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

NCT ID: NCT02582684

Last Updated: 2018-05-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 122 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-08
• Study Completion Date: 2017-09-26

Brief 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.

Detailed 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.

Conditions

HIV-1 Infection

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1: DTG 50 mg + 3TC 300 mg

Dolutegravir 50mg and Lamivudine 300mg, orally daily

Group Type: EXPERIMENTAL

Dolutegravir

Intervention Type: DRUG

Participants were prescribed 50 mg of DTG orally daily

Lamivudine

Intervention Type: DRUG

Participants were prescribed 300 mg of 3TC orally daily.

Interventions

Dolutegravir

Participants were prescribed 50 mg of DTG orally daily

Intervention Type: DRUG

Lamivudine

Participants were prescribed 300 mg of 3TC orally daily.

Intervention Type: DRUG

Other Intervention Names

DTG; 3TC

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roy Gulick, MD, MPH

Role: STUDY_CHAIR

Weill Medical College of Cornell University

Babafemi Taiwo, MBBS

Role: STUDY_CHAIR

Northwestern University

Locations

University of Southern California CRS (1201)

Los Angeles, California, United States

UCLA CARE Center CRS (601)

Los Angeles, California, United States

Ucsd, Avrc Crs (701)

San Diego, California, United States

Harbor-UCLA Med. Ctr. CRS (603)

Torrance, California, United States

University of Colorado Hospital CRS (6101)

Aurora, Colorado, United States

Univ. of Miami AIDS CRS (901)

Miami, Florida, United States

The Ponce de Leon Center CRS (5802)

Atlanta, Georgia, United States

Northwestern University CRS (2701)

Chicago, Illinois, United States

Rush Univ. Med. Ctr. ACTG CRS (2702)

Chicago, Illinois, United States

Massachusetts General Hospital ACTG CRS (101)

Boston, Massachusetts, United States

Brigham and Women's Hosp. ACTG CRS (107)

Boston, Massachusetts, United States

Washington University CRS (2101)

St Louis, Missouri, 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

Columbia Physicians and Surgeons CRS (30329)

New York, New York, United States

University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)

Rochester, New York, United States

3201 Chapel Hill CRS

Chapel Hill, North Carolina, United States

Greensboro CRS (3203)

Greensboro, North Carolina, United States

Univ. of Cincinnati CRS (2401)

Cincinnati, Ohio, United States

The Ohio State Univ. AIDS CRS (2301)

Columbus, Ohio, 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

Vanderbilt Therapeutics CRS (3652)

Nashville, Tennessee, United States

31443 Trinity Health and Wellness Center CRS

Dallas, Texas, United States

Houston AIDS Research Team CRS (31473)

Houston, Texas, United States

Puerto Rico-AIDS CRS (5401)

San Juan, , Puerto Rico

Countries

United States; Puerto Rico

References

Nyaku AN, Zheng L, Gulick RM, Olefsky M, Berzins B, Wallis CL, Godfrey C, Sax PE, Acosta EP, Haas DW, Smith KY, Sha BE, Van Dam CN, Taiwo BO; ACTG A5353 Study Team. Dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA <500 000 copies/mL: week 48 outcomes from ACTG 5353. J Antimicrob Chemother. 2019 May 1;74(5):1376-1380. doi: 10.1093/jac/dky564.

Reference Type: DERIVED

PMID: 30668695 (View on PubMed)

Taiwo BO, Zheng L, Stefanescu A, Nyaku A, Bezins B, Wallis CL, Godfrey C, Sax PE, Acosta E, Haas D, Smith KY, Sha B, Van Dam C, Gulick RM. ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)-infected Participants With HIV-1 RNA <500000 Copies/mL. Clin Infect Dis. 2018 May 17;66(11):1689-1697. doi: 10.1093/cid/cix1083.

Reference Type: DERIVED

PMID: 29253097 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Related Links

http://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf?sfvrsn=8

DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 November 2014

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm355128.pdf

FDA Snapshot Definition (refer to Appendix A in FDA Snapshot PDF)

http://rsc.tech-res.com/docs/default-source/safety/manual_for_expedited_reporting_aes_to_daids_v2.pdf?sfvrsn=12

DAIDS Adverse Events Manual, Version 2.0 January 2010

Other Identifiers

2UM1AI068636

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ACTG A5353

Identifier Type: -

Identifier Source: org_study_id