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

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.

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

Eligibility Criteria:
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.