Phase II Safety and Acceptability of an Investigational Injectable Product, TMC278LA, for Pre-Exposure Prophylaxis (TMC278LA)

HPTN 076 - Phase II Safety and Acceptability of an Investigational Injectable Product, TMC278 LA, for Pre-Exposure Prophylaxis (PrEP)

This is a multi-site, double-blinded, two-arm, two:one, randomized, trial comparing the safety of an intramuscular (IM) injection of TMC278 LA to a placebo given once every eight weeks over a 40 week period among sexually active, HIV- uninfected women.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus (HIV)
• Intervention / Treatment: Drug: Rilpivirine; Drug: Placebo

Detailed Description

This is a multi-site, double-blinded, two-arm, two:one randomized, placebo-controlled trial comparing the safety of TMC278 LA for 48 weeks after the initial 1M injection to a saline (0.9%NaCI) placebo IM injection among sexually active, HIV-uninfected women who are assessed by the clinic staff as being at "low risk" for HIV acquisition (in keeping with a safety trial). Approximately 132 women will be randomized to TMC278 LA and placebo in approximately a two:one ratio (88 and 44 in the TMC278 LA and placebo arm, respectively).

Approximately 96 women will be enrolled in SSA and approximately 36 women will be enrolled in the US. In order to screen for initial safety and tolerability of the active product, a run-in period with oral rilpivirine will precede the injection of TMC278 LA. Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit. A subset of approximately 24 women at US sites will have vaginal tissue collection for PK studies at a single follow-up visit (Tissue Subset).

Participants who present with Grade 2 or greater RELATED AEs during the oral-run in phase will not receive the injectable TMC278 LA. Participants who present with Grade 3 or 4 UNRELATED AEs will not proceed to the injectable phase unless approved by the Clinical Management Committee (CMC).

Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections).

Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections).

Study sites:

• Bronx Prevention Center CRS, USA
• New Jersey Medical School CRS, USA
• Emavundleni CRS, Cape Town, South Africa
• Spilhaus CRS, Harare, Zimbabwe

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Cape Town, South Africa
    • Emavundleni Clinical Research Site
• United States
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School Clinical Research Center
  • New York
    • Bronx, New York, United States, 10451
      • Bronx Prevention Center
• Zimbabwe
  • Harare
    • Belgravia, Harare, Zimbabwe
      • Spilhaus Clinical Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria: Women who meet all of the following criteria will be eligible for inclusion in the study:

• Women, 18- 45 years (inclusive) of age at Enrollment
• Female at birth
• Willing and able to provide informed consent to take part in the study
• Willing and able to provide adequate locator information
• Willing and able to provide acceptability and adherence assessments throughout the study
• Understands and agrees to local reporting requirements for sexually transmitted infections (STis)
• No evidence of an active STI, women who have an STI (Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC), or syphilis) identified at the Screening visit are ineligible*
• Per participant report, no diagnosis of GC, CT, or syphilis in the last 6 months
• Availability to return for all study visits and participate in all study-related procedures, barring unforeseen circumstances
• Per participant report, using (or willing to use) an acceptable form of contraception (e.g., intrauterine device [IUD], hormonal contraception [DMPA], oral, injectable, transdermal patch, implants) from screening until one month after last study visit or surgical sterilization of the participant
• Must agree to use condoms for the duration of the study
• Must agree not to participate in other concurrent drug or vaccine trials
• Normal laboratory values**

(HIV tests performed at Screening and Enrollment are non- reactive/negative (see Study Specific Procedures (SSP) Manual)

• Hemoglobin (women) =:: 10.5 g/dL
• Absolute neutrophil count1,000 cells/mm 3
• Platelet count=:: 100,000/mm3
• Calculated creatinine clearance =:: 70 mL!minute using the Cockcroft-Gault equation
• Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) < 2 times the upper limit of normal (ULN)
• Total bilirubin < 2.5 ULN

• Urine protein< 2+

  • Women who have an STI identified at the Screening visit (CT, GC, or syphilis) will be provided treatment but are ineligible. Women who report having CT, GC, or syphilis in the last six months are ineligible.

    • Specimens for Screening labs must be obtained within 28 days prior to study Enrollment.

3.1.1 Inclusion Criteria for the Tissue Subset (US sites only) A subset of approximately 24 participants at US sites will participate in more intensive sampling of vaginal tissue during Week 36 (preferred) or Week 44.

For these participants, the following additional criteria need to be met:

•Satisfactory Pap results in the 12 calendar months prior to biopsy consistent with Grade 0 according to the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated August 2009), or satisfactory evaluation with no treatment required of Grade 1 or higher Pap result per American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines in the 12 calendar months prior to biopsy is required, as indicated.

If there is no documentation of satisfactory Pap results, and if indicated, the participant should be offered to have the test performed by the site prior to enrollment in the Tissue Subset. If Pap testing is indicated and participants decline, they are not eligible for the Tissue Subset.

• In addition to documentation of satisfactory Pap results, women must have normal laboratory results for coagulation tests to be eligible for the Tissue Subset. Abnormal coagulation test results may indicate an increased risk of bleeding.
• Women have to be willing to abstain from vaginal intercourse and practices involving insertion of anything in the vagina (drug, douche, penis, or sex toy) for 3 days prior to vaginal biopsy and for 7 days post-biopsy, to minimize risk of HIV-1 infection and bleeding complications after the procedure.
• Participants must not be pregnant at the time of vaginal sampling, based on pregnancy test results from previous visits and on the result of urine pregnancy test performed on the same day before the proposed vaginal sampling.
• Women undergoing biopsy must have received all prior injections of study product, in accordance with the protocol, to be eligible for inclusion.

Exclusion Criteria: Women who meet any of the following criteria will be excluded from the study:

• Experiencing early menopause using clinical criteria (amenorrhea greater than six months in absence of pregnancy) or a prior report of an abnormal Follicle Stimulating Hormone (FSH) test
• PrEP or post-exposure prophylaxis (PEP) for HIV exposure within 90 days prior to Screening
• Pregnant or last pregnancy outcome 90 days or less prior to Screening
• Currently breastfeeding
• Intends to become pregnant during the period of study participation
• Experiencing uncontrolled depression or active suicidal ideation
• History of recurrent urticaria
• Any history of anaphylaxis or severe allergy resulting in angioedema
• Any serious acute, chronic, or progressive disease (e.g. known history of neoplasm, cancer, insulin-dependent diabetes, cardiac disease, auto-immune disease), or with signs of cardiac disease, renal failure, or severe malnutrition
• Any laboratory abnormalities that are Grade 2 or higher, according to the DAIDS Toxicology tables (please see Section 6.1 for a list of Screening laboratory tests)
• Recreational injection drug use in the 52 weeks prior to screening
• Participating or plans to participate in another research study involving study drugs, vaccines or medical devices
• Participated in another research study involving study drugs, vaccines or medical devices within the four weeks prior to screening; may be longer than four weeks depending on half-life of study drug
• Past participation in an HIV vaccine study
• Has plans to relocate and cannot attend the visits at the clinic
• Per participant report at Screening, current or anticipated ongoing use and/or unwillingness to abstain from contraindicated medications or supplements (listed in the SSP Manual)
• Abnormal resting EKG at screening including:
• Abnormal sinus rhythm (heart rate below 40 or above 100 beats per minute)
• QTcF interval> 450 ms
• QRS interval < 50 ms
• QRS interval > 120 ms
• PR interval> 210 ms
• History of additional risk factors for Torsade de Pointes (TdP), such as heart failure, hypokalemia, hypomagnesia, family history of known long QT syndrome, or sudden death at young age (S 40 years) in a first-degree relative (i.e., biological parent, sibling, or offspring)
• Currently active Tuberculosis (TB), or undergoing treatment for the same (by self-report)
• Any signs or symptoms consistent with acute (pre-seroconversion) HIV infection, or self-reported concern about recent HIV infection
• Any reactive or positive HIV test at Screening or Enrollment, even if the person is confirmed to be HIV-uninfected
• Has any other condition that, in the opinion of the site loR or designee, would preclude informed consent, make study participation unsafe, interfere with adherence, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives (e.g., at increased risk of cardiovascular vents)

Women who do not meet eligibility criteria because of an abnormal EKG, risk factors for TdP, an STI (GC, CT, or syphilis) present at Screening or report of an STI (GC, CT, or syphilis) in the past 6 months, or a history of arrhythmia may not be re-screened.

Women who present at Screening with symptoms consistent with an acute HIV infection or who have a reactive HIV test may not be re-screened. Women who do not meet eligibility criteria for the study for other reason(s) may be re-screened at a future date at the discretion of the site loR.

3.2.1 Exclusion Criteria for the Tissue Subset (US sites only)

Participants of the Tissue Subset must meet the above eligibility criteria to be enrolled in HPTN 076. Participants interested in participating in the Tissue Subset must meet additional inclusion and exclusion criteria. Women who meet any of the following criteria will be excluded from the Tissue Subset:

• Unwillingness to abstain from the following medications for a period of 10 days before a biopsy procedure:
• Aspirin*

• Non-steroidal anti-inflammatory drugs (NSAIDS)

  *Daily use of low-dose aspirin (no more than 81 mg) is allowed at the discretion of the loR.

• Unwillingness to abstain from the following medications for 3 days prior to vaginal biopsy and for 7 days post-biopsy: Heparin, including Lovenox®, Warfarin, Plavix® (clopidogrel bisulfate), and any other drugs that are associated with increased risk of bleeding following biopsy procedures at the discretion of the loR.
• Carcinoma in situ of the cervix or invasive cervical cancer. Abnormalities of the vaginal mucosa or significant vaginal symptom(s), which in the opinion of the loR represent a contraindication to biopsy (including but not limited to presence of any unresolved injury, and infectious or inflammatory condition of the local mucosa).
• Hysterectomy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rilpivirine; Arm 1: Participants randomized to the active arm will receive rilpivirine 25 mg capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of TMC278 LA, 1200 mg dose, at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion 1200 mg of TMC278 LA will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections).	Drug: Rilpivirine; Rilpivirine (TMC278), a non-nucleoside reverse transcriptase inhibitor (NNRTI) is a substituted diaryl-pyrimidine (DAPY) derivative with potent antiviral activity against HIV. It is approved by the US FDA for once daily oral administration and is effective as part of treatment for ARV-na'ive HIV-infected patients as rilpivirine 25 mg capsules. It is also co-formulated with TDF and FTC for use as a once- daily single fixed-dose combination (Complera™).
Placebo Comparator: Placebo; Arm 2: Participants randomized to the placebo arm will receive placebo capsules once daily for four weeks to be taken orally with a meal. Participants will then receive IM injections of saline (0.9% NaCI) at eight week intervals (at Weeks 4, 12, 20, 28, 36 and 44). On each dosing occasion placebo will be delivered in two, 2 mL injections, one in each gluteus maximus muscle. All participants will receive a total of six doses (12 IM injections).	Drug: Placebo; Participants randomized to the placebo arm will receive oral placebo capsules prior to injection of saline solution (0.9%NaCI). Participants will be observed while taking the study product by site staff on approximately six occasions during the first two weeks of the oral run-in at Week 0 (Enrollment), at Week 2 (Oral Run-in Safety Visit), and on four separate DOT visits between Weeks 0 and 2. Cervicovaginal and rectal fluid will be collected for PK studies at a single follow-up visit.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Any Grade 2 or Higher AEs During Injection Phase	Number of participants experiencing any Grade 2 or higher clinical and laboratory AEs to evaluate the safety of the injectable product, TMC278 LA (1200 mg dose administered at Weeks 4, 12, 20, 28, 36 and 44), through 48 weeks after initial injection (at Week 52) in women in SSA and the US.	Up to 52 weeks

Collaborators and Investigators

• Sponsor: PATH
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); Bill and Melinda Gates Foundation
• Investigators: Principal Investigator: Jessica Justman, MD, Bronx-Lebanon Hospital Center Clinical Research Site; Principal Investigator: Shobha Swaminathan, MD, New Jersey Medical School Clinical Research Site; Principal Investigator: Zvavahera Michael Chirenje, MD, MSc, Spilhaus Clinical Research Site; Study Chair: Linda-Gail Bekker, PhD, The Desmond Tutu HIV Centre

Publications and helpful links

General Publications

• Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapia M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernandez T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallas EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. doi: 10.1056/NEJMoa1011205. Epub 2010 Nov 23.
• Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, Malahleha M, Owino F, Manongi R, Onyango J, Temu L, Monedi MC, Mak'Oketch P, Makanda M, Reblin I, Makatu SE, Saylor L, Kiernan H, Kirkendale S, Wong C, Grant R, Kashuba A, Nanda K, Mandala J, Fransen K, Deese J, Crucitti T, Mastro TD, Taylor D; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012 Aug 2;367(5):411-22. doi: 10.1056/NEJMoa1202614. Epub 2012 Jul 11.
• Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, Henderson FL, Pathak SR, Soud FA, Chillag KL, Mutanhaurwa R, Chirwa LI, Kasonde M, Abebe D, Buliva E, Gvetadze RJ, Johnson S, Sukalac T, Thomas VT, Hart C, Johnson JA, Malotte CK, Hendrix CW, Brooks JT; TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012 Aug 2;367(5):423-34. doi: 10.1056/NEJMoa1110711. Epub 2012 Jul 11.
• Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, Chiamwongpaet S, Kitisin P, Natrujirote P, Kittimunkong S, Chuachoowong R, Gvetadze RJ, McNicholl JM, Paxton LA, Curlin ME, Hendrix CW, Vanichseni S; Bangkok Tenofovir Study Group. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013 Jun 15;381(9883):2083-90. doi: 10.1016/S0140-6736(13)61127-7. Epub 2013 Jun 13.
• Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum C; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012 Aug 2;367(5):399-410. doi: 10.1056/NEJMoa1108524. Epub 2012 Jul 11.
• Haberer JE, Kahane J, Kigozi I, Emenyonu N, Hunt P, Martin J, Bangsberg DR. Real-time adherence monitoring for HIV antiretroviral therapy. AIDS Behav. 2010 Dec;14(6):1340-6. doi: 10.1007/s10461-010-9799-4.
• Bekker LG, Beyrer C, Quinn TC. Behavioral and biomedical combination strategies for HIV prevention. Cold Spring Harb Perspect Med. 2012 Aug 1;2(8):a007435. doi: 10.1101/cshperspect.a007435.
• Soto RJ, Ghee AE, Nunez CA, Mayorga R, Tapia KA, Astete SG, Hughes JP, Buffardi AL, Holte SE, Holmes KK; Estudio Multicentrico Study Team. Sentinel surveillance of sexually transmitted infections/HIV and risk behaviors in vulnerable populations in 5 Central American countries. J Acquir Immune Defic Syndr. 2007 Sep 1;46(1):101-11.
• Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV transmission: how to make them work better. Lancet. 2008 Aug 23;372(9639):669-84. doi: 10.1016/S0140-6736(08)60886-7. Epub 2008 Aug 5.
• Kashuba AD, Patterson KB, Dumond JB, Cohen MS. Pre-exposure prophylaxis for HIV prevention: how to predict success. Lancet. 2012 Jun 30;379(9835):2409-2411. doi: 10.1016/S0140-6736(11)61852-7. Epub 2011 Dec 6. No abstract available.
• Seneviratne HK, Tillotson J, Lade JM, Bekker LG, Li S, Pathak S, Justman J, Mgodi N, Swaminathan S, Sista N, Farrior J, Richardson P, Hendrix CW, Bumpus NN. Metabolism of Long-Acting Rilpivirine After Intramuscular Injection: HIV Prevention Trials Network Study 076 (HPTN 076). AIDS Res Hum Retroviruses. 2021 Mar;37(3):173-183. doi: 10.1089/AID.2020.0155. Epub 2021 Jan 13.
• Tolley EE, Li S, Zangeneh SZ, Atujuna M, Musara P, Justman J, Pathak S, Bekker LG, Swaminathan S, Stanton J, Farrior J, Sista N. Acceptability of a long-acting injectable HIV prevention product among US and African women: findings from a phase 2 clinical Trial (HPTN 076). J Int AIDS Soc. 2019 Oct;22(10):e25408. doi: 10.1002/jia2.25408.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): April 13, 2015
• Study Completion (Actual): March 9, 2017

Study Registration Dates

• First Submitted: May 21, 2014
• First Submitted That Met QC Criteria: June 13, 2014
• First Posted (Estimate): June 17, 2014

Study Record Updates

• Last Update Posted (Actual): August 27, 2018
• Last Update Submitted That Met QC Criteria: July 27, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: HIV Pre-exposure Prophylaxis;; long-acting injectable;; HIV PrEP;; biomedical HIV prevention research
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Rilpivirine
• Other Study ID Numbers: HPTN 076; UM1AI068619 (U.S. NIH Grant/Contract); 1015131 (Other Grant/Funding Number: Bill & Melinda Gates Foundation (along with NIH for HPTN))