Dolutegravir Plus Lamivudine Dual Therapy in Treatment Naïve HIV-1 Patients

HIV-1 Infection Clinical Trial

Official title:

A Study to Evaluate Dolutegravir Plus Lamivudine Dual Therapy for the Treatment of Naïve HIV-1-infected Participants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02582684
• Other study ID #: ACTG A5353
• Secondary ID: 2UM1AI068636
• Status: Completed
• Phase: Phase 2
• Start date: December 8, 2015
• Est. completion date: September 26, 2017

Study information

• Verified date: April 2018
• Source: AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study was done to see if the combination of two anti-HIV medicines, dolutegravir (DTG, Tivicay) and lamivudine (3TC, Epivir) taken once a day, provide a safe, effective, and well-tolerated treatment for HIV. DTG is a type of HIV medicine called an integrase inhibitor; 3TC is a type of HIV medicine called a reverse transcriptase inhibitor. DTG works by blocking integrase and 3TC works by blocking reverse transcriptase, two HIV proteins (enzymes). This prevents HIV from multiplying and lowers the viral load (amount of HIV in the blood). Both DTG and 3TC are currently part of Food and Drug Administration (FDA) recommended regimens along with a third active drug. Since some HIV medicines have side effects and are costly, there is interest in whether HIV can be successfully controlled with fewer than three HIV drugs.

Description:

This study was a phase II, single-arm, open-label pilot study designed to estimate the efficacy of dolutegravir (DTG) plus lamivudine (3TC) as initial combination ART (antiretroviral therapy) in HIV-1 infected treatment naive participants. The target enrollment was 120 participants with a cap of N=90 participants with screening HIV-1 RNA <= 100,000 copies/mL. The study aimed to enroll >= 20% women. The expected follow-up for each participant was 52 weeks.

Visits occurred at screening, entry, and weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 from study entry. All signs/symptoms within 30 days prior to entry were recorded. Subsequently, grade 2 or higher rash and all other grade 3 or higher signs and symptoms were recorded. All participants underwent routine monitoring including plasma HIV-1 RNA levels, CD4+ cell count, hematology, chemistry, urinalysis, and pregnancy testing (for women of reproductive potential).

Population-based protease (PR), reverse transcriptase (RT) and integrase genotyping were done at the time of confirmed virologic failure. Plasma samples were stored for potential future studies to assess the impact of adherence, drug-resistant minority viral variants, and DTG exposure on virologic and CD4+ cell count responses to DTG plus 3TC. All participants also underwent UGT1A1 genotyping.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 122
• Est. completion date: September 26, 2017
• Est. primary completion date: February 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

NOTE: Further information on the eligibility criteria can be found in the study protocol.

Inclusion Criteria:

• HIV-1 infection.

• Plasma HIV-1 RNA =1000 copies/mL and <500,000 copies/mL obtained within 90 days prior to study entry.

• No evidence of any RT, any integrase, or major protease resistance mutation (according to the 2014 IAS-USA drug resistance mutations list, available at https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) based on pre-ARV (antiretroviral) treatment genotype performed any time prior to study entry.

• ARV treatment drug-naive (defined as no previous ARV treatment at any time prior to study entry, with the exception of successful post-exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP).

• The following laboratory values obtained within 45 days prior to study entry:

• ANC (absolute neutrophil count) =750/mm^3

• Hemoglobin =10.0 g/dL

• Platelets = 50,000/mm^3

• Calculated creatinine clearance (CrCl) =50 mL/min, as estimated by the Cockcroft-Gault equation

• AST (aspartate aminotransferase) <5 x ULN (upper limit of normal)

• ALT (alanine aminotransferase) <5x ULN

• Total bilirubin <1.5 x ULN

• Hepatitis B surface antigen negative within 45 days prior to study entry.

• For women with reproductive potential, negative serum or urine pregnancy test at screening and within 48 hours prior to study entry.

• If participating in sexual activity that could lead to pregnancy, female participants with reproductive potential must have agreed to use one form of contraceptive as listed in the protocol while receiving protocol-specified medications and for 30 days after stopping the medications.

• Ability and willingness of participant or legal representative to provide informed consent.

Exclusion Criteria:

• Serious illness requiring systemic treatment and/or hospitalization.

• Treatment within 30 days prior to study entry with immune modulators such as systemic steroids, interleukins, interferons, granulocyte colony-stimulating factor (G-CSF), erythropoietin, or any investigational therapy.

• Pregnancy or breastfeeding.

• Receipt of systemic cytotoxic chemotherapy or dofetilide.

• Known allergy/sensitivity to any of the study drugs or their formulations.

• Active drug or alcohol use or dependence that may interfere with adherence to study requirements, in the opinion of the site investigator.

• Active hepatitis C virus (HCV) treatment or anticipated need for treatment within study period.

• Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

• Severe hepatic impairment (Class C) as determined by Child-Pugh classification.

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• Dolutegravir
Participants were prescribed 50 mg of DTG orally daily
• Lamivudine
Participants were prescribed 300 mg of 3TC orally daily.

Locations

Country	Name	City	State
Puerto Rico	Puerto Rico-AIDS CRS (5401)	San Juan
United States	The Ponce de Leon Center CRS (5802)	Atlanta	Georgia
United States	University of Colorado Hospital CRS (6101)	Aurora	Colorado
United States	Brigham and Women's Hosp. ACTG CRS (107)	Boston	Massachusetts
United States	Massachusetts General Hospital ACTG CRS (101)	Boston	Massachusetts
United States	3201 Chapel Hill CRS	Chapel Hill	North Carolina
United States	Northwestern University CRS (2701)	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS (2702)	Chicago	Illinois
United States	Univ. of Cincinnati CRS (2401)	Cincinnati	Ohio
United States	The Ohio State Univ. AIDS CRS (2301)	Columbus	Ohio
United States	31443 Trinity Health and Wellness Center CRS	Dallas	Texas
United States	Greensboro CRS (3203)	Greensboro	North Carolina
United States	Houston AIDS Research Team CRS (31473)	Houston	Texas
United States	UCLA CARE Center CRS (601)	Los Angeles	California
United States	University of Southern California CRS (1201)	Los Angeles	California
United States	Univ. of Miami AIDS CRS (901)	Miami	Florida
United States	Vanderbilt Therapeutics CRS (3652)	Nashville	Tennessee
United States	Columbia Physicians and Surgeons CRS (30329)	New York	New York
United States	Cornell CRS (7804)	New York	New York
United States	Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803)	New York	New York
United States	Hosp. of the Univ. of Pennsylvania CRS (6201)	Philadelphia	Pennsylvania
United States	The Miriam Hospital ACTG CRS (2951)	Providence	Rhode Island
United States	University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)	Rochester	New York
United States	Washington University CRS (2101)	Saint Louis	Missouri
United States	Ucsd, Avrc Crs (701)	San Diego	California
United States	Harbor-UCLA Med. Ctr. CRS (603)	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
AIDS Clinical Trials Group	National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Virologic Status at Week 24	Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 24 Window are provided below.; Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition).	At 24 weeks after study entry
Secondary	Virologic Status at Week 12	Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 12 Window are provided below.; Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition).	At 12 weeks after study entry
Secondary	Virologic Status at Week 48	Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 48 Window are provided below.; Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition).	At 48 weeks after study entry
Secondary	Virologic Failure	Virologic failure is defined as follows: Weeks 16 or 20: confirmed plasma HIV-1 RNA > 400 copies/mL; Week 24 or later: confirmed plasma HIV-1 RNA > 200 copies/mL; Participants were evaluated for virologic failure regardless of whether on study treatment.; Confirmation was determined based on any two consecutive evaluations meeting the virologic failure definition regardless of the time between them.; Participants discontinuing the study (for any reason, including death and lost to follow-up) were considered virologic failures if their last measurement met the definition of virologic failure but no confirmatory measurement was obtained. All other participants' follow-up was censored immediately after the last available plasma HIV-1 RNA measurement.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Secondary	Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/mL - Missing = Failure	Proportion of participants with HIV-1 RNA < 50 copies/mL by week, ITT (Intention To Treat; missing/off study/off treatment = failure) population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Secondary	Proportion of Participants With Plasma HIV-1 RNA < 200 Copies/mL - Missing = Failure	Proportion of participants with HIV-1 RNA < 200 copies/mL by week, ITT (missing/off study/off treatment = failure) population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Secondary	Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL - Missing = Ignored	Proportion of participants with HIV-1 RNA < 50 copies/mL by week, ITT (missing = ignored) population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Secondary	Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- ITT Missing = Ignored	Proportion of participants with HIV-1 RNA < 200 copies/mL by week, ITT (missing = ignored) population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Secondary	Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL- As Treated	Proportion of participants with HIV-1 RNA < 50 copies/mL by week, as treated population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Secondary	Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- As Treated	Proportion of participants with HIV-1 RNA < 200 copies/mL by week, as treated population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Secondary	CD4+ Cell Count	CD4+ cell counts by study week.	Baseline, weeks 4, 12, 24, and 48
Secondary	Change in CD4+ Cell Count	Change in CD4+ cell counts by study week. Change was calculated as value at the later visit minus the value at baseline.	Baseline, weeks 4, 12, 24, and 48
Secondary	Number of HIV-1 Drug Resistance Mutation Occurrences in Participants	Number of HIV-1 drug resistance mutation occurrences participants with virologic failure and FDA snapshot non-successes. Participants that had one drug class resistance mutation may have one or more mutations.	at the time of virologic failure
Secondary	Fasting Lipids and Glucose	Fasting lipids include: total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and glucose. Fasting was set to be 8 hours prior to the sample collection.	Baseline and week 48
Secondary	Creatinine Clearance	Creatinine clearance was estimated by the Cockcroft-Gault equation.	Baseline, weeks 4, 12, 24, 32, 40 and 48
Secondary	Number of Participants With Grade 3 of Higher Adverse Events	Number of participants who experienced an AE (sign/symptom or laboratory abnormality) of Grade 3 or higher. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see reference in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening.	from study treatment dispensation through up to week 52 or until study discontinuation

External Links

•   DAIDS Adverse Events Manual, Version 2.0 January 2010
•   DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 November 2014
•   FDA Snapshot Definition (refer to Appendix A in FDA Snapshot PDF)