhea 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Testicular pain 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Vaginal discharge 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vaginal dysplasia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vaginal hemorrhage 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vaginal ulceration 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Varicocele 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vulvar dysplasia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Vulvovaginal pruritus 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Blood and lymphatic system disorders Any event 12 (4) 2 (<1) 0 0 1 (<1) 15 (5) 7 (2) 4 (1) 0 0 0 11 (4) Anemia 5 (2) 1 (<1) 0 0 0 6 (2) 3 (1) 1 (<1) 0 0 0 4 (1) Eosinophilia 2 (<1) 1 (<1) 0 0 0 3 (1) 2 (<1) 0 0 0 0 2 (<1) Lymphadenopathy 2 (<1) 0 0 0 0 2 (<1) 2 (<1) 2 (<1) 0 0 0 4 (1) Iron deficiency anemia 1 (<1) 0 0 0 0 1 (<1) 2 (<1) 0 0 0 0 2 (<1) Leukocytosis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Lymphadenitis 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 0 0 Normocytic anemia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Splenomegaly 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hypochromic anemia 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Renal and urinary disorders Any event 11 (4) 1 (<1) 0 0 1 (<1) 13 (5) 7 (2) 2 (<1) 0 0 0 9 (3) Dysuria 5 (2) 0 0 0 0 5 (2) 2 (<1) 0 0 0 0 2 (<1) Proteinuria 0 1 (<1) 0 0 1 (<1) 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Urinary calculus 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Glomerulonephritis 0 0 0 0 1 (<1) 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) Micturition urgency 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Nephrolithiasis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Nephropathy 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Pollakiuria 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Renal failure 0 0 0 0 0 0 0 2 (<1) 0 0 0 2 (<1) Urethral caruncle 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Urethral discharge 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Urethral pain 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1)

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Urinary incontinence 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Eye disorders Any event 8 (3) 4 (1) 0 0 0 12 (4) 7 (2) 1 (<1) 0 0 0 8 (3) Astigmatism 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Blepharitis 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Chalazion 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Diabetic retinopathy 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Dry eye 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Eye allergy 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Eye irritation 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Glare 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Glaucoma 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Meibomian gland dysfunction 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Myopia 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Uveitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vitreous detachment 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Asthenopia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Blepharospasm 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Cataract 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Chorioretinal disorder 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Conjunctivitis allergic 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) Eye pruritus 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Lacrimation increased 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Ear and labyrinth disorders Any event 7 (2) 2 (<1) 0 0 1 (<1) 10 (4) 6 (2) 0 0 0 0 6 (2) Vertigo 2 (<1) 2 (<1) 0 0 0 4 (1) 2 (<1) 0 0 0 0 2 (<1) Cerumen impaction 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Ear pain 1 (<1) 0 0 0 1 (<1) 2 (<1) 3 (1) 0 0 0 0 3 (1) Deafness 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Noninfective myringitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vertigo positional 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Hypoacusis 0 0 0 0 0 0 2 (<1) 0 0 0 0 2 (<1) Tinnitus 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Immune system disorders

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Any event 10 (4) 0 0 0 0 10 (4) 3 (1) 0 0 0 0 3 (1) Seasonal allergy 6 (2) 0 0 0 0 6 (2) 1 (<1) 0 0 0 0 1 (<1) Hypersensitivity 2 (<1) 0 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) Food allergy 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Mite allergy 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Vascular disorders Any event 5 (2) 5 (2) 0 0 0 10 (4) 3 (1) 1 (<1) 0 0 0 4 (1) Hypertension 3 (1) 1 (<1) 0 0 0 4 (1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Circulatory collapse 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Hot flush 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hypertensive crisis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Intermittent claudication 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Peripheral artery thrombosis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Peripheral ischemia 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Superficial thrombophlebitis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Hyperemia 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Peripheral venous disease 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Hepatobiliary disorders Any event 2 (<1) 3 (1) 1 (<1) 0 0 6 (2) 0 0 1 (<1) 0 0 1 (<1) Hyperbilirubinemia 0 2 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Bile duct stone 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Cholecystitis 0 0 1 (<1) 0 0 1 (<1) 0 0 0 0 0 0 Cholelithiasis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hepatic steatosis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Toxic hepatitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hydrocholecystis 0 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 0 Nonalcoholic steatohepatitis 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Hepatic cirrhosis 0 0 0 0 0 0 0 0 1 (<1) 0 0 1 (<1) Cardiac disorders Any event 2 (<1) 1 (<1) 0 0 0 3 (1) 0 0 0 0 0 0 Cardiovascular disorder 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 Atrioventricular block first degree 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Congenital, familial and genetic disorders Any event 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 0 0 0 0 1 (<1) Gilbert's syndrome 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0

LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) System Organ Class and Event 1 2 3 4 NR* Total 1 2 3 4 NR* Total Follicular keratosis 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Endocrine disorders Any event 1 (<1) 0 0 0 0 1 (<1) 1 (<1) 1 (<1) 0 0 0 2 (<1) Hypogonadism 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Goiter 0 0 0 0 0 0 0 1 (<1) 0 0 0 1 (<1) Hypothyroidism 0 0 0 0 0 0 1 (<1) 0 0 0 0 1 (<1) Surgical and medical procedures Any event 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 Tooth extraction 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 *NR indicates event severity grade was not reported. CAR denotes current antiretroviral therapy, ITT-E intention-to-treat exposed, LA long acting.

Table S4. Serious Adverse Events – Maintenance Phase

LA Arm CAR Arm N=283 N=283 Event no. participants (%) Any serious adverse event 18 (6) 12 (4) Hepatitis A 3 (1) 1 (<1) Anogenital warts 1 (<1) 1 (<1) Pyelonephritis 1 (<1) 0 Anal fistula 1 (<1) 0 Colitis 1 (<1) 0 Enterocolitis 1 (<1) 0 Umbilical hernia 1 (<1) 0 Adenocarcinoma of colon 1 (<1) 0 Laceration 1 (<1) 0 Pyrexia 1 (<1) 0 Bile duct stone 1 (<1) 0 Cholecystitis 1 (<1) 0 Hydrocholecystis 1 (<1) 0 Weight decreased 1 (<1) 0 Diabetic ketoacidosis 1 (<1) 0 Arthritis 1 (<1) 0 Priapism 1 (<1) 0 Peripheral artery thrombosis 1 (<1) 0 Peripheral ischemia 1 (<1) 0 Anal abscess 0 1 (<1) Bronchitis pneumococcal 0 1 (<1) Gastroenteritis 0 1 (<1) Viral infection 0 1 (<1) Large intestine perforation 0 1 (<1) Rectal fissure 0 1 (<1) Breast cancer 0 1 (<1) Kaposi's sarcoma 0 1 (<1) Road traffic accident 0 1 (<1) Tibia fracture 0 1 (<1) Systemic inflammatory response syndrome 0 1 (<1) Drug abuse 0 1 (<1) Suicide attempt 0 1 (<1) Some participants experienced multiple serious adverse events. CAR denotes current antiretroviral therapy, and LA long-acting.

Table S5. Adverse Events Leading to Withdrawal – Maintenance Phase

LA Arm CAR Arm Preferred Term, n (%) N=283 N=283 Any event 9 (3) 4 (1) Acute hepatitis B 2 (<1) 0 Hepatitis A 2 (<1) 0 Acute hepatitis C 1 (<1) 0 Secondary syphilis 1 (<1) 0 Injection site pain 2 (<1) 0 Discomfort 1 (<1) 0 Fatigue 0 1 (<1) Diarrhea 1 (<1) 0 Nausea 0 1 (<1) Vomiting 1 (<1) 0 Amnesia 0 1 (<1) Disturbances in attention 0 1 (<1) Dizziness 0 1 (<1) Dysarthria 0 1 (<1) Transaminases increased 1 (<1) 0 Adenocarcinoma of colon 1 (<1) 0 Sucide attempt 0 1 (<1) Renal failure 0 1 (<1)

CAR denotes current antiretroviral therapy, LA long acting.

Table S6. Emergent Laboratory Abnormalities by Maximum Toxicity Grade – Maintenance Phase

Maximum Toxicity Grade LA Arm, N=283 CAR Arm, N=283 no. participants (%) no. participants (%) Event 1 2 3 4 Total 1 2 3 4 Total Chemistry Alanine aminotransferase (IU/L) 28 (10) 9 (3) 4 (1) 3 (1) 44 (16) 22 (8) 4 (1) 1 (<1) 2 (<1) 29 (10) Albumin (g/L) 1 (<1) 0 0 0 1 (<1) 0 0 0 0 0 Alkaline phosphatase (IU/L) 6 (2) 1 (<1) 1 (<1) 0 8 (3) 3 (1) 0 0 0 3 (1) Aspartate aminotransferase (IU/L) 32 (11) 13 (5) 5 (2) 4 (1) 54 (19) 25 (9) 6 (2) 2 (<1) 2 (<1) 35 (12) Bilirubin (µmol/L) 28 (10) 8 (3) 0 1 (<1) 37 (13) 12 (4) 1 (<1) 0 1 (<1) 14 (5) Carbon dioxide (mmol/L) 87 (31) 8 (3) 0 0 95 (34) 95 (34) 7 (2) 0 0 102 (36) Cholesterol (mmol/L) 30 (11) 15 (5) 0 0 45 (16) 18 (6) 8 (3) 0 0 26 (9) Creatine kinase (IU/L) 37 (13) 9 (3) 13 (5) 10 (4) 69 (24) 19 (7) 19 (7) 4 (1) 10 (4) 52 (18) Creatinine (µmol/L) 4 (1) 1 (<1) 0 0 5 (2) 9 (3) 2 (<1) 0 1 (<1) 12 (4) Direct bilirubin (µmol/L) 0 0 14 (5) 0 14 (5) 0 0 2 (<1) 0 2 (<1) Estimated GFR† (mL/sec/1.73 m2) 0 36 (13) 2 (<1) 0 38 (13) 0 61 (22) 12 (4) 1 (<1) 74 (26) Glucose (mmol/L) 62 (22) 24 (8) 1 (<1) 1 (<1) 88 (31) 69 (24) 20 (7) 0 1 (<1) 90 (32) Hyperglycemia (mmol/L) 51 (18) 23 (8) 1 (<1) 0 75 (27) 57 (20) 19 (7) 0 0 76 (27) Hyperkalemia (mmol/L) 3 (1) 1 (<1) 0 0 4 (1) 2 (<1) 1 (<1) 0 1 (<1) 4 (1) Hypernatremia (mmol/L) 6 (2) 0 0 0 6 (2) 5 (2) 0 0 0 5 (2) Hypoglycemia (mmol/L) 12 (4) 1 (<1) 0 0 13 (5) 12 (4) 1 (<1) 0 0 13 (5) Hypokalemia (mmol/L) 5 (2) 0 0 0 5 (2) 4 (1) 0 0 0 4 (1) Hyponatremia (mmol/L) 12 (4) 1 (<1) 0 0 13 (5) 10 (4) 0 1 (<1) 0 11 (4) LDL cholesterol calculation (mmol/L) 31 (11) 7 (2) 4 (1) 0 42 (15) 11 (4) 1 (<1) 0 0 12 (4) Lipase (U/L) 20 (7) 24 (8) 14 (5) 4 (1) 62 (22) 24 (8) 23 (8) 7 (2) 1 (<1) 55 (19) Phosphate (mmol/L) 22 (8) 44 (16) 11 (4) 0 77 (27) 22 (8) 39 (14) 6 (2) 0 67 (24) Potassium (mmol/L) 8 (3) 1 (<1) 0 0 9 (3) 6 (2) 1 (<1) 0 1 (<1) 8 (3) Sodium (mmol/L) 18 (6) 1 (<1) 0 0 19 (7) 15 (5) 0 1 (<1) 0 16 (6) Triglycerides (mmol/L) 14 (5) 3 (1) 2 (<1) 0 19 (7) 24 (8) 5 (2) 1 (<1) 0 30 (11) Hematology Hemoglobin (g/L) 3 (1) 0 1 (<1) 0 4 (1) 5 (2) 0 2 (<1) 0 7 (2) Leukocytes (109/L) 1 (<1) 1 (<1) 0 0 2 (<1) 2 (<1) 1 (<1) 0 0 3 (1) Neutrophils (109/L) 8 (3) 6 (2) 0 0 14 (5) 5 (2) 6 (2) 0 1 (<1) 12 (4) Platelets (109/L) 10 (4) 1 (<1) 0 0 11 (4) 3 (1) 1 (<1) 1 (<1) 1 (<1) 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. CAR denotes current antiretroviral therapy, and LA long-acting. 44

Table S7. Patient-Reported Outcomes

A. HIVTSTc

Adjusted Mean Treatment N* Adjusted Mean (SE) Difference (95% CI) P-value LA 263 29.6 (0.49) 4.1 (2.8, 5.5) <0.001 CAR 266 25.5 (0.48)

HIVTSQ change version (HIVTSQc) was administered only at week 48 to assess how treatment satisfaction in participants receiving CAB + RPV or CAR had changed from the induction phase of the study and to address potential ceiling effects observed with the use of HIVTSQs alone at baseline and at weeks 24 and 44.

Based on ANOVA: HIVTSTc Total Score = induction baseline (week −20) HIV-1 RNA (<100,000, 100,000 c/mL) + sex at birth (female, male) + age (<50, 50 years) + race (white, nonwhite) + treatment (LA, CAR).

CAB denotes cabotegravir, CAR current antiretroviral therapy, LA long acting.

*Participants who completed the questionnaire at Week 48 or early withdrawal.

B. Preference Question

Participants in the LA arm were asked to respond to this question:

For the past 44 weeks you have received long acting injectable HIV medication every month. Today we would like you to compare your experience on the long acting injections with the oral medication you received during the induction phase of the study. Which therapy do you prefer? Please tick the box. □ Monthly injections of long-acting HIV treatment □ Daily oral HIV treatment

ITT-E Population Questionnaire Responders Response, n (%) N=283 N=259 Preferred LA treatment 257 (90.8) 257 (99.2) Preferred daily oral treatment 2 (0.7) 2 (0.8) No response 24 (8.5) − ITT-E denotes intention-to-treat exposed, LA long acting.

References

1. Centers for Disease Control and Prevention (CDC). Revised Surveillance Case Definition for HIV Infection – United States, 2014. MMWR 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; 23:132–141.

3. Levey AS, Stevens LA, Schmid CH, et.al. A new equation to estimate glomerular filtration rate. Ann Int Med 2009; 150:604–612.