Clinical trial NCT00945282: Safety and Tolerability Study to Evaluate Lower Dose of GSK2248761 in Antiretroviral Treatment-Naive HIV-1 Infected Adults.
Official title: A Proof of Concept Study for GSK2248761 (An Extension of NV-05A-002: A Phase I/IIa Double-Blind Study to Evaluate the Safety and Tolerability, Antiretroviral Activity, Pharmacokinetics and Pharmacodynamics of IDX12899 in Antiretroviral Treatment-Naive HIV-1 Infected Subjects, Completed by Idenix)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infection, Human Immunodeficiency Virus
Keywords: IDX12899
adaptive
monotherapy
pharmacokinetics
Treatment-naive
HIV-1
GSK2248761
NNRTI
HIV Infections
treatment naive
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2009-07-24
Enrollment: 8
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: GSK has in-licensed a novel NNRTI-class candidate (GSK2248761, IDX12899) for the treatment of subjects with HIV-1 infection from Idenix Pharmaceuticals. Idenix Pharmaceuticals completed a proof-of-concept study evaluating GSK2248761 monotherapy over seven days in forty treatment-naïve subjects infected with HIV-1. GSK2248761 doses sequentially evaluated were 800 mg QD, 400 mg QD, 200 mg QD and 100mg QD.

This study will evaluate a lower dose, or doses, of GSK2248761 to better characterize the dose-response and concentration-response curves. The results from this study will be used to select doses for future clinical studies in HIV-1 infected subjects.


Eligibility criteria: Inclusion Criteria:

* Male or Female, 21 to 65 years of age.
* Female of non-childbearing potential defined as: being post-menopausal, defined as 12 months of spontaneous amenorrhea and having a serum FSH level \>40 MIU/ml at Screening OR have had a documented bilateral tubal ligation or hysterectomy of at least 6 months prior to study initiation, bilateral oophorectomy or bilateral tubal ligation.
* Plasma HIV-1 RNA value \>= 5000 copies/mL.
* CD4+ count \>= 200 cells/mm3.
* Is antiretroviral treatment-naïve and agrees not to start antiretroviral therapy prior to clinic check-in (Day-1).
* Subject agrees to start a standard HAART regimen on Day 8 of the study or Kaletra monotherapy for 28 days within 24 hours after the last dose of study medication.
* Capable of giving written informed consent, which includes being willing and able to comply with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

* Subject is pregnant as determined by a positive urine/serum pregnancy test at Screening and Day -1.
* Lactating females.
* Male subjects of reproductive potential and unwilling to use double barrier method of contraception (e.g., condom plus spermicide) and continue to use an adequate method of birth control for at least 30 days after the last dose of the study drug.
* Has 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.
* History of regular alcohol consumption within 6 months of Screening as defined as: an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (\~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits
* Has a positive pre-study drug screen. Drugs that will be screened for include amphetamines, barbiturates, cocaine and PCP.
* 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 Principal Investigator, 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 drugs include GSK2248761 placebo or the follow-up HAART or Kaletra therapy.

* Received an immunomodulating agent (e.g., interleukin-2) or immunotherapeutic vaccine within 30 days before Day -1.
* Requires a medication that is a known substrate, inhibitor and/or inducer of CYP3A4.
* Has received an investigational drug or participated in any other research trial within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dosing day.
* Has ever had an AIDS-defining illness.
* Has a history of or has a currently active clinically important disease other than HIV-1 infection that, in the opinion of the Investigator, may put the subject at risk because of participation in this study (including renal and hepatic impairment, active infections including tuberculosis or opportunistic infection, malignancy and cardiac dysfunction).
* Has an intestinal malabsorption (e.g., structural defects, digestive failure, enzyme deficiencies, etc).
* Has a pre-existing NNRTI drug resistance based on genotyping at Screening.
* Where participation in the study would result in donation of blood or blood products in excess of 500mL within a 56 day period.
* Subject has any of the following laboratory parameters at Screening (a single repeat is allowed for eligibility determination): Hemoglobin \<8.5 g/dL, Neutrophil count \<1000 cells/mm3, Platelet count \<100,000 cells/mm3, Serum creatinine \> the upper limit of normal (ULN), AST or ALT \<= 2.5 x ULN.
* Exclusion Criteria for Screening ECG (A single repeat is allowed for eligibility determination): Exclusion Criteria for Screening ECG: Heart rate: (males) \<45 and \>100 bpm (females) \<50 and \>100 bpm, QRS duration: \>120 msec, QTc interval (Bazett): \> 450 msec. Non-sustained (\>= 3 consecutive beats) or sustained ventricular tachycardia. Sinus Pauses \>2.5 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: Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs)
timeFrame: Up to 38 days
measure: Change From Baseline in Hematology Paramaters- Basophils, Eosinophils, Lymphocytes, Monocytes, White Blood Cell Count
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Hematology Paramaters- Hemoglobin
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Hematology Paramaters- Platelet Count
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Hematology Paramaters- Red Blood Cell Count
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Hematology Parameters- Total Neutrophil
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Hematology Paramaters- Mean Corpuscle Hemoglobin (MCH)
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Hematology Paramaters- Mean Corpuscle Volume (MCV)
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Hematology Paramaters- Hematocrit
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Hematology Paramaters-Mean Corpuscle Hemoglobin Concentration
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Clinical Chemistry Paramaters- Albumin and Total Protein
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Clinical Chemistry Parameters- Blood Urea Nitrogen, Triglycerides, Glucose, Creatinine, Calcium, Cholesterol, Total Bilirubin, and Direct Bilirubin.
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Clinical Chemistry Paramaters- Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Clinical Chemistry Paramaters-sodium, Potassium and Carbondioxide or Bicarbonate
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Clinical Chemistry Paramaters- Phosphorus
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Clinical Chemistry Paramaters- Uric Acid
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Clinical Chemistry Paramaters- Thyroxine, Free
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in Clinical Chemistry Paramaters- Thyroxine Total, Thyroxine Binding Globulin, Total T3.
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 2, 4 , 7 , Day 8 and Follow-up (Day 14)
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Day 1, Day 4, Day 7, Day 8 and follow-up
measure: Change From Baseline in Vital Signs-systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 1, 4, 7 , Day 8 and Follow-up (Day 14)
measure: Change From Baseline in HR
timeFrame: Baseline (pre-dose at Day -1 or Day 1) and Day 1 (4-hour), Day 4 (Pre-dose and 4 hour), Day 7 (pre-dose and 4-hour), Day 8 and follow up (Day 14)
measure: Change From Baseline Through Day 8 in Plasma HIV-1 RNA
timeFrame: Baseline (pre-dose Day 1) to Day 8
measure: Change From Baseline to Nadir in Plasma HIV-1 RNA
timeFrame: Baseline (pre-dose Day 1) to Day 8
measure: HIV-1 Rate of Decline by Treatment
timeFrame: Day 1 to Day 8
measure: GSK2248761 Pharmacokinetic (PK) Parameters Following Dose Administration on Day 1: Area Under the Plasma Concentration Time Curve 0 to Infinite (AUC[0-∞]) and Area Under the Plasma Concentration Time Curve (AUC [0-24])
timeFrame: Day 1 (Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose)
measure: GSK2248761 PK Parameters Following Dose Administration on Day 1: Maximum Observed Concentration (Cmax) and Concentration at 24 Hours Post Dose (C24)
timeFrame: Day 1 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours)
measure: GSK2248761 PK Parameters Following Dose Administration on Day 7: Predose Concentration (C0), Concentration at End of Dosing Interval (Cτ), Minimum Observed Concentration During One Dosing Interval (Cmin) and Cmax
timeFrame: Day 7 (Pre -dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose)
measure: GSK2248761 PK Parameters Following Dose Administration on Day 1: Time to Maximum Observed Concentration (Tmax), Terminal Half-life (t1/2), Absorption Lag Time (Tlag)
timeFrame: Day 1 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose)
measure: GSK2248761 PK Parameters Following Dose Administration on Day 1: Apparent Clearance (CL/F)
timeFrame: Day 1 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose)
measure: GSK2248761 PK Parameters Following Dose Administration on Day 7: AUC(0-τ)
timeFrame: Day 7 (Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose)
measure: GSK2248761 PK Parameters Following Dose Administration on Day 7: Tmax
timeFrame: Day 7 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose)
measure: GSK2248761 PK Parameters Following Dose Administration on Day 7: t1/2
timeFrame: Day 7 (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose)
measure: Change From Baseline in CD4+ and CD8+ T-lymphocyte Cell Count at Day1 and Day 8.
timeFrame: Baseline (Screening), Day 1 and Day 8
Secondary outcomes:
measure: Percent Change From Baseline in CD4+ and CD8+ T-lymphocyte Cell Count at Day 1 and Day 8
timeFrame: Baseline (Screening), Day 1 and Day 8
measure: Accumulation Ratio for AUC , Cmax, Cτ, and Time Invariance Ratio Following Repeat Administration
timeFrame: (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose ) on Day 1 and Day 7
measure: Change From Baseline in Reverse Transcriptase Sequences of HIV-1 at Day 8
timeFrame: Baseline (Screening) and Day 8
measure: Assessment of the Achievement of Pre-dose GSK2248761 Steady State Concentration Following Repeat Dose Administration on Day 2 Through 7
timeFrame: Day 7 (Pre - dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose) and Days 2, 3, 4. 5 and 6: pre-dose only
measure: PK Data of Day 1 AUC(0-inf) and Day 7 AUC(0-tau) at Different Doses for the Assessment of Dose Proportionality
timeFrame: (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose ) From Day 1 to Up to Day 7
measure: PK Data of Cmax and Ctau at Different Doses for the Assessment of Dose Proportionality
timeFrame: (Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose ) From Day 1 to Up to Day 7
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Zala C, St Clair M, Dudas K, Kim J, Lou Y, White S, Piscitelli S, Dumont E, Pietropaolo K, Zhou XJ, Mayers D. Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects. Antimicrob Agents Chemother. 2012 May;56(5):2570-5. doi: 10.1128/AAC.05597-11. Epub 2012 Feb 6.