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Study to Evaluate the Safety Tolerability and Acceptability of Long Acting Injections of the Human Immunodeficiency Virus (HIV) Integrase Inhibitor, GSK1265744, in HIV Uninfected Men (ECLAIR)

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ClinicalTrials.gov Identifier: NCT02076178
Recruitment Status : Completed
First Posted : March 3, 2014
Results First Posted : December 15, 2017
Last Update Posted : December 15, 2017
Sponsor:
Collaborator:
Information provided by (Responsible Party):

February 27, 2014
March 3, 2014
September 28, 2017
December 15, 2017
December 15, 2017
March 27, 2014
May 15, 2015   (Final data collection date for primary outcome measure)
  • Number of Participants With Any Grade 2 or Higher Event in the Injection Phase [ Time Frame: Up to Week 41 ]
    Clinical adverse event (AE) were graded using the Division of Acquired Immunodeficiency Syndrome (DAIDS) table for grading the severity of adult and pediatric AE Version 1.0, December 2004; Clarification August 2009. The grades were: 1 (mild)=Symptoms causing no or minimal interference with usual social and functional activities; 2 (moderate)= Symptoms causing greater than minimal interference with usual social and functional activities; 3 (severe)= Symptoms causing inability to perform usual social and functional activities; 4 (potentially life threatening): Symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. Data has been presented for any Grade 2 or higher event in the injection phase for injection phase (Week 5- Week 41).
  • Number of Participants Who Recieved Injection Site Reaction (ISR) Related Concomitant Medication in the Injection Phase [ Time Frame: Up to Week 41 ]
    The concurrent medications that were consumed by participants during the injection phase were of the class nervous system, musculo-skeletal system, genito urinary systems and sex hormones, various, respiratory system, dermatologicals, alimentary tract and metabolism, sensory organs, systemic hormonal preparations, excluding sex hormones, blood and blood forming organs, cardiovascular system. The participants who took medication from any of the above class of during the injection phase (Week 5-Week 41) have been presented.
  • Number of Participants Who Experienced Grade 2 or Higher Laboratory Results in the Injection Phase [ Time Frame: Up to Week 41 ]
    The severity of laboratory results was graded according to the DAIDS table for grading the severity of adult and pediatric AE Version 1.0, December 2004; Clarification August 2009. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening. Data for Number of participants who experienced grade 2 or higher laboratory results in the injection phase (Week 5-Week 14) have been presented.
  • Number of Participants Who Had Abnormal Electrocardiogram (ECG) Findings in the Injection Phase [ Time Frame: Up to Week 41 ]
    Full 12-lead ECGs included heart rate, PR, QRS, QT and QTc intervals. Measurements were taken from the participant following 5 minutes of rest in a semi-supine position. ECGs were performed at Week 5, Week 17, Week 29 and Week 41 in the injection phase (Week 5-Week 41). ECG abnormalities characterized as abnormal-not clinically significant (A-NCS) and abnormal-clinically significant (A-CS) upto Week 41 have been presented. There were no A-CS findings for ECG in the injection phase.
  • Change From Baseline in Vital Sign Assessment for Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) in the Injection Phase [ Time Frame: Baseline (Week 5) to Week 41 ]
    Vital signs measurements were performed for SBP and DBP following 5 minutes of rest. Baseline was defined as the first injection at Week 5 for the injection phase. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value at Week 17, Week 29 and Week 41.
  • Change From Baseline in Vital Sign Assessment for Heart Rate (HR) in the Injection Phase [ Time Frame: Baseline (Week 5) to Week 41 ]
    Vital signs measurements were performed for HR following 5 minutes of rest. Baseline was defined as the first injection at Week 5 for the injection phase. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value at Week 17, Week 29 and Week 41.
  • Number of Participant With ISR for the Injection Phase Defined by Maximum Grades [ Time Frame: Up to Week 41 ]
    Common ISR included pain, erythema, nodules and any other ISR with greater or equal to 5 participants. The number of participants who experienced pain events by needle length, swelling events by needle length, bump events by needle length for injection phase by maximum grades have been presented for the injection phase (Week 5-Week 41).
  • Safety and Tolerability as assessed by adverse events [ Time Frame: Up to Week 41 (Final visit) ]
    To evaluate the safety and tolerability of the injectable agent, 744 LA (800 mg dose administered at three time points at 12 week intervals) through Week 41 in HIV-uninfected men as assessed by adverse events
  • Safety and Tolerability as assessed by concurrent medication required [ Time Frame: Up to Week 41 (Final visit) ]
    To evaluate the safety and tolerability of the injectable agent, 744 LA (800 mg dose administered at three time points at 12 week intervals) through Week 41 in HIV-uninfected men as assessed by concurrent medication required
  • Safety and Tolerability as assessed by clinical laboratory tests [ Time Frame: Up to Week 41 ]
    To evaluate the safety and tolerability of the injectable agent, 744 LA (800 mg dose administered at three time points at 12 week intervals) through Week 41 in HIV-uninfected men as assessed by clinical laboratory tests (Hematology/Chemistry testing and Urinalysis)
  • Safety and Tolerability as assessed by Electrocardiogram (ECG) [ Time Frame: Up to Week 41 ]
    To evaluate the safety and tolerability of the injectable agent, 744 LA (800 mg dose administered at three time points at 12 week intervals) through Week 41 in HIV-uninfected men as assessed by ECG
  • Safety and Tolerability as assessed by vital signs assessments [ Time Frame: Up to Week 41 ]
    To evaluate the safety and tolerability of the injectable agent, 744 LA (800 mg dose administered at three time points at 12 week intervals) through Week 41 in HIV-uninfected men as assessed by vital signs assessments
  • Safety and Tolerability as assessed by injection site reactions (ISRs) [ Time Frame: Up to Week 41 (Final visit) ]
    To evaluate the safety and tolerability of the injectable agent, 744 LA (800 mg dose administered at three time points at 12 week intervals) through Week 41 in HIV-uninfected men as assessed by and injection site reactions (ISRs)
Complete list of historical versions of study NCT02076178 on ClinicalTrials.gov Archive Site
  • Plasma Pharmacokinetic Assessment for Area Under the Plasma Concentration-time Curve Over the Dosing Interval [AUC(0-tau)] in the Injection Phase [ Time Frame: Up to Week 41 ]
    Blood samples for pharmacokinetic analysis were collected starting on the first day of the First Injection Phase prior to the injection. At each injection visit a blood sample was collected prior to the injection at Week 5, Week 17 and Week 29, 1 Week post-injection at Week 6, Week 18, and Week 30, and 12 Week post-injection at Week 17, Week 29, and Week 41. The sample collected 12 Week following each injection served as the pre-dose sample for the subsequent dosing interval. Two additional samples were collected 4 and 8 Week after the first injection (Week 9 and Week 13), and 1 additional sample was collected 6 Week following the second and third injections (Week 23 and Week 35). Assessment was carried out for AUC(0-tau) a measure of the amount of drug available at target tissue (in plasma) for a fixed dosing interval (i.e.12 hours).
  • Plasma Pharmacokinetic Assessment for Concentration at the End of the Dosing Interval (Ctau) and Maximum Observed Concentration (Cmax) in the Injection Phase [ Time Frame: Up to Week 41 ]
    Blood samples for pharmacokinetic analysis were collected starting on the first day of the First Injection Phase prior to the injection. At each injection visit a blood sample was collected prior to the injection at Week 5, Week 17 and Week 29, 1 Week post-injection at Week 6, Week 18, and Week 30, and 12 Week post-injection at Week 17, Week 29, and Week 41. The sample collected 12 Week following each injection served as the pre-dose sample for the subsequent dosing interval. Two additional samples were collected 4 and 8 Week after the first injection (Week 9 and Week 13), and 1 additional sample was collected 6 Week following the second and third injections (Week 23 and Week 35). Assessment was carried out for Ctau defined as the concentration at the end of the dosing interval and Cmax defined as the maximum observed plasma concentration.
  • Plasma Pharmacokinetic Assessment for Time to Maximum Observed Concentration (Tmax), Apparent Terminal Phase Half-life for (t½) in the Injection Phase [ Time Frame: Up to Week 41 ]
    Blood samples for pharmacokinetic analysis were collected starting on the first day of the First Injection Phase prior to the injection. At each injection visit a blood sample was collected prior to the injection at Week 5, Week 17 and Week 29, 1 Week post-injection at Week 6, Week 18, and Week 30, and 12 Week post-injection at Week 17, Week 29, and Week 41. The sample collected 12 Week following each injection served as the pre-dose sample for the subsequent dosing interval. Two additional samples were collected 4 and 8 Week after the first injection (Week 9 and Week 13), and 1 additional sample was collected 6 Week following the second and third injections (Week 23 and Week 35). Assessment was carried out for tmax defined as the time to the maximum observed plasma concentration and t½ defined as the time taken for the concentration of drug in the blood to decrease by half of the original amount.
  • Plasma Pharmacokinetic Assessment for AUC(0-tau) by Demographic Factor Body Mass Index (BMI) and Needle Length in the Injection Phase [ Time Frame: Up to Week 41 ]
    The median BMI was 26 kilogram per meter square. Plasma pharmacokinetic assessments were performed for AUC (0-tau) by BMI, either above or below the median BMI (50 percent upper and lower, where upper summary included all participants with BMI greater than or equal to the median BMI of the population and lower summary included all participants with BMI below the median BMI). Assessments was also performed for AUC (0-tau) by needle length (1.5 inch and 2 inch). Needle length and BMI were correlated in that the longer needle was recommended for participants with BMI greater than 30 kilogram per meter square.
  • Plasma Pharmacokinetic Assessment for Ctau and Cmax by Demographic Factor BMI and Needle Length in the Injection Phase [ Time Frame: Up to Week 41 ]

    The median BMI was 26 kilogram per meter square. Plasma pharmacokinetic assessments were performed for Ctau and Cmax by BMI, either above or below the median BMI (50 percent upper and lower, where upper summary included all participants with BMI greater than or equal to the median BMI of the population and lower summary included all participants with BMI below the median BMI.

    ). Assessments was also performed for Ctau and Cmax by needle length (1.5 inch and 2 inch). Needle length and BMI were correlated in that the longer needle was recommended for participants with BMI greater than 30 kilogram per meter square.

  • Plasma Pharmacokinetic Assessment for Tmax and t½ by Demographic Factor BMI and Needle Length in the Injection Phase [ Time Frame: Up to Week 41 ]
    The median BMI was 26 kilogram per meter square. Plasma pharmacokinetic assessments were performed for tmax and t½ by BMI, either above or below the median BMI (50 percent upper and lower, where upper summary included all participants with BMI greater than or equal to the median BMI of the population and lower summary included all participants with BMI below the median BMI). Assessments was also performed for tmax and t½ by needle length (1.5 inch and 2 inch). Needle length and BMI were correlated in that the longer needle was recommended for participants with BMI greater than 30 kilogram per meter square.
  • Number of Participants With Severity of ISRs and ISR Symptoms for Injection Phase Defined by Grades and Needle Length [ Time Frame: Up to Week 41 ]
    Acceptability of cabetogravir injections was assessed number of participants who had severe ISRs and ISR symptom. ISR examination for severity included an assessment of pain, pruritis, warm to touch, bruising, discoloration, erythema, swelling, induration and bump events. Common ISR Symptoms for Injection Phase included pain, erythema, nodules and any other ISRs with greater or equal to five participants. Data has been presented for the injection phase (W5-W41) by grades and needle length.
  • Number of Participants With AE, Grade 2-4 AE and Serious Adverse Events (SAE) in the Oral Phase [ Time Frame: Up to Week 4 ]
    Clinical AE were graded using the DAIDS table for grading the severity of adult and pediatric AE Version 1.0, December 2004; Clarification August 2009. The grades were: 1 (mild)=Symptoms causing no or minimal interference with usual social and functional activities; 2 (moderate)= Symptoms causing greater than minimal interference with usual social and functional activities; 3 (severe)= Symptoms causing inability to perform usual social and functional activities; 4 (potentially life threatening): Symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. Data has been presented for any Grade 2 or higher event in the injection phase for injection phase (Week 5- Week 41).
  • Number of Participants Who Received Concurrent Medication in Overall Study Duration [ Time Frame: Up to Week 41 ]
    The concurrent medications that were consumed by participants during the injection phase were of the class nervous system, musculo-skeletal system, genito-urinary systems and sex hormones, various, respiratory system, dermatologicals, alimentary tract and metabolism, anti-infectives for systemic use, sensory organs, systemic hormonal preparations excluding sex hormones, blood and blood forming organs, cardiovascular system, anti-neoplastic and immunomodulating agents, anti-parasitic products, insecticides and repellents . The participants who took medication from any of the above class of during the during the overall study duration injection phase (Day 1 until Week 41) have been presented.
  • Number of Participants Who Experienced Maximum Clinical Chemistry Including Liver Chemistry and Hematology Toxicities in the Oral Phase by Grades [ Time Frame: Up to Week 4 ]
    The severity of clinical chemistry including liver chemistry and hematology toxicities was graded according to the DAIDS table for grading the severity of adult and pediatric AE Version 1.0, December 2004; Clarification August 2009. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, potentially life threatening. Data for maximum clinical chemistry and hematology toxicities for oral phase (Day 1 upto Week 4) by grades have been presented.
  • Plasma pharmacokinetic profile for 744 [ Time Frame: Up to Week 41 ]
    The following pharmacokinetic parameters were evaluated following each IM injection of 744 LA through 41 weeks. For each 12-week dosing interval, parameters include: Individual plasma PK parameters for each injection interval will be determined, including: area under the plasma concentration time curve over the dosing interval (AUC(0-tau)), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), concentration at the end of the dosing interval (Ctau), and apparent terminal phase half-life for LA administration (t½) and lambda z as a measure of absorption rate constant (lambda z) if data allow
  • 744 PK parameters as assessed by patient demographics (age, race, weight, BMI, and ethnicity) [ Time Frame: Up to Week 41 ]
    The following pharmacokinetic parameters following each IM injection of 744 LA through 41 weeks. AUC(0-tau), Ctau, Cmax, t1/2, and lambda z) by age, race, weight, BMI and ethnicity
  • Safety and tolerability of oral 744 [ Time Frame: Up to Week 4 ]
    To evaluate the safety and tolerability of oral 744 in HIV-uninfected men as assessed by adverse events, clinical laboratory tests (Hematology/Chemistry testing and Urinalysis) and concurrent medication required
  • Acceptability of 744 LA injections [ Time Frame: Week 5 to Week 41 ]
    Acceptability of 744 LA injections was assessed by incidence and severity of ISRs and ISR symptom score
  • Statistical evaluation for concentration-effect relationships for various safety parameters [ Time Frame: Up to Week 81 ]
    Pearson's correlations between PK parameters and safety parameters (occurrence of AEs, maximum intensity of AE per subject, and clinical laboratory parameters of special interest) may be presented. Logistic regression may be used to examine correlation between PK parameters and presence or absence of AEs of special interest from selected system organ class
Not Provided
Not Provided
 
Study to Evaluate the Safety Tolerability and Acceptability of Long Acting Injections of the Human Immunodeficiency Virus (HIV) Integrase Inhibitor, GSK1265744, in HIV Uninfected Men (ECLAIR)
A Phase IIa Study to Evaluate the Safety, Tolerability and Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, GSK1265744, in HIV Uninfected Men (ECLAIR)
This study is a Phase IIa, randomized, multi-site, two-arm, double-blinded study to evaluate the safety, tolerability, and acceptability of GSK1265744 long acting injectable formulation (744 LA) in adult male subjects. To evaluate the safety and tolerability of the injectable agent, 744 LA (800 milligrams (mg) dose administered at three time points at 12 week intervals) through Week 41 in HIV-uninfected men. Eligible participants will be randomized in a 5:1 ratio to receive 744 LA or matching placebo. Participants will receive daily oral 744 (30 mg tablets) or matching placebo for 4 weeks during the Oral Phase of the study, followed by a one week washout period. Following safety lab assessments from the Oral Phase, participants will enter the Injection Phase and receive Intramuscular (IM) injections of 744 LA or placebo at three time points at 12 week intervals. IM injections will consist of 800 mg of 744 or a matching control
Not Provided
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Infection, Human Immunodeficiency Virus
  • Drug: 744 Tablet
    White to almost white oval shaped film coated 30 mg tablets for oral administration
  • Drug: 744 LA Injection
    Sterile white to slightly coloured suspension containing 200 mg/mL of 744 as free acid for administration by intramuscular (IM) injection
  • Drug: Placebo Tablet
    Microcrystalline cellulose, Opadry film-coating, white OY-S-28876
  • Drug: Placebo Injection
    Sterile saline 0.9% Sodium Chloride Injection
  • Experimental: Arm 1
    Participants will receive daily oral 744 (30 mg tablets) for 4 weeks, followed by a one week washout period followed by intra-muscular (IM) injections of 800 mg of 744 LA at three time points at 12 week intervals as: Week 5, Week 17, and Week 29
    Interventions:
    • Drug: 744 Tablet
    • Drug: 744 LA Injection
  • Experimental: Arm 2
    Participants will receive daily oral matching placebo for 4 weeks, followed by a one week washout period followed by intra-muscular (IM) injections of saline at three time points at 12 week intervals as: Week 5, Week 17, and Week 29
    Interventions:
    • Drug: Placebo Tablet
    • Drug: Placebo Injection
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
127
February 23, 2016
May 15, 2015   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Non-reactive HIV test at screening or enrollment.
  • Males 18 to 65 years old at the time of signing the informed consent.
  • At risk of acquiring HIV, defined as having at least one casual sex partner in the past 24 months.
  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring at the time of screening.
  • If participating in sexual activity with a female of child-bearing potential, men must agree to use condoms. Subjects who are sexual partners of females with child bearing potential must also agree to practice an acceptable method of contraception for the duration of the study, such as double barrier (male condom/spermicide, male condom/diaphragm) or female partner use of hormonal contraception, intrauterine device (IUD) or other method with published data showing that the lowest expected failure rate for that is less than 1% per year. All subjects participating in the study must be counseled on safer sexual practices including the use of effective barrier methods to minimize risk of HIV transmission.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • Willing to undergo all required study procedures

Exclusion Criteria:

  • One or more reactive HIV test results at screening or enrollment, even if HIV infection is not confirmed. Negative HIV Ribonucleic acid (RNA) must also be documented at screening.
  • Assessed by the Investigator of Record or designee as being at "high risk" for HIV infection. This may include one or more of the following:

The negative partner in an HIV serodiscordant couple Men who exchange sex for goods or money Men who have engaged in unprotected receptive anal intercourse within the past 6 months Men who have had greater than 3 sexual partners within the past 3 months Men who have had a sexually transmitted disease within the past 6 months Any other behavior assessed by the investigator as "high risk"

  • Co-enrollment in any other HIV interventional research study (provided by self-report or other available documentation) or prior enrollment and receipt of the active arm (i.e., NOT a placebo) of a HIV vaccine trial (provided by available documentation).
  • Use of antiretroviral (ARV) therapy (e.g., for Post exposure prophylaxis (PEP) or Pre exposure prophylaxis (PrEP) in the past 30 days, five half-lives, or twice the duration of the biological effect of the applied treatment (whichever is longer) prior to study enrollment.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of drug or alcohol consumption that in the opinion of the Principal Investigator will interfere with study participation.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
  • Any of the following laboratory values during the screening period. Positive Hepatitis C antibody result Positive Hepatitis B surface antigen (HBsAg) Hemoglobin less than 11 gram (g)/deci liter (dL) Absolute neutrophil count less than 750 cells/mm^3 Platelet count less than or equal to 100,000/mm^3 Presence of a coagulopathy as defined by an INR greater than 1.5 or a PTT greater than 45sec Calculated creatinine clearance less than 70 mL/minute using the Cockcroft-Gault equation A single repeat test is allowed during the Screening period to verify a result, with the exception of HIV tests.
  • Subjects with an alanine aminotransferase (ALT), alkaline phosphatase (ALP) or bilirubin greater than or equal to1.5xULN (isolated bilirubin greater than 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%).
  • History of the following cardiac diseases: myocardial infarction, congestive heart failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia.
  • The subject's systolic blood pressure is outside the range of 90-160mmHg, or diastolic blood pressure is outside the range of 45-90mmHg or heart rate is outside the range of 45-100 beats per minute (bpm).
  • Exclusion criteria for screening (ECG (a single repeat is allowed for eligibility determination) for Male Subjects:

Heart rate (A heart rate from 100 to 110 bpm can be rechecked within 30 minutes to verify eligibility)-less than 45 and greater than 100 bpm.

QRS duration-greater than 120 msec. QTc interval (B or F)-greater than 450 msec. Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher], Wolf Parkinson White [WPW] syndrome).

Sinus Pauses greater than 3 seconds. Any significant arrhythmia which, in the opinion of the principal investigator and medical monitor, will interfere with the safety for the individual subject.

Non-sustained or sustained ventricular tachycardia (greater than or equal to 3 consecutive ventricular ectopic beats).

  • Ongoing intravenous drug use - episodic use or any use in the past 90 days is exclusionary (as assessed by the study investigator).
  • The subject has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of ISRs.
  • Use of high dose aspirin or any other anticoagulant or antiplatelet medication that would interfere with the ability to receive intramuscular injections.
  • Active skin disease or disorder (i.e., infection, inflammation, dermatitis, eczema, drug rash, psoriasis, urticaria). Mild cases of localized acne or folliculitis or other mild skin condition may not be exclusionary at the discretion of the Investigator of Record or Medical Monitor).
Sexes Eligible for Study: Male
18 Years to 65 Years   (Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT02076178
201120
No
Not Provided
Not Provided
ViiV Healthcare
ViiV Healthcare
GlaxoSmithKline
Study Director: GSK Clinical Trials ViiV Healthcare
ViiV Healthcare
October 2017

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