Clinical trial NCT00920426: Study to Compare the Safety and Anti-HIV Effect of GSK1265744 Versus Placebo in HIV-1 Infected Adults (ITZ112929)
Official title: A Phase 2a Study to Compare Antiviral Effect, Safety, Tolerability and Pharmacokinetics of GSK1265744 Monotherapy Versus Placebo in HIV-1 Infected Adults (ITZ112929)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infection, Human Immunodeficiency Virus
Keywords: HIV
naive
Phase II
integrase inhibitor
GSK1265744
newly diagnosed
pharmacokinetics
AIDS
integrase
HIV Infections
Treatment naive
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Shionogi
name: GlaxoSmithKline
First posted: 2009-06-15
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this randomized, double-blinded study is to test the safety of GSK1265744 and how well it works on reducing the amount of HIV in the blood. It will also look at how people react to and how a human body uses GSK1265744. This study will compare the effects of GSK1265744 and placebo.

The study will consist of 1 or 2 parts to look at doses of GSK1265744. About 8 people will take part in Part 1 of the study receiving dose A. If additional dosing information is needed after Part 1, about 6 people will take part in Part 2 of the study receiving dose B.


Eligibility criteria: Inclusion Criteria:

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

* Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
* A female subject is eligible to participate if she is of non-childbearing potential, defined as:
* Pre-menopausal females with a documented bilateral oophorectomy, tubal ligation or hysterectomy; or
* Postmenopausal defined as 12 months of spontaneous amenorrhea. A follicle stimulating hormone level will be performed to confirm post-menopausal status. For this study, FSH levels \> 40 MlU/ml and estradiol \< 40 pg/ml (\<140 pmol/L) is confirmatory.
* Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until 14 days after the last dose of study medication.
* CD4+ cell count greater than or equal to 200 cells/mm3 and plasma HIV-1 RNA greater than or equal to 5000 copies/mL at Screening.
* No current antiretroviral therapy and have not received any in the 12 weeks prior to first dose.
* For subjects who have received antiretroviral treatment in the past, adequate treatment options to construct HAART therapy with at least 3 active antiretrovirals for Optimized Therapy, as selected by the Investigator.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

* A positive screening Hepatitis B surface antigen; positive screening hepatitis C virus (HCV) antibody and detectable HCV ribonucleic acid (RNA) on subsequent testing. If the hepatitis C antibody is positive but the HCV RNA is undetectable, the subject may be included in the study.
* AST and ALT \> 3ULN at Screening. A single repeat is allowed for eligibility determination.
* Inadequate renal function at Screening, defined as either a serum creatinine \>1.5 mg/dL or a calculated creatinine clearance (CrCl) ≤ 50 mL/min. A single repeat serum creatinine is allowed to determine eligibility.
* Any acute laboratory abnormality at screening which, in the opinion of the investigator, should preclude the subject's participation in the study of an investigational compound. Any grade 4 laboratory abnormality at screening, with the exception of CPK, will exclude a subject from study participation unless the investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the sponsor. A single repeat is allowed for eligibility determination.
* A positive drug screen at screening and baseline. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine or PCP.
* History of regular alcohol consumption, defined as an average weekly intake of \>14 drinks for males or \>7 drinks for females, within 6 months of Screening.

Note: One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.

* Any condition (including alcohol or drug abuse) which, in the opinion of the investigator, could interfere with the subject's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the subject.
* Prior treatment with an integrase inhibitor (greater than or equal to 1 dose).
* Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 days of study drug administration or anticipated need for such treatment within the study.
* Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (such as hydroxyurea or foscarnet) within 30 days of study drug administration.
* Treatment with any vaccine within 30 days prior to receiving study medication.
* An active Center for Disease Control and Prevention (CDC) Category C disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy during the trial.
* Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
* Lactating females.
* Use of multivitamins or antacids within 24 hours prior to the first dose of investigational product.
* 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 GSK Medical Monitor, contraindicates their participation. In addition, if heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.

Note: Study medications refer to GSK1265744 or placebo.

* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* History of clinically relevant pancreatitis or hepatitis within the previous 6 months.
* Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs.
* Exclusion Criteria for Screening ECG (A single repeat is allowed for eligibility determination):

Exclusion Criteria for Screening ECG:

Males Females Heart rate \<45 and \>100 bpm \<50 and \>100 bpm QRS duration \>120 msec \>120 msec QTc interval (Bazett) \> 450 msec \> 450 msec Non-sustained (≥ 3 consecutive beats) or sustained ventricular tachycardia. Sinus Pauses \>3 seconds. 2nd degree (Type II) or higher AV block. Evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes (except early repolarization)).

Primary outcomes:
measure: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV-1) Ribonucleic Acid (RNA) to Day 11
timeFrame: Baseline (Day 1) and Day 11
measure: GSK1265744 Pharmacokinetic (PK) Parameters Following Dose Administration on Day 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Participant Across All Treatments(AUC[0-24])
timeFrame: Day 1 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
measure: GSK1265744 PK Parameters Following Dose Administration on Day 1: Concentration at 24 Hours Post Dose (C24)
timeFrame: Day 1 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
measure: GSK1265744 PK Parameters Following Dose Administration on Day 10: Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau])
timeFrame: Day 10 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
measure: GSK1265744 PK Parameters Following Dose Administration on Day 10: Predose Concentration (C0), Concentration at End of Dosing Interval (Ctau), Minimum Observed Concentration During One Dosing Interval (Cmin)
timeFrame: Day 10 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
measure: GSK1265744 PK Parameters Following Dose Administration on Day 1 and Day 10: Maximum Observed Concentration (Cmax)
timeFrame: Pre-dose (within 15 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose on Days 1 and 10
measure: GSK1265744 PK Parameters Following Dose Administration on Day 1 and Day 10: Time to Cmax (Tmax)
timeFrame: Pre-dose (within 15 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose on Days 1 and 10
measure: GSK1265744 PK Parameters Following Dose Administration on Day 1 and Day 10: Terminal Half-life (t1/2) and Absorption Lag Time (Tlag)
timeFrame: Day 1 and Day 10
measure: GSK1265744 PK Parameters Following Last Repeat Administration on Day 10: Apparent Clearance Following Oral Dosing (CL/F)
timeFrame: Day 10 (Pre-dose [within 15 minutes prior to dosing] and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8hours post-dose)
measure: Number of Participants With Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Day 1 to Day 11
measure: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (ANC- Absolute Neutrophil Count), White Blood Cell Count
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Hematology Parameters: Hemoglobin
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Hematology Parameters: Mean Corpuscle Hemoglobin
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Hematology Parameters: Mean Corpuscle Volume
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Hematology Parameters: Platelet Count
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Hematology Parameters: Red Blood Cell Count
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Hematology Parameters: Reticulocytes
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Clinical Chemistry Data: Albumin, Total Protein
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Clinical Chemistry Data: Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatine Kinase, Lipase
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Direct Bilirubin, Total Bilirubin, Calcium, Cholesterol, Creatinine, Glucose, High Density Lipoprotein (HDL) Cholesterol Direct, Low Density Lipoprotein (LDL) Cholesterol Calculation, Triglycerides, Urea/Blood Urea Nitrogen
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Change From Baseline in Clinical Chemistry Data: Chloride, Carbon Dioxide Content/Bicarbonate, Magnesium, Sodium, Potassium
timeFrame: Baseline (Day 1) and Day 3, 7, 10
measure: Number of Participants With Urinalysis Data
timeFrame: Day 1 to Day 10
measure: Change From Baseline in Vital Sign: Systolic and Diastolic Blood Pressure
timeFrame: Baseline (Day 1, pre-dose) and Day 1 (2 hours post dose), 4, 7, 10
measure: Change From Baseline in Vital Sign: Heart Rate
timeFrame: Baseline (Day 1, pre-dose) and Day 1 (2 hours post dose), 4, 7, 10
measure: Change From Baseline in Electrocardiogram (ECG) Parameters
timeFrame: Baseline (Day 1, pre-dose) and Day 1 (2 hours post dose), 4, 7, 10
Secondary outcomes:
measure: Change From Baseline in Plasma HIV-1 RNA
timeFrame: Baseline (Day 1 pre-dose) and Day 1 (post dose), 2, 3, 4, 7, 8, 9, 10
measure: Change From Baseline in Plasma HIV-1 RNA to Nadir Over 11 Days
timeFrame: Baseline (Day 1) and Day 11
measure: Plasma HIV-1 RNA Rate of Decline (Slope) Over 11 Days
timeFrame: Up to Day 10
measure: Number of Participants With HIV-1 RNA<400 Copies/mL
timeFrame: Up to Day 11
measure: Number of Participants With HIV-1 RNA<50 Copies/mL
timeFrame: Up to Day 11
measure: Change From Baseline in CD4+ Cell Count to Day 11
timeFrame: Baseline (Day 1) and Day 11
measure: Pre-morning Dose Concentrations (C0) on Day 2 Through 10 to Assess the Achievement of Steady State of GSK1265744 Following Repeat Administration
timeFrame: Day 1 24 hours (Day 2), Pre-dose on Days 3, 4, 7, 8, 9 and 10
measure: Accumulation Ratios for AUC, Cmax, and Ctau
timeFrame: Days 1 and 10
measure: Day 1 AUC(0-24) at Different Doses for the Assessment of Dose Proportionality Using Power Model
timeFrame: Day 1
measure: Day 1 Cmax and C24 at Different Doses for the Assessment of Dose Proportionality Using Power Model
timeFrame: Day 1
measure: Day 10 AUC(0-tau) at Different Doses for the Assessment of Dose Proportionality Using Power Model
timeFrame: Day 10
measure: Day 10 Cmax, C0 and Ctau at Different Doses for the Assessment of Dose Proportionality Using Power Model
timeFrame: Day 10
Other outcomes:
Locations:
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Vero Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: