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

HIV Infections Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02178800
• Other study ID #: HPTN 077
• Secondary ID: 11964
• Status: Completed
• Phase: Phase 2
• Start date: February 2015
• Est. completion date: July 13, 2018

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 199
• Est. completion date: July 13, 2018
• Est. primary completion date: April 5, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• GSK1265744 Tablets
30-mg tablets, taken orally
• Injectable GSK1265744
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
• Placebo for GSK1265744 Tablets
Taken orally
• Injectable Placebo for GSK1265744
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

Locations

Country	Name	City	State
Brazil	Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS	Rio de Janeiro
Malawi	Malawi CRS	Lilongwe
South Africa	Vulindlela CRS	Durban	KwaZulu-Natal
South Africa	Soweto HPTN CRS	Johannesburg	Gauteng
United States	Chapel Hill CRS	Chapel Hill	North Carolina
United States	UCLA CARE Center CRS	Los Angeles	California
United States	Bridge HIV CRS	San Francisco	California
United States	George Washington Univ. CRS	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Brazil,  Malawi,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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