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

• ClinicalTrials.gov Identifier: NCT02582684
• Recruitment Status: Completed
• First Posted: October 21, 2015
• Results First Posted: March 30, 2018
• Last Update Posted: May 9, 2018
• Sponsor: AIDS Clinical Trials Group
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): AIDS Clinical Trials Group

Tracking Information

• First Submitted Date: October 20, 2015
• First Posted Date: October 21, 2015
• Results First Submitted Date: February 28, 2018
• Results First Posted Date: March 30, 2018
• Last Update Posted Date: May 9, 2018
• Actual Study Start Date: December 8, 2015
• Actual Primary Completion Date: February 28, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 10, 2018)

Virologic Status at Week 24 [ Time Frame: At 24 weeks after study entry ]

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).

Original Primary Outcome Measures (submitted: October 20, 2015)

Virologic Success at Week 24 [ Time Frame: 24 weeks ]

Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition). Participants with HIV-1 RNA ≥50 copies/mL or who discontinued study treatment or did not have HIV-1 RNA data are counted as non-success.

Current Secondary Outcome Measures (submitted: April 10, 2018)

• Virologic Status at Week 12 [ Time Frame: At 12 weeks after study entry ]
  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).
• Virologic Status at Week 48 [ Time Frame: At 48 weeks after study entry ]
  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).
• Virologic Failure [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 ]
  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
    1. Participants were evaluated for virologic failure regardless of whether on study treatment.
    2. Confirmation was determined based on any two consecutive evaluations meeting the virologic failure definition regardless of the time between them.
    3. 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.
• Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/mL - Missing = Failure [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 ]
  Proportion of participants with HIV-1 RNA < 50 copies/mL by week, ITT (Intention To Treat; missing/off study/off treatment = failure) population.
• Proportion of Participants With Plasma HIV-1 RNA < 200 Copies/mL - Missing = Failure [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 ]
  Proportion of participants with HIV-1 RNA < 200 copies/mL by week, ITT (missing/off study/off treatment = failure) population.
• Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL - Missing = Ignored [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 ]
  Proportion of participants with HIV-1 RNA < 50 copies/mL by week, ITT (missing = ignored) population.
• Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- ITT Missing = Ignored [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 ]
  Proportion of participants with HIV-1 RNA < 200 copies/mL by week, ITT (missing = ignored) population.
• Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL- As Treated [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 ]
  Proportion of participants with HIV-1 RNA < 50 copies/mL by week, as treated population.
• Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- As Treated [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48 ]
  Proportion of participants with HIV-1 RNA < 200 copies/mL by week, as treated population.
• CD4+ Cell Count [ Time Frame: Baseline, weeks 4, 12, 24, and 48 ]
  CD4+ cell counts by study week.
• Change in CD4+ Cell Count [ Time Frame: Baseline, weeks 4, 12, 24, and 48 ]
  Change in CD4+ cell counts by study week. Change was calculated as value at the later visit minus the value at baseline.
• Number of HIV-1 Drug Resistance Mutation Occurrences in Participants [ Time Frame: at the time of virologic failure ]
  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.
• Fasting Lipids and Glucose [ Time Frame: Baseline and week 48 ]
  Fasting lipids include: total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and glucose. Fasting was set to be 8 hours prior to the sample collection.
• Creatinine Clearance [ Time Frame: Baseline, weeks 4, 12, 24, 32, 40 and 48 ]
  Creatinine clearance was estimated by the Cockcroft-Gault equation.
• Number of Participants With Grade 3 of Higher Adverse Events [ Time Frame: from study treatment dispensation through up to week 52 or until study discontinuation ]
  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.

Original Secondary Outcome Measures (submitted: October 20, 2015)

• Virologic Success at Week 12 [ Time Frame: measured through 12 weeks after study entry ]
• Virologic success at week 48 [ Time Frame: measured through 48 weeks after study entry ]
  1. Participants are evaluated for virologic failure regardless of whether on study treatment.
  2. Confirmation will be determined based on any two consecutive evaluations meeting the virologic failure definition regardless of the time between them.
  3. Participants discontinuing the study (for any reason, including death and lost to follow-up) will be considered a virologic failure if their last measurement meets the definition of virologic failure but no confirmatory measurement was obtained. All other participants' follow-up will be censored immediately after the last available plasma HIV-1 RNA measurement.
• Plasma HIV-1 RNA level [ Time Frame: measured through 48 weeks after study entry ]
• CD4+ Cell Count [ Time Frame: measured through 48 weeks after study entry ]
• HIV-1 drug resistance mutations in participants with virologic failure [ Time Frame: measured through 48 weeks after study entry ]
• Lipid values [ Time Frame: measured through 48 weeks after study entry ]
• Sign/symptoms or laboratory toxicities of Grade 3 or higher, or of any grade which led to a permanent change or discontinuation of study treatment [ Time Frame: measured through 52 weeks after study entry ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dolutegravir Plus Lamivudine Dual Therapy in Treatment Naïve HIV-1 Patients
• Official Title: A Study to Evaluate Dolutegravir Plus Lamivudine Dual Therapy for the Treatment of Naïve HIV-1-infected Participants
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV-1 Infection

Intervention

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

Study Arms

Experimental: Arm 1: DTG 50 mg + 3TC 300 mg

Dolutegravir 50mg and Lamivudine 300mg, orally daily

Interventions:

• Drug: Dolutegravir
• Drug: Lamivudine

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 31, 2017): 122
• Original Estimated Enrollment (submitted: October 20, 2015): 120
• Actual Study Completion Date: September 26, 2017
• Actual Primary Completion Date: February 28, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT02582684
• Other Study ID Numbers: ACTG A5353; 2UM1AI068636 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: AIDS Clinical Trials Group
• Study Sponsor: AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Roy Gulick, MD, MPH; Weill Medical College of Cornell University
• Study Chair: Babafemi Taiwo, MBBS; Northwestern University

• PRS Account: AIDS Clinical Trials Group
• Verification Date: April 2018