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

NCT01641809 | Completed Phase 2 Results

• 1 other identifier: 116482
• Study Type: interventional
• Target: 244
• Locations: 2 countries
• Sites: 48

Brief Summary

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.

Conditions

Infection, Human Immunodeficiency Virus; HIV Infections

Keywords

HIV -1; GSK1265744; maintenance phase; dose selection

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/Milliliter (mL) at Week 48 Using the Missing, Switch, Discontinuation Equals Failure (MSDF) Algorithm

  Plasma samples were collected for quantitative analysis of HIV-1 RNA. Percentage of participants with HIV-1 RNA \<50 copies/mL at Week 48 was determined using the MSDF algorithm based on the current US Food and Drug Administration (FDA) definition of Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to visit window) as well as participants who switch their concomitant antiretroviral therapy prior to the visit of interest as non-responders. Virological response within an analysis window was determined by the last available HIV-1 RNA measurement in that window while the participant was on-treatment. MSDF response rate was calculated as number of responders in the analysis window divided by the number of participants in the analysis population. ITT-E Population comprised of all randomized participants who received at least one dose of investigational product.

  Week 48

Secondary Outcomes (43)

• Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the MSDF Algorithm

  Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96

• Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the Observed Case Analysis

  Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96

• Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using the MSDF Algorithm

  Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300 and 312

• Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using Observed Case Analysis

  Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324

• Absolute Values for Plasma Logarithm to the Base 10 (log10) HIV-1 RNA Over Time by Visit

  Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324

Study Arms (4)

Arm 1 GSK1265744 10 mg

EXPERIMENTAL

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; Drug: Rilpivirine 25 mg; Drug: Placebo; Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)

Arm 2 GSK1265744 30 mg

EXPERIMENTAL

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; Drug: Rilpivirine 25 mg; Drug: Placebo; Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)

Arm 3 GSK1265744 60 mg

EXPERIMENTAL

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; Drug: Rilpivirine 25 mg; Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)

Arm 4 Efavirenz 600 mg

ACTIVE COMPARATOR

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; Drug: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC)

Interventions

GSK1265744 10 mg DRUG

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.

Arm 1 GSK1265744 10 mg

GSK1265744 30 mg DRUG

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.

Arm 2 GSK1265744 30 mg

GSK1265744 60 mg DRUG

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.

Arm 3 GSK1265744 60 mg

Efavirenz 600 mg DRUG

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.

Arm 4 Efavirenz 600 mg

Rilpivirine 25 mg DRUG

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.

Arm 1 GSK1265744 10 mg; Arm 2 GSK1265744 30 mg; Arm 3 GSK1265744 60 mg

Placebo DRUG

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.

Arm 1 GSK1265744 10 mg; Arm 2 GSK1265744 30 mg

Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) DRUG

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.

Arm 1 GSK1265744 10 mg; Arm 2 GSK1265744 30 mg; Arm 3 GSK1265744 60 mg; Arm 4 Efavirenz 600 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (48)

GSK Investigational Site

Birmingham, Alabama, 35294, United States

Location

GSK Investigational Site

Phoenix, Arizona, 85015, United States

Location

GSK Investigational Site

Little Rock, Arkansas, 72207, United States

Location

GSK Investigational Site

Bakersfield, California, 93301, United States

Location

GSK Investigational Site

Beverly Hills, California, 90211, United States

Location

GSK Investigational Site

Long Beach, California, 90813, United States

Location

GSK Investigational Site

Los Angeles, California, 90069, United States

Location

GSK Investigational Site

San Francisco, California, 94115, United States

Location

GSK Investigational Site

Denver, Colorado, 80209, United States

Location

GSK Investigational Site

Washington D.C., District of Columbia, 20007, United States

Location

GSK Investigational Site

Washington D.C., District of Columbia, 20037, United States

Location

GSK Investigational Site

Fort Lauderdale, Florida, 33308, United States

Location

GSK Investigational Site

Fort Lauderdale, Florida, 33316, United States

Location

GSK Investigational Site

Ft. Pierce, Florida, 34982, United States

Location

GSK Investigational Site

Miami, Florida, 33137, United States

Location

GSK Investigational Site

Oakland Park, Florida, 33309, United States

Location

GSK Investigational Site

Orlando, Florida, 32803, United States

Location

GSK Investigational Site

West Palm Beach, Florida, 33407, United States

Location

GSK Investigational Site

Atlanta, Georgia, 30339, United States

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GSK Investigational Site

Augusta, Georgia, 30912, United States

Location

GSK Investigational Site

Macon, Georgia, 31201, United States

Location

GSK Investigational Site

Savannah, Georgia, 31401, United States

Location

GSK Investigational Site

Indianapolis, Indiana, 46202, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02111, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55415, United States

Location

GSK Investigational Site

Kansas City, Missouri, 64111, United States

Location

GSK Investigational Site

Omaha, Nebraska, 68198, United States

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GSK Investigational Site

Las Vegas, Nevada, 89106, United States

Location

GSK Investigational Site

Hillsborough, New Jersey, 08844, United States

Location

GSK Investigational Site

Neptune City, New Jersey, 07753, United States

Location

GSK Investigational Site

Albany, New York, 12209, United States

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GSK Investigational Site

Buffalo, New York, 14201, United States

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GSK Investigational Site

New York, New York, 10065, United States

Location

GSK Investigational Site

Valhalla, New York, 10595, United States

Location

GSK Investigational Site

Chapel Hill, North Carolina, 27599, United States

Location

GSK Investigational Site

Providence, Rhode Island, 02906, United States

Location

GSK Investigational Site

Charleston, South Carolina, 29425, United States

Location

GSK Investigational Site

Austin, Texas, 78751, United States

Location

GSK Investigational Site

Dallas, Texas, 75246, United States

Location

GSK Investigational Site

Annandale, Virginia, 22003, United States

Location

GSK Investigational Site

Vancouver, British Columbia, V6Z 2C7, Canada

Location

GSK Investigational Site

Vancouver, British Columbia, V6Z 2T1, Canada

Location

GSK Investigational Site

Toronto, Ontario, M4N 3M5, Canada

Location

GSK Investigational Site

Toronto, Ontario, M4T 3A7, Canada

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GSK Investigational Site

Toronto, Ontario, M5G 1K2, Canada

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GSK Investigational Site

Montreal, Quebec, H2L 4E9, Canada

Location

GSK Investigational Site

Montreal, Quebec, H2L 4P9, Canada

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GSK Investigational Site

Montreal, Quebec, H3A 1T1, Canada

Location

Related Publications (3)

• Mills A, Richmond GJ, Newman C, Osiyemi O, Cade J, Brinson C, De Vente J, Margolis DA, Sutton KC, Wilches V, Hatch S, Roberts J, McCoig C, Garris C, Vandermeulen K, Spreen WR. Long-acting cabotegravir and rilpivirine for HIV-1 suppression: switch to 2-monthly dosing after 5 years of daily oral therapy. AIDS. 2022 Feb 1;36(2):195-203. doi: 10.1097/QAD.0000000000003085.

  PMID: 34652287 DERIVED

• Patel P, Xue Z, King KS, Parham L, Ford S, Lou Y, Bakshi KK, Sutton K, Margolis D, Hughes AR, Spreen WR. Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir. J Antimicrob Chemother. 2020 Aug 1;75(8):2240-2248. doi: 10.1093/jac/dkaa147.

  PMID: 32361755 DERIVED

• Margolis DA, Brinson CC, Smith GHR, de Vente J, Hagins DP, Eron JJ, Griffith SK, Clair MHS, Stevens MC, Williams PE, Ford SL, Stancil BS, Bomar MM, Hudson KJ, Smith KY, Spreen WR; LAI116482 Study Team. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015 Oct;15(10):1145-1155. doi: 10.1016/S1473-3099(15)00152-8. Epub 2015 Jul 19.

  PMID: 26201299 DERIVED

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections

Interventions

cabotegravir; efavirenz; Rilpivirine; abacavir; Lamivudine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2012
• First Posted: July 17, 2012
• Study Start: August 6, 2012
• Primary Completion: October 10, 2013
• Study Completion: January 15, 2019
• Last Updated: January 30, 2020
• Results First Posted: January 30, 2020

Record last verified: 2020-01

Locations

US (40); CA (8)