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Evaluating the Safety and Efficacy of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women

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ClinicalTrials.gov Identifier: NCT03164564
Recruitment Status : Recruiting
First Posted : May 23, 2017
Last Update Posted : August 4, 2020
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE May 22, 2017
First Posted Date  ICMJE May 23, 2017
Last Update Posted Date August 4, 2020
Actual Study Start Date  ICMJE November 7, 2017
Estimated Primary Completion Date May 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2019)
  • Number of documented incident HIV infections in Steps 1 and 2 [ Time Frame: Measured through Week 81 ]
    HIV incidence rate will be calculated as the total number of participants with confirmed incident HIV infection during study follow-up of Step 1 and Step 2 divided by the person-years accumulated in each arm.
  • Number of Grade 2 or higher clinical and laboratory adverse events (AEs) [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    AEs will be summarized using MedDRA System Organ Class and preferred terms.
Original Primary Outcome Measures  ICMJE
 (submitted: May 22, 2017)
  • Number of documented incident HIV infections in Steps 1 and 2 [ Time Frame: Measured through Week 81 ]
    HIV incidence rate will be calculated as the total number of participants with confirmed incident HIV infection during study follow-up of Step 1 and Step 2 divided by the person-years accumulated in each arm.
  • Number of Grade 3 or higher clinical and laboratory adverse events (AEs) [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    AEs will be summarized using MedDRA System Organ Class and preferred terms.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 20, 2019)
  • Number of documented incident HIV infections in Steps 1, 2 and 3 [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Number of documented incident HIV infections in participants in subgroups broken down by baseline age [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Number of documented incident HIV infections in participants in subgroups broken down by baseline HSV-2 status [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Number of documented incident HIV infections in participants in subgroups broken down by baseline contraceptive use method [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Number of documented incident HIV infections in participants in subgroups broken down by baseline body mass index (BMI) less than/greater than or equal to 25 kg/m^2 [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Plasma concentrations of CAB in participants randomized to CAB/CAB LA [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    Plasma samples for drug concentrations will be collected throughout the study from all participants, although PK testing may be limited to a subset of the samples.
  • Plasma and dried blood spot (DBS) concentrations of tenofovir/tenofovir diphosphate (TFV/TFV-DP) in a subset of participants randomized to TDF/FTC [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    Plasma and DBS samples for drug concentrations will be collected throughout the study from all participants, although PK testing may be limited to a subset of the samples.
  • Number of participants willing to use CAB LA and TDF/FTC [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    Assessed through administration of brief behavioral surveys.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2017)
  • Number of documented incident HIV infections in participants in subgroups broken down by baseline age [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Number of documented incident HIV infections in participants in subgroups broken down by baseline HSV-2 status [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Number of documented incident HIV infections in participants in subgroups broken down by baseline contraceptive use method [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Number of documented incident HIV infections in participants in subgroups broken down by baseline body mass index (BMI) less than/greater than or equal to 25 kg/m^2 [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    For each of the specified baseline factors, a Cox proportional hazards model will be fit with treatment arm, baseline factor and their interaction as covariates, stratified by site.
  • Plasma and dried blood spot (DBS) levels of CAB in participants randomized to CAB/CAB LA [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    Plasma and DBS samples for drug concentrations will be collected throughout the study from all participants, although PK testing may be limited to a subset of the samples.
  • Plasma levels of tenofovir/tenofovir diphosphate (TFV/TFV-DP) in participants randomized to TDF/FTC [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    Plasma samples for drug concentrations will be collected throughout the study from all participants, although PK testing may be limited to a subset of the samples.
  • Number of participants willing to use CAB LA and TDF/FTC [ Time Frame: Measured through participant's last study visit, up to 4.6 years after study entry, depending on when they enroll in the study ]
    Assessed through administration of brief behavioral surveys.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluating the Safety and Efficacy of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women
Official Title  ICMJE A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women
Brief Summary This study will evaluate the safety and efficacy of the long-acting injectable agent cabotegravir (CAB LA) compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) in HIV-uninfected women.
Detailed Description

The purpose of this study is to evaluate the safety and efficacy of the long-acting injectable integrase inhibitor cabotegravir (CAB LA) compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) in a population of sexually active HIV-uninfected women at risk for HIV.

This study will take place in three steps. Participants will be randomly assigned to one of two arms:

Arm A:

Step 1: Participants will receive daily oral CAB and TDF/FTC placebo for 5 weeks.

Step 2: Participants will receive injections of CAB LA at two time points 4 weeks apart and every 8 weeks thereafter and daily TDF/FTC placebo beginning at Week 5.

Arm B:

Step 1: Participants will receive daily TDF/FTC and oral CAB placebo for 5 weeks.

Step 2: Participants will receive daily TDF/FTC and intramuscular (IM) placebo injections at two time points 4 weeks apart and every 8 weeks thereafter beginning at Week 5.

Step 2 will continue until the last enrolled participant reaches approximately 76 weeks on Step 2 (Week 81 for the last enrolled participant).

In Step 3, all participants (Arms A and B) will receive daily TDF/FTC for up to 48 weeks, starting no later than 8 weeks after the last injection.

At the end of Step 3, all participants will then transition to locally available HIV prevention services, including services for PrEP, if available.

Study visits will occur at Day 0 and at Weeks 2 and 4 during Step 1. During Step 2, participants will attend up to 24 visits, depending on when they enroll in the study. Study visits will occur every 12 weeks during Step 3. Study visits may include physical examinations; blood, urine, and vaginal swab collection; risk reduction, adherence counseling, and contraception counseling.

HPTN 084-01 is a sub-study of HPTN 084. The purpose of this study is to examine the safety, tolerability, and acceptability of CAB LA for the prevention of HIV among adolescent females. Participants will receive oral CAB for 5 weeks, followed by 34 weeks on CAB LA, then quarterly visits for 48 weeks after final injection. All participants who have received at least one injection will be followed for 48 weeks after their last injection. Total study duration per participant will be approximately 21 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE HIV Infections
Intervention  ICMJE
  • Drug: Oral CAB
    CAB 30 mg tablet
    Other Name: Cabotegravir
  • Drug: Oral TDF/FTC
    TDF/FTC 300 mg/200 mg fixed dose combination tablet
    Other Names:
    • Tenofovir disoproxil fumarate/emtricitabine
    • Truvada
  • Drug: Placebo for oral CAB
    Placebo tablets
  • Drug: Placebo for oral TDF/FTC
    Placebo tablets
  • Drug: CAB LA
    600 mg administered as one 3 mL (600 mg) intramuscular injection in the gluteal muscle
    Other Name: Cabotegravir long-acting injectable
  • Drug: Placebo for CAB LA
    Administered as one 3 mL intramuscular injection in the gluteal muscle
Study Arms  ICMJE
  • Experimental: Arm A: CAB + Placebo TDF/FTC + CAB LA
    During Step 1, participants will receive daily oral CAB and oral TDF/FTC placebo for 5 weeks. In Step 2, participants will receive injections of CAB LA at two time points 4 weeks apart and every 8 weeks thereafter and daily oral TDF/FTC placebo beginning at Week 5. In Step 3, participants will receive daily TDF/FTC for up to 48 weeks, starting no later than 8 weeks after the last injection.
    Interventions:
    • Drug: Oral CAB
    • Drug: Oral TDF/FTC
    • Drug: Placebo for oral TDF/FTC
    • Drug: CAB LA
  • Active Comparator: Arm B: TDF/FTC + Placebo CAB + Placebo CAB LA
    During Step 1, participants will receive daily TDF/FTC and oral CAB placebo for 5 weeks. In Step 2, participants will receive daily TDF/FTC and placebo for CAB LA injections at two times points 4 weeks apart and every 8 weeks thereafter beginning at Week 5. In Step 3, participants will receive daily TDF/FTC for up to 48 weeks, starting no later than 8 weeks after the last injection.
    Interventions:
    • Drug: Oral TDF/FTC
    • Drug: Placebo for oral CAB
    • Drug: Placebo for CAB LA
Publications * Scarsi KK. Chasing the cabotegravir tail: implications for prevention. Lancet HIV. 2020 Jul;7(7):e451-e453. doi: 10.1016/S2352-3018(20)30165-X. Epub 2020 Jun 1.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 22, 2017)
3200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 31, 2022
Estimated Primary Completion Date May 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Born female
  • 18-45 years at the time of screening
  • Willing and able to provide informed consent
  • Willing and able to undergo all required study procedures
  • Non-reactive HIV test results at Screening and Enrollment. Note: HIV-uninfected, based on HIV test results obtained at Screening and just prior to randomization at the Enrollment visit. All HIV test results from the Screening visit must be obtained and must all be negative/non-reactive. This includes testing for acute HIV infection, which must be performed within 14 days of Enrollment. In addition, at least one HIV test result using blood drawn at the Enrollment visit must be obtained prior to randomization into the study and must be negative/non-reactive. Individuals who have one or more reactive or positive HIV test result(s) will not be enrolled, even if subsequent confirmatory testing indicates that they are not HIV-infected (see SSP Manual). Those with any enrollment HIV test result positive will proceed through the HIV algorithm per the SSP but will not be able to receive study product regardless of subsequent test results.
  • Sexually active (i.e., vaginal intercourse on a minimum of two separate days in the 30 days prior to Screening)
  • Score of greater than or equal to 5 using a modified VOICE risk score
  • No plans to re-locate or travel away from the site for greater than or equal to 8 consecutive weeks during study participation
  • Creatinine clearance of greater than or equal to 60 mL/min (using Cockcroft-Gault equation) (use sex at birth for calculation)

    • Although not protocol exclusionary, sites should carefully consider the advisability of enrolling participants with calculated creatinine clearance between 60-70 mL/min, as limited changes in creatinine clearance during study conduct will lead to protocol-mandated product holds and may alter the risk-benefit considerations of study participation
  • Hepatitis B virus (HBV) surface antigen (HBsAg) negative and accepts vaccination
  • Alanine aminotransferase (ALT) less than 2 x upper limit of normal (ULN) and total bilirubin (Tbili) less than or equal to 2.5 x ULN
  • HCV antibody negative
  • If of reproductive potential (defined as pre-menopausal women who have not had a sterilization procedure per self-report, such as hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy), must have a negative beta human chorionic gonadotropin (βHCG) pregnancy test (sensitivity of less than or equal to 25 mIU/mL) performed (and results known) on the same day as and before initiating the protocol-specified study product(s) at Enrollment.
  • Have documented evidence of surgical sterilization, OR documented evidence of no uterus (e.g., hysterectomy), OR must agree to use a reliable form of long acting contraception, during the trial and for 52 weeks after stopping the long acting injectable, or 30 days after stopping oral study product, from the list below:

    • Intrauterine device (IUD) or intrauterine system (IUS) that meets less than 1% failure rate as stated in the product label
    • Hormone-based contraceptive that meets less than 1% failure rate when used consistently and correctly as stated in the product label (implants or injectables only; this excludes combined oral contraception)
  • No medical condition that, in the opinion of the study investigator, would interfere with the conduct of the study (e.g., provided by self-report, or found upon medical history and examination or in available medical records)
  • No alcohol or substance use that, in the opinion of the study investigator, would interfere with the conduct of the study (e.g., provided by self-report, or found upon medical history and examination or in available medical records)

Exclusion Criteria:

  • One or more reactive HIV test results at Screening or Enrollment, even if HIV infection is not confirmed
  • Pregnant or currently breastfeeding, or intends to become pregnant and/or breastfeed during the study
  • Co-enrollment in any other HIV interventional research study (provided by self-report or other available documentation), with one exception: IMPAACT 2026 (co-enrollment in IMPAACT 2026 is permitted for participants who become pregnant)
  • Current or past enrollment in an HIV vaccine or broadly neutralizing antibody trial
  • Current or chronic history of 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)
  • History of seizure disorder, per self-report
  • Clinically significant cardiovascular disease, as defined by history/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically significant cardiac disease
  • Inflammatory skin conditions that compromise the safety of IM injections, per the discretion of the Investigator of Record (IoR). Mild skin conditions may not be exclusionary at the discretion of the IoR or designee
  • Has a tattoo or other dermatological condition overlying the buttock region which in the opinion of the IoR or designee may interfere with interpretation of injection site reactions (ISRs)
  • Coagulopathy (primary or iatrogenic) which would contraindicate IM injection
  • Active or planned use of prohibited medications as described in the Investigator Brochure (IB) or listed in the Study Specific Procedures Manual (SSP) (provided by self-report, or obtained from medical history or medical records)
  • Known or suspected allergy to study product components (active or placebo), including egg or soy products (egg and soy products are contained in Intralipid)
  • If potentially able to conceive, unwilling to adhere to long acting contraception (IUD/IUS, injection, or implant) with a less than 1% failure rate when used consistently and correctly as stated in the product package insert/ manufacturer's guidelines
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Listed Location Countries  ICMJE Botswana,   Kenya,   Malawi,   South Africa,   Swaziland,   Uganda,   Zimbabwe
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03164564
Other Study ID Numbers  ICMJE HPTN 084
38070 ( Registry Identifier: DAIDS-ES Registry Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Sinead Delany-Moretlwe, MBBCh, PhD, DTM&H Wits Reproductive Health and HIV Institute CRS (WRHI CRS)
Study Chair: Mina Hosseinipour, MD, MPH University of North Carolina (UNC) Project-Malawi, Tidziwe Centre
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP