Evaluating the Safety, Tolerability, and Pharmacokinetics of an Investigational, Injectable HIV Medicine (GSK1265744) in HIV-Uninfected Adults

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the safety, tolerability, and pharmacokinetics (which is how the body interacts with drugs) of an investigational, injectable HIV medicine (GSK1265744) in healthy, HIV-uninfected adults.

Detailed Description
-----------------
This study will evaluate GSK1265744, which is an investigational, injectable HIV medicine. The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of GSK1265744 in healthy, HIV-uninfected adults. This study will enroll two cohorts of participants (Cohort 1 and Cohort 2). Within each cohort, participants will be randomly assigned to one of two groups: Group 1 will receive GSK1265744 tablets (also called oral 744) and injections (also called GSK1265744 long acting or 744LA), and Group 2 will receive placebo tablets and injections. Participants in Cohort 1 will attend several study visits through Week 81 or Week 105. Participants in Cohort 2 will attend several study visits through Week 85 or Week 109. From study entry through Week 4, participants in both cohorts will take a GSK1265744 tablet (Group 1) or a placebo tablet (Group 2) once a day. For 1 week after participants stop taking their assigned tablets, study researchers will assess safety and tolerability. If no safety or tolerability concerns are identified, participants will enter the injection phase of the study. Participants in Cohort 1 will receive two injections of GSK1265744 (Group 1) or placebo (Group 2) at Weeks 5, 17, and 29. Participants in Cohort 2 will receive one injection of GSK1265744 (Group 1) or placebo (Group 2) at Weeks 5, 9, 17, 25, and 33. All study visits will include HIV counseling, a physical examination, a medical history review, and a blood collection. Select study visits will include adherence counseling, central nervous system (CNS) symptom assessment, behavioral and acceptability assessments, a urine collection, an electrocardiogram (ECG), and rectal and/or vaginal swabs.

Official Title
-----------------
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and Women

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Drug: GSK1265744 Tablets
* Drug: Injectable GSK1265744
* Drug: Placebo for GSK1265744 Tablets
* Drug: Injectable Placebo for GSK1265744


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women, 18 to 65 years old at the time of screening Willing to provide informed consent for the study In the last 12 months (at the time of screening): No self-reported unprotected anal or vaginal intercourse with someone known to be HIV-infected or of unknown HIV infection status No self-reported stimulant use (cocaine [including crack], methamphetamine, or non-physician-prescribed pharmaceutical-grade stimulants) or inhaled nitrate No self-reported illicit injection drug use of any kind No self-reported diagnosis of gonorrhea (GC), chlamydia (CT), incident syphilis, bacterial vaginosis, or trichomoniasis Not reporting five or more different sexual partners, regardless of use of protection or knowledge of HIV status. More information on this criterion is available in the protocol. In general good health, as evidenced by the following laboratory values, which must be from specimens obtained within 45 days prior to study enrollment: Non-reactive/negative HIV test results. More information on this criterion is available in the protocol. Hemoglobin greater than 11 g/dL Absolute neutrophil count greater than 750 cells/mm^3 Platelet count greater than or equal to 100,000/mm^3 Calculated creatinine clearance greater than or equal to 70 mL/minute using the Cockcroft-Gault equation Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to the upper limit of normal (ULN) Total bilirubin less than or equal to Grade 1 and direct bilirubin less than or equal to ULN Hepatitis B surface antigen (HBsAg) negative Hepatitis C Ab negative Note: Chemistry and hematology parameters which do not meet the inclusion criteria above may be repeated once during screening. 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). More information on this criterion is available in the protocol. 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) Willing to undergo all required study procedures Additional requirements for all women: 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 urine pregnancy test performed (and results known) within 48 hours before initiating the protocol-specified medication(s) at enrollment. Women are considered menopausal if they have not had a menses for at least 12 months and have a follicle stimulating hormone (FSH) level of greater than 40 IU/L; if FSH testing is not available, they must have had amenorrhea for 24 or more consecutive months. (FSH testing is not a protocol requirement.) If of reproductive potential and participating in sexual activity that could lead to pregnancy, women must agree to use a form of contraception during the trial and for 30 days after stopping the oral study medication or for 52 weeks after stopping the long acting injectable 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 Exclusion Criteria: One or more reactive or positive HIV test result at Screening or Enrollment, even if HIV infection is not confirmed Any active sexually transmitted infection detected by laboratory testing at Screening Co-enrollment in any other HIV interventional research study or other concurrent studies which may interfere with this study (as provided by self-report or other available documentation; exceptions may be made if appropriate after consultation with the Clinical Management Committee [CMC].) Past or current participation in HIV vaccine trial. An exception will be made for participants that can provide documentation of receipt of placebo (not active arm). Use of antiretroviral therapy (ART) (e.g., for non-occupational post-exposure prophylaxis [PEP] or PrEP) in the 90 days prior to study entry Clinically significant cardiovascular disease, including: ECG (one repeat ECG is allowed during screening; may be performed on the same day) with: heart rate less than 45 or greater than 100 beats per minute for men, and less than 50 or greater than 100 beats per minute for women interval from the beginning of the Q wave to the end of the S wave (QRS) duration greater than 120 msec corrected QT (QTc) interval (B or F) greater than 450 msec evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes) (except early repolarization) any clinically significant conduction abnormality (including but not specific to left or right complete bundle branch block, atrioventricular [AV] block [2nd degree (type II) or higher], Wolf Parkinson White [WPW] syndrome) (any question of clinical significance should be referred to the CMC for adjudication) sinus pauses greater than 3 seconds any clinically significant arrhythmia that, in the opinion of the Investigator of Record (IoR) or designee, will interfere with the safety for the individual participant (any question of clinical significance should be referred to the CMC for adjudication) or history of non-sustained (greater than or equal to 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 (CABG) surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically significant cardiac disease Systolic blood pressure at screening outside the range of 90 to 140 mm Hg or diastolic blood pressure outside the range of 45 to 90 mm Hg (confirmed on repeat measurement) Underlying skin disease or currently active skin disorder (e.g., infection, inflammation, dermatitis, eczema, psoriasis, urticaria). Mild cases of localized acne or folliculitis or other mild skin condition may not be exclusionary at the discretion of the IoR or designee in consultation with the CMC. Has a tattoo or other dermatological condition overlying the buttock region that in the opinion of the IoR or designee, in consultation with the CMC, may interfere with interpretation of injection site reactions 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) Coagulopathy (primary or iatrogenic) that would contraindicate IM injection (concomitant anticoagulant or anti-platelet therapy use should be discussed with the CMC) Active or planned use of prohibited medications as described in the Investigator's Brochure or listed in the Study Specific Procedures (SSP) Manual (provided by self-report, or obtained from medical history or medical records) A score of greater than or equal to 8 on the WHO Alcohol Use Disorders Identification Test (AUDIT) at screening. Note: A score of greater than or equal to 8 indicates a medium to high level of problem alcohol use. For women: pregnant or currently breastfeeding, or intends to become pregnant and/or breastfeed during the study A history of seizure disorder, by self-report

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: GSK1265744<br>Participants in Cohorts 1 and 2 will receive one GSK1265744 tablet orally every day from study entry through Week 4. They will then receive an injection of GSK1265744-at Weeks 5, 17, and 29 for participants in Cohort 1 and at Weeks 5, 9, 17, 25, and 33 for participants in Cohort 2. | Drug: GSK1265744 Tablets<br>* 30-mg tablets, taken orally<br>* Other names: Oral 744;Drug: Injectable GSK1265744<br>* Cohort 1: 800-mg injection, administered as two 400-mg intramuscular (IM) gluteal injections Cohort 2: 600-mg injection, administered as one IM gluteal injection<br>* Other names: 744LA;|
| Placebo Comparator: Group 2: Placebo<br>Participants in Cohorts 1 and 2 will receive one placebo tablet orally every day from study entry through Week 4. They will then receive an injection of placebo-at Weeks 5, 17, and 29 for participants in Cohort 1 and at Weeks 5, 9, 17, 25, and 33 for participants in Cohort 2. | Drug: Placebo for GSK1265744 Tablets<br>* Taken orally<br>Drug: Injectable Placebo for GSK1265744<br>* Cohort 1: Sodium Chloride for Injection USP, 0.9%; administered as two 400-mg IM gluteal injections Cohort 2: Sodium Chloride for Injection USP, 0.9%; administered as one 600-mg IM gluteal injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Any Grade 2 or Higher Clinical Adverse Events (AEs) and Laboratory Abnormalities That Occur From the Initial Injection to Week 41 Among Participants Who Receive at Least One Injection (Injectable Phase Only) | An adverse events (AE) or laboratory abnormality can be an unfavorable or unintended sign, symptom or disease temporally associated with the use of an investigational product, whether or not considered related to the product. AE severity was graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0, November 2014. The outcome in this table is stratified by arm. | Measured through Week 41 | 
| Number of Participants Who Discontinue Injectable Study Product for Reasons of Toxicity, Tolerability, or Acceptability That Occur From the Initial Injection to Week 41 Among Participants Who Receive at Least One Injection (Injectable Phase Only) | Stratified by arm | Measured through Week 41 | 
| Plasma Drug Levels of GSK1265744 at Designated Time Points After Each Injection of 744LA (Injectable Formulation of GSK1265744) | Geometric means and 90% prediction intervals by sex at birth and cohort are reported. | Measured through Week 41 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Grade 2 or Higher Clinical Adverse Events (AEs) and Laboratory Abnormalities During Tail Phase | An adverse events (AE) or laboratory abnormality can be an unfavorable or unintended sign, symptom or disease temporally associated with the use of an investigational product, whether or not considered related to the product. AE severity was graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0, November 2014. The outcome in this table is stratified by arm. | Measured from 12 weeks after last injection through Week 105 for Cohort 1 and 8 weeks after last injection through Week 109 for Cohort 2 | 
| Number of Participants Experiencing Grade 2 or Higher Clinical Adverse Events (AEs) and Laboratory Abnormalities Prior to Completion of the Oral Phase | An adverse events (AE) or laboratory abnormality can be an unfavorable or unintended sign, symptom or disease temporally associated with the use of an investigational product, whether or not considered related to the product. AE severity was graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0, November 2014. The outcome in this table is stratified by arm. | Measured through Week 5 | 
| Number of Participants Willing to Use an Injectable Agent Such as the Study Product for HIV Prevention in the Future | Stratified by Visit and Cohort | Measured from week 6 through Week 30 in cohort 1 and Week 34 in cohort 2 | 
| Number of Participants With HIV Infections Through the Study Period, Stratified by Arm |  | Measured through Week 105 for Cohort 1 and Week 109 for Cohort 2 | 
| Self-reported Sexual Behavior (Number of Sexual Partners) During the Study Period | Week 29/31 is a combination of week 29, cohort 1 and week 33, cohort 2. The outcome in this table is stratified by arm. | Measured through Week 77 | 
| Number of Injectable Hormonal-contraception-using Female Participants Experiencing Grade 2 or Higher Clinical AE and Laboratory Abnormalities During Oral Phase | An adverse events (AE) or laboratory abnormality can be an unfavorable or unintended sign, symptom or disease temporally associated with the use of an investigational product, whether or not considered related to the product. AE severity was graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0, November 2014. The outcome in this table is stratified by arm. | Measured through Week 4 | 
| Number of Injectable Hormonal-contraception-using Female Participants Experiencing Grade 2 or Higher Clinical AE and Laboratory Abnormalities During Injection Phase |  | Measured from first injection through 12 weeks after last injection for Cohort 1 and 8 weeks after last injection for Cohort 2 | 
| Number of Injectable Hormonal-contraception-using Female Participants Who Discontinue Study Product for Reasons of Toxicity, Tolerability, or Acceptability During Oral Phase | Stratified by arm | Measured through Week 4 | 
| Number of Injectable Hormonal-contraception-using Female Participants Who Discontinue Study Product for Reasons of Toxicity, Tolerability, or Acceptability During Injection Phase |  | Measured from first injection through 12 weeks after last injection for Cohort 1 and 8 weeks after last injection for Cohort 2 | 
| Number of Participants Who Discontinue Oral Study Product for Reasons of Toxicity, Tolerability, or Acceptability Prior to Completion of the Oral Phase | Stratified by arm | Measured through Week 4 |