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)

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

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

Lead Investigator Site

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- Hospital Civil de Guadalajara Fray Antonio Alcalde, Villanueva 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

Lead Investigator Site

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 Hospital Universitario Virgen del Rocío, Sevilla Fernández 71 Maria Del Mar Masia Hospital General de Elche, Elche Canuto 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

Lead Investigator Site

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 Josha Research, Bloemfontein Lombaard 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

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)

• 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.

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

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:

• 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.

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

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.

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.

Figure S1. Timeliness of Injections Relative to Target.

1800

1567 1600

1400

1200

1000

800

600

Number of Number Injection Visits 353 400 296 332 267 242 195 200 54 8 20 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 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.

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.

LA, n/N CAR, n/N 0.6 All patients 5/308 3/308

2.0 Female 2/99 0/104 Sex at birth 0.0 Male 3/209 3/204

1.9 NNRTI 4/155 1/155 Third agent -2.0 in baseline INSTI 0/102 2/99 regimen 2.0 PI 1/51 0/54

-1.3 <35 0/80 1/80 1.7 Age, years 35-49 4/162 1/132 0.5 ≥50 1/66 1/96

0.4 White 3/214 2/207 1.1 Non-white 2/94 1/101 Race 1.9 Black/Afr Amer 2/62 1/77 0.4 Non-black/AfrAmer 3/246 2/231

-3.7 <350 0/23 1/27 −19 CD4+ cell 3.6 350-499 2/56 0/57 count 0.4 ≥500 3/229 2/224

-10.0 -5.0 0.0 5.0 10.0 15.0 Unadjusted Difference in Proportion ± 95% CI Favors LA Favors CAR

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.

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

A Any Injection Site Reaction 100

80 64 60

40 35 23 22 18 18 17 14 15

20 13 12 10 Participants with ISRs (%) ISRs Participantswith

0 4 8 12 16 20 24 28 32 36 40 44 48 Study Week

B Pain C Nodule 100 100

80 80 64 60 60

40 35 40 23 22 18 18 17 14 15

20 13 12 10 20

Participants with ISRs (%) ISRs Participantswith (%) ISRs Participantswith 3 2 1 3 0.6 1 0.7 0.3 0.7 2 0.4 0.8 0 0 4 8 12 16 20 24 28 32 36 40 44 48 4 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 ISRs (%) ISRs Participantswith Participants with ISRs (%) ISRs Participantswith 5 2 1 2 1 1 1 0.7 1 1 1 0.4 3 2 0 1 0.3 1 0.7 0.7 1 0.4 1 0.4 0 0 4 8 12 16 20 24 28 32 36 40 44 48 4 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 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.

Table S1. Summary of Antiretroviral Agents Taken at Baseline.

LA Arm CAR Arm LA Arm CAR Arm ART, n (%) N=308 N=308 ART, n (%) N=308 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.

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

LA Arm CAR Arm N=308 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 1 0 therapy (even if only for peri-partum treatment), or only single or dual NRTI therapy prior to starting combination antiretroviral therapy Evidence of hepatitis B virus infection based on the results of testing 1 0 at screening for hepatitis B surface antigen Any drug holiday during the window between initiating first 0 2 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 Uninterrupted antiretroviral therapy for ≥6 months prior to screening. 8 12 Any prior switch must have occurred due to tolerability/safety, access to medications or simplification and must NOT have been done for virologic failure Females of non-childbearing potential, or if childbearing potential, 1 1 has a negative serum hCG test at screening and agrees to use an acceptable birth control method 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.

Table S3. Additional Secondary Endpoints.

A. HIV-1 RNA Plasma RNA at Week 48

Assessment N LA Arm N CAR Arm

HIV-1 RNA, Baseline 308 1.52 (0.17) 308 1.51 (0.04) mean (SD) log10 copies/mL Week 48 265 1.51 (0.05) 292 1.52 (0.11) HIV-1 RNA change from baseline, Week 48 265 -0.013 (0.19) 292 0.012 (0.12) mean (SD) log10 copies/mL

CAR denotes current antiretroviral therapy, LA long acting.

B. Post-Baseline HIV-1 Disease Progression

LA Arm CAR Arm Parameter, n (%) N=308 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.

Table S4. Confirmed Virologic Failure.

On-Treatment RAMs (HIV-1 RNA) Drug Sensitivity (Fold Change) at Baseline RAMs HIV-1 SVF Timepoint SVF Timepoint* (PBMC/HIV-1 DNA on Day 1) Treatment Arm Subtype 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 DLV (30) EFV (3.3) RAL (16) 2 LA A1/A none E138E/K none N155H none ETR (5.2) EVG (33) none none NVP (11) CAB (2.7) RPV (6.5) DLV (15) EFV (4.2) V108I V108V/I 3 LA AG none N88N/S none none ETR (5.8) none none E138K E138K NVP (16) RPV (3.7) CAR 4 A1 M184V G190S none none Phenotypic assay failed for RT/PR none M184M/I none (EFV+3TC+AZT) CAR 3TC (>97.2) 5 B M184I none none none none none none none (EVG/c+FTC+TDF) FTC (>97.2) CAR 6 B none none none none none none none none none (EVG/c+FTC+TAF) CAR 7 B none M230M/I none none none none none none none EVG/c+FTC+TDF

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).

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 no. participants (%) no. participants (%) System Organ Class and Event 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)

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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 1 (<1) 1 (<1) 0 0 0 2 (<1) 0 0 0 0 0 0 infection 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)

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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) 24

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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)

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 imbalance 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

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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 1 (<1) 1 (<1) 0 0 0 2 (<1) 1 (<1) 0 0 0 0 1 (<1) disease 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)

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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 2 (<1) 2 (<1) 1 (<1) 1 (<1) 0 6 (2) 2 (<1) 2 (<1) 0 0 0 4 (1) increased 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 1 (<1) 0 0 0 0 1 (<1) 0 0 0 0 0 0 time prolonged 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)

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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)

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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)

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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)

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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

Maximum Toxicity Grade* LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) System Organ Class and Event 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.

Table S6. Serious Adverse Events – Maintenance Phase.

LA Arm CAR Arm N=308 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.

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

LA Arm CAR Arm N=308 N=308 Event 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. CAR denotes current antiretroviral therapy, and LA long-acting.

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

Maximum Toxicity Grade LA Arm, N=308 CAR Arm, N=308 no. participants (%) no. participants (%) 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. CAR denotes current antiretroviral therapy, and LA long-acting.

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, Overall LA Population, At SVF Visit, Overall LA Population, Participants Geometric Mean Participants Geometric Mean CVF SVF with CVF (CVb%) [min, max] with CVF (CVb%) [min, max]

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.

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

Adjusted Mean Adjusted Mean Treatment Study N N Mean Change from Difference Arm Week (Observed) (LOCF) Score* (SD) Baseline (95% CI) (95% CI), LA − CAR

Baseline 302 302 55.25 (9.14) - -

LA 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)

Baseline 298 298 55.40 (8.68) - -

CAR 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.

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).