Safety and Acceptability of Cabotegravir in HIV Uninfected Women in KwaZulu-Natal, South Africa

The CAPRISA 014 trial aims to assess the safety and acceptability of the long-acting (LA) injectable antiretroviral agent, cabotegravir LA (GSK1265744), in HIV uninfected women in KwaZulu-Natal, South Africa.

The CAPRISA 014 trial is designed to establish the safety and acceptability of cabotegravir LA in sexually active, at-risk HIV-uninfected women. A total of 632 HIV uninfected women (18 to 30 years) from two sites in KwaZulu-Natal, South Africa will be enrolled. The trial will be approximately 24 months, with an additional 12 months post-trial safety observation. The study is divided into three periods:

Period 1 - Clinical trial oral lead-in (up to 34 days) - Consenting participants will be randomized to receive daily oral cabotegravir (30mg tablets) or daily oral placebo for approximately 30 days, to assess safety and tolerability prior to exposure to the LA injectable formulation.

Period 2 - Clinical trial follow-up with injectable (approximately 48-96 weeks) - Participants who have successfully completed Period 1 will receive intra-muscular (IM) gluteal injections of cabotegravir LA (800 mg, administered as two 400 mg injections) or placebo every 12 weeks. The end of Period 2 marks the completion of clinical trial follow-up.

Period 3 - Post-trial safety follow-up off-product (approximately 12 months) - During this post-trial safety observation period, participants will be followed up (off product) for approximately 12 months after completion of period 2.

Eligibility Criteria:
Inclusion Criteria:

* Able and willing to provide written informed consent to be screened for, and to enrol in, the study.
* Able and willing to provide adequate locator information for study retention purposes.
* Sexually active, defined as having had vaginal intercourse at least once in the past 30 days prior to screening.
* HIV negative on testing performed by study staff
* Have a negative pregnancy test performed by study staff
* Agree to use a non-barrier form of contraceptive
* Agree to adhere to study visits and procedures.
* Haemoglobin \> 11 g/dL,
* ALT \< ULN
* AST \< ULN
* Total bilirubin \< Grade 1
* Direct bilirubin \< ULN
* Creatinine clearance ≥60 mL/min
* Hepatitis B surface antigen (HBsAg) negative
* Hepatitis C Ab negative
* In general good health, as assessed clinically

Exclusion Criteria:

* Past or current participation in any other HIV interventional research study or other concurrent studies which may interfere with this study.
* Clinically significant cardiovascular disease, including:
* ECG with:
* heart rate \<50 or \>100 beats per minute (one repeat ECG is allowed during screening; can be performed on the same day)
* QRS duration \>120 msec
* QTc interval (B or F) \> 450 msec
* evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes (except early repolarization)
* any conduction abnormality (including but not specific to left or right complete bundle branch block, Atrioventricular block \[2nd degree (type II) or higher\], Wolf Parkinson White syndrome)
* sinus pauses \> 3 seconds
* any significant arrhythmia which, in the opinion of the Principal Investigator or designee, will interfere with the safety for the individual participant
* history of non-sustained (3 consecutive ventricular ectopic beats on ECG at screening or entry) or sustained ventricular tachycardia
* History/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting surgery or percutaneous transluminal coronary angioplasty or any clinically significant cardiac disease
* Underlying skin disease or currently active skin disorder (e.g., infection, inflammation, dermatitis, eczema, psoriasis, urticaria). Mild cases of localized disease or other mild skin condition may not be exclusionary at the discretion of the Principal Investigator or designee.
* Has a tattoo or other dermatological condition overlying the buttock region which in the opinion of the Principal Investigator or designee, may interfere with interpretation of injection site reactions.
* History of acute or chronic liver disease (e.g., non-alcoholic or alcoholic steatohepatitis) or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome, asymptomatic gallstones, or cholecystectomy).
* Coagulopathy (primary or iatrogenic) which would contraindicate IM injection.
* Active or planned use of prohibited medications as described in the SSP manual (updated regularly from the Investigator's Brochure).
* Pregnant or currently breastfeeding, or intends to become pregnant and/or breastfeed during the study.
* Known Hypersensitivity to egg, soya or peanut protein.
* Has any other condition that, based on the opinion of the Principal Investigator or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.