Dose Ranging Study of GSK1265744 Plus Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus-1 (HIV-1) Virologic Suppression Followed by Virologic Suppression Maintenance by GSK1265744 Plus Rilpivirine

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01641809
First received: June 28, 2012
Last updated: May 22, 2014
Last verified: May 2014
  Purpose

The study is designed to select a dose of GSK1265744 primarily on the basis of antiviral activity and tolerability in HIV-1 infected, antiretroviral naive subjects.

This study consists of two parts:

Induction Phase: Approximately 200 subjects will be randomized (50 subjects in each of the 4 treatment arms). The Induction Phase consists of a 24 week dose-ranging evaluation of GSK1265744 at blinded doses of 10 mg, 30 mg and 60 mg once-daily and a control arm of open-label efavirenz (EFV) 600 mg once daily. The background dual nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral therapy (ART) for all arms will be either abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) as selected by the Investigator. Subjects randomized to a GSK1265744 containing arm, who successfully complete 24 weeks on study and demonstrate virologic suppression (defined as having a plasma HIV-1 ribonucleic acid [RNA] <50 copies per milliliter [c/mL] before Week 24, with no signs of virologic rebound) will become eligible for the Maintenance Phase of this study.

Maintenance Phase: The background NRTIs will be discontinued and the subjects will continue their randomized dose of GSK1265744 in combination with rilpivirine (RPV) 25 mg once-daily for an additional 72 weeks. The Maintenance phase will evaluate the ability of this two drug ART regimen to maintain virologic suppression through Week 48, Week 72 and Week 96. Subjects randomized to the EFV arm will continue on their randomized regimen through Week 96.

After completion of the maintenance phase, subjects could enroll in the Open-Label Phase to continue GSK1265744 + RPV treatment as long as they continue to derive clinical benefit and until it is locally approved and commercially available.


Condition Intervention Phase
Infection, Human Immunodeficiency Virus
Drug: GSK1265744 10 mg
Drug: GSK1265744 30 mg
Drug: GSK1265744 60 mg
Drug: Efavirenz 600 mg
Drug: Rilpivirine 25 mg
Drug: Placebo
Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase IIb, Dose Ranging Study of Oral GSK1265744 in Combination With Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus -1 (HIV-1) Virologic Suppression Followed by an Evaluation of Maintenance of Virologic Suppression When Oral GSK1265744 is Combined With Oral Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult Subjects

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 will be based on Intent-to-Treat Exposed (ITT-E) Population (all randomized subjects who received at least one dose of study drug) using the missing, switch, or discontinuation equals failure (MSDF) algorithm.


Secondary Outcome Measures:
  • Proportion of subjects with plasma HIV-1 RNA <400 and <50 copies/mL over time by visit [ Time Frame: Through Week 96 ] [ Designated as safety issue: No ]
    Proportion of subjects with plasma HIV-1 RNA <400 and <50 copies/mL over time by visit will be calculated using the MSDF and observed algorithm.

  • Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 16 and Week 24 in Induction Phase [ Time Frame: 16 weeks, 24 weeks ] [ Designated as safety issue: No ]
    Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 16 and Week 24 in Induction Phase will be based on ITT-E Population and MSDF algorithm.

  • The proportion of subjects with HIV-1 RNA <50 copies/mL from Week 24 through Week 96 by visit in Maintenance Phase [ Time Frame: 24 weeks through Week 96 ] [ Designated as safety issue: No ]
    The proportion of subjects with HIV-1 RNA <50 copies/mL from Week 24 through Week 96 will be determined by visit for the ITT-ME Population (all randomized subjects who received at least one dose of investigational product [IP] during the Maintenance Phase of the study) using MSDF algorithm.

  • Absolute values and change from Baseline in plasma HIV-1 RNA by visit [ Time Frame: Baseline (Study Day 1), and up to Week 96 ] [ Designated as safety issue: No ]
    Plasma for quantitative HIV-1 RNA will be collected at every visit from baseline till Follow-up. Methods to determine absolute plasma HIV-1 RNA may include but are not limited to the Abbott RealTime HIV-1 Assay lower limit of detection (LLOD) 40 c/mL. Change from Baseline will be calculated as post-Baseline value minus the Baseline value.

  • Incidence of disease progression [ Time Frame: Up to Week 96 ] [ Designated as safety issue: No ]
    Disease progression includes HIV-associated conditions, acquired immunodeficiency syndrome (AIDS) and death. HIV-associated conditions will be assessed according to the 1993 Centers for disease control and prevention (CDC) Revised Classification System for HIV Infection in Adults.

  • Absolute values and changes from baseline in CD4+ cell counts by visit [ Time Frame: Baseline (Study Day 1), and up to Week 96 ] [ Designated as safety issue: No ]
    Lymphocyte subsets (including CD4+) will be collected for assessment by flow cytometry.

  • Incidence of treatment emergent genotypic and phenotypic resistance to GSK1265744, RPV and other on-study ART for protocol-defined virologic failures [ Time Frame: Up to Week 96 ] [ Designated as safety issue: No ]
    Development of viral resistance to GSK1265744 and other on-study ART in subjects experiencing virologic failure through Week 24, and viral resistance to GSK1265744 and rilpivirine in subjects experiencing virologic failure from Week 24 through Week 96 will be evaluated. Genotypic and phenotypic analyses may be carried out using, but not limited to, Standard Phenosense and GenoSure testing methods for protease (PRO) and reverse transcriptase (RT), or with GeneSeq Integrase and PhenoSense Integrase assays.

  • Incidence and severity of Adverse Events (AEs) and laboratory abnormalities over time [ Time Frame: Up to Week 96 ] [ Designated as safety issue: No ]
    The incidence and severity of AEs and laboratory abnormalities will be determined throughout the study for the Safety Population (all randomized subjects who will be exposed to IP). AEs should be graded according to the Division of AIDS (DAIDS) toxicity scales. AEs and laboratory abnormalities will also be summarized separately for Induction Phase, and Maintenance Phase using the Maintenance Safety Population (all randomized subjects who will be exposed to IP during the Maintenance Phase of the study).

  • Absolute values and changes in laboratory parameters by visit [ Time Frame: Up to Week 96 ] [ Designated as safety issue: No ]
    Monitoring of hematology, blood chemistry and fasting lipids will be done, and changes by visit will be summarized.

  • Proportion of subjects who discontinue treatment due to AEs [ Time Frame: Up to Week 96 ] [ Designated as safety issue: No ]
    Proportion of subjects who discontinue treatment due to AEs will be determined throughout the study for the Safety Population; subjects who discontinue treatment due to AEs through Week 24 will be also determined in the Induction Phase; and subjects who discontinue treatment due to AEs from Week 24 through Week 96, will be determined using the Maintenance Safety Population.

  • Incidence of any clinically significant changes in QRS duration, QTc interval, HR, PR interval based on electrocardiograph (ECG) readings by visit [ Time Frame: Baseline (Study Day 1), and up to Week 96 ] [ Designated as safety issue: No ]
    ECGs will be performed in triplicate at least 5 minutes apart and following 5 minutes of rest in a semi-supine position within 1 hour prior to first dose. Subsequent ECG evaluations during the study should be obtained 2 to 4 hours after GSK1265744 dose.

  • Plasma GSK1265744 pharmacokinetic (PK) parameters [area under the concentration time curve over the dosing interval (AUC[0-tau]), maximum observed concentration (Cmax), and concentration at the end of a dosing interval (Ctau)] [ Time Frame: 2 weeks, 12 weeks, 26 weeks, and 36 weeks (Pre-dose and 2 to 4 hours (h) post dose) ] [ Designated as safety issue: No ]
    The Plasma GSK1265744 PK parameters will be estimated by non-compartmental analysis and/or population PK. The PK data collected in this study will be included in the analysis to investigate the exposure-response relationship and the integrated drug-viral dynamic modeling which will ultimately be used in guiding dose selection.

  • Plasma rilpivirine PK parameters [AUC(0-tau), Cmax, Ctau] [ Time Frame: 2 weeks, 12 weeks, 26 weeks, and 36 weeks (Pre-dose and 2 to 4 hours (h) post dose) ] [ Designated as safety issue: No ]
    The Plasma rilpivirine PK parameters will be estimated by non-compartmental analysis and/or population PK.

  • Adherence to IP [ Time Frame: Up to Week 96 ] [ Designated as safety issue: No ]
    Medication adherence to IP will be based on pill counts by visit.


Enrollment: 244
Study Start Date: August 2012
Estimated Study Completion Date: December 2020
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1 GSK1265744 10 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 10 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 10 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
Drug: GSK1265744 10 mg
GSK1265744 10 mg will be administered orally once daily in combination with investigator-selected background NRTIs in the Induction Phase of the study and in combination with Rilpivirine 25 mg in the Maintenance Phase of the study.
Drug: Rilpivirine 25 mg
Rilpivirine 25 mg will be administered orally once daily in combination with GSK1265744 10 mg, 30 mg and 60 mg in the Maintenance Phase of the study.
Drug: Placebo
Placebo matching to GSK1265744 will be administered along with GSK1265744 10 mg and 30 mg in the Induction phase and Maintenance phase of the study.
Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
The background dual NRTI therapy for all arms in the Induction Phase and Efavirenz 600 mg arm in the Maintenance Phase will be either abacavir 600 mg + lamivudine 300 mg (ABC/3TC) or tenofovir 300 mg + emtricitabine 200 mg (TDF/FTC) as selected by the Investigator.
Experimental: Arm 2 GSK1265744 30 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 30 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 30 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
Drug: GSK1265744 30 mg
GSK1265744 30 mg will be administered orally once daily in combination with investigator-selected background NRTIs in the Induction Phase of the study and in combination with Rilpivirine 25 mg in the Maintenance Phase of the study.
Drug: Rilpivirine 25 mg
Rilpivirine 25 mg will be administered orally once daily in combination with GSK1265744 10 mg, 30 mg and 60 mg in the Maintenance Phase of the study.
Drug: Placebo
Placebo matching to GSK1265744 will be administered along with GSK1265744 10 mg and 30 mg in the Induction phase and Maintenance phase of the study.
Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
The background dual NRTI therapy for all arms in the Induction Phase and Efavirenz 600 mg arm in the Maintenance Phase will be either abacavir 600 mg + lamivudine 300 mg (ABC/3TC) or tenofovir 300 mg + emtricitabine 200 mg (TDF/FTC) as selected by the Investigator.
Experimental: Arm 3 GSK1265744 60 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 60 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 60 mg + Rilpivirine 25 mg once daily from Week 24 to Week 96.
Drug: GSK1265744 60 mg
GSK1265744 60 mg will be administered orally once daily in combination with investigator-selected background NRTIs in the Induction Phase of the study and in combination with Rilpivirine 25 mg in the Maintenance Phase of the study.
Drug: Rilpivirine 25 mg
Rilpivirine 25 mg will be administered orally once daily in combination with GSK1265744 10 mg, 30 mg and 60 mg in the Maintenance Phase of the study.
Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
The background dual NRTI therapy for all arms in the Induction Phase and Efavirenz 600 mg arm in the Maintenance Phase will be either abacavir 600 mg + lamivudine 300 mg (ABC/3TC) or tenofovir 300 mg + emtricitabine 200 mg (TDF/FTC) as selected by the Investigator.
Active Comparator: Arm 4 Efavirenz 600 mg
In the Induction Phase and Maintenance Phase subjects will receive oral tablets of Efavirenz 600 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine).
Drug: Efavirenz 600 mg
Efavirenz 600 mg will be administered orally once daily in combination with investigator-selected background NRTIs in the Induction Phase and Maintenance Phase of the study.
Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)
The background dual NRTI therapy for all arms in the Induction Phase and Efavirenz 600 mg arm in the Maintenance Phase will be either abacavir 600 mg + lamivudine 300 mg (ABC/3TC) or tenofovir 300 mg + emtricitabine 200 mg (TDF/FTC) as selected by the Investigator.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 infected male or female subjects >= 18 years of age
  • Screening plasma HIV-1 RNA >=1000 c/mL
  • CD4+ cell count >=200 cells/millimeter (mm)^3
  • ART-naive defined as having =<10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection
  • Female subjects of child bearing potential are eligible to enter if they are not pregnant and willing to use protocol-specified methods of contraception to prevent pregnancy during the study

Exclusion Criteria:

  • Any evidence at screening of an active Centers for Disease and Prevention Control (CDC) Category C disease
  • Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
  • History of ongoing or clinically relevant hepatitis within the previous 6 months, and subjects with moderate to severe hepatic impairment will be excluded
  • Women who are breastfeeding
  • Subject, who in the investigator's judgment, poses a significant suicide risk
  • Any clinically significant finding on screening or baseline electrocardiograph (ECG)
  • The presence of any specific laboratory abnormalities at Screening
  • History of cardiac disease
  • Clinically relevant pancreatitis
  • Subjects who are unlikely to complete the dosing schedule due to a pre-existing physical or mental condition
  • Any condition which impairs the absorption, distribution, metabolism or excretion of the investigational product
  • Any evidence of primary resistance based upon the presence of a major resistance associated mutation in the Screening HIV genotype, or any historical genotype
  • Treatment with any protocol-specified excluded medication
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01641809

  Show 50 Study Locations
Sponsors and Collaborators
ViiV Healthcare
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare
  More Information

No publications provided

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT01641809     History of Changes
Other Study ID Numbers: 116482
Study First Received: June 28, 2012
Last Updated: May 22, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
HIV -1
GSK1265744
maintenance phase
dose selection

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Abacavir
Efavirenz
Emtricitabine
Lamivudine
Reverse Transcriptase Inhibitors
Tenofovir
Tenofovir disoproxil
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014