Safety and Tolerability Study to Evaluate Lower Dose of GSK2248761 in Antiretroviral Treatment-Naive HIV-1 Infected Adults. - Full Text View

Sponsor:	GlaxoSmithKline
Information provided by:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00945282

Purpose

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.

Condition	Intervention	Phase
HIV-1 Infection	Drug: Lopinavir/ritonavir Drug: HAART Drug: GSK2248761 Drug: Placebo	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator), Parallel Assignment, Safety/Efficacy Study
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)

Resource links provided by NLM:

MedlinePlus related topics: AIDS

Drug Information available for: Ritonavir Lopinavir

U.S. FDA Resources

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:

GSK2248761 PK parameters following dose administration on Day 1 and Day 7. [ Time Frame: 8 days ] [ Designated as safety issue: No ]
Safety and tolerability parameters, including adverse event, clinical laboratory, electrocardiogram (EGC) and vital sign assesssments. [ Time Frame: 14 days ] [ Designated as safety issue: No ]
Change from baseline through Day 8 in plasma HIV-1 RNA. [ Time Frame: 8 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change from baseline in reverse transcriptase sequences of HIV-1 at Day 8. [ Time Frame: 8 days ] [ Designated as safety issue: No ]
Change from baseline CD4+ and CD8+ T-Lymphocyte cell count and percentages at Day 8. [ Time Frame: 8 days ] [ Designated as safety issue: No ]
GSK2248761 PK parameters on Day 2 through Day 7. [ Time Frame: 8 days ] [ Designated as safety issue: No ]
Day 1 and Day 7 PK data at different doses for the assessment of dose proportionality. [ Time Frame: 8 days ] [ Designated as safety issue: No ]

Enrollment:	8
Study Start Date:	October 2009
Study Completion Date:	December 2009
Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Cohort 2: Experimental In Cohort 2 subjects will receive either GSK2248761 in the range of 10 mg - 20 mg or 40 mg - 90 mg or placebo once a day for 7 days. On Day 8 subjects will receive either Kaletra or HAART for 28 days. The doctor will choose the most appropriate medications for HAART. The dose for Cohort 2 will be determined following evaluation of results from Cohort 1. Cohort 2 may not be done.	Drug: Lopinavir/ritonavir Lopinavir 400 mg and ritonovir 100 mg every 12 hours for 28 days. Lopinavir/ritonavir is approved by the FDA as an HIV medication in the protease inhibitor class. Kaletra is a trademark of Abbott Laboratories. Drug: HAART Highly Active Antiretroviral therapy of the doctor's choice. Drug: Placebo Placebo is a capsule with no drug in it. Drug: GSK2248761 GSK2248761 10 mg -20 mg or 40 mg - 90 mg once a day for 7 days. GSK2248761 is an investigational (not approved by the FDA) HIV drug in the class of non-nucleoside reuptake inhibitor class.
Cohort 1: Experimental In Cohort 1 subjects will receive either GSK2248761 30 mg or placebo once a day for 7 days. On Day 8 subjects will receive either Kaletra or HAART for 28 days. The doctor will choose the most appropriate medications for HAART.	Drug: Lopinavir/ritonavir Lopinavir 400 mg and ritonovir 100 mg every 12 hours for 28 days. Lopinavir/ritonavir is approved by the FDA as an HIV medication in the protease inhibitor class. Kaletra is a trademark of Abbott Laboratories. Drug: HAART Highly Active Antiretroviral therapy of the doctor's choice. Drug: GSK2248761 GSK2248761 30 mg capsule once a day for 7 days. GSK2248761 is an investigational (not approved by the FDA) HIV drug in the class of non-nucleoside reuptake inhibitor class. Drug: Placebo Placebo is a capsule with no drug in it.

Arms

Assigned Interventions

Cohort 2: Experimental

In Cohort 2 subjects will receive either GSK2248761 in the range of 10 mg - 20 mg or 40 mg - 90 mg or placebo once a day for 7 days. On Day 8 subjects will receive either Kaletra or HAART for 28 days. The doctor will choose the most appropriate medications for HAART. The dose for Cohort 2 will be determined following evaluation of results from Cohort 1. Cohort 2 may not be done.

Drug: Lopinavir/ritonavir

Lopinavir 400 mg and ritonovir 100 mg every 12 hours for 28 days. Lopinavir/ritonavir is approved by the FDA as an HIV medication in the protease inhibitor class. Kaletra is a trademark of Abbott Laboratories.

Drug: HAART

Highly Active Antiretroviral therapy of the doctor's choice.

Drug: Placebo

Placebo is a capsule with no drug in it.

Drug: GSK2248761

GSK2248761 10 mg -20 mg or 40 mg - 90 mg once a day for 7 days. GSK2248761 is an investigational (not approved by the FDA) HIV drug in the class of non-nucleoside reuptake inhibitor class.

Cohort 1: Experimental

In Cohort 1 subjects will receive either GSK2248761 30 mg or placebo once a day for 7 days. On Day 8 subjects will receive either Kaletra or HAART for 28 days. The doctor will choose the most appropriate medications for HAART.

Drug: Lopinavir/ritonavir

Lopinavir 400 mg and ritonovir 100 mg every 12 hours for 28 days. Lopinavir/ritonavir is approved by the FDA as an HIV medication in the protease inhibitor class. Kaletra is a trademark of Abbott Laboratories.

Drug: HAART

Highly Active Antiretroviral therapy of the doctor's choice.

Drug: GSK2248761

GSK2248761 30 mg capsule once a day for 7 days. GSK2248761 is an investigational (not approved by the FDA) HIV drug in the class of non-nucleoside reuptake inhibitor class.

Drug: Placebo

Placebo is a capsule with no drug in it.

Eligibility

Ages Eligible for Study:	21 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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)).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00945282

Locations

Argentina
GSK Investigational Site
Buenos Aires, Argentina, B1602DBG

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director:

GSK Clinical Trials

GlaxoSmithKline

More Information

No publications provided

Responsible Party:	GSK ( Study Director )
Study ID Numbers:	113020, SGN113020
Study First Received:	July 23, 2009
Last Updated:	January 7, 2010
ClinicalTrials.gov Identifier:	NCT00945282 History of Changes
Health Authority:	Argentina: Ministry of Health - A.N.M.A.T

Keywords provided by GlaxoSmithKline:

GSK2248761
HIV-1
Treatment-naive
pharmacokinetics
monotherapy

adaptive
NNRTI
IDX12899
HIV Infections
treatment naive

Additional relevant MeSH terms:

Anti-Infective Agents
HIV Protease Inhibitors
Anti-HIV Agents
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Infection
Antiviral Agents

Pharmacologic Actions
Protease Inhibitors
Lopinavir
Anti-Retroviral Agents
Ritonavir
Therapeutic Uses

ClinicalTrials.gov processed this record on February 08, 2010