An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir (DTG) Plus Lamivudine (3TC) With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Participants (Gemini 2)

ViiV Healthcare

Status and phase: Completed; Phase 3

Conditions: Infection, Human Immunodeficiency Virus; HIV Infections

Treatments: Drug: Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC FDC); Drug: Lamivudine (3TC); Drug: Dolutegravir (DTG)

Study type: Interventional

Funder types: Industry

Identifiers

NCT02831764

205543

2016-000459-28 (EudraCT Number)

Details and patient eligibility

About

This study will compare safety, efficacy, and tolerability of a two drug regimen of dolutegravir (DTG) plus (+) lamivudine (3TC) administered once daily with DTG plus two nucleoside reverse transcriptase inhibitors (tenofovir disoproxil fumarate [TDF]/emtricitabine [FTC] fixed dose combination [FDC]) administered once daily in human immunodeficiency virus (HIV) 1 infected adult participants that have not previously received antiretroviral therapy. The study is designed to demonstrate the non inferior antiviral activity of DTG + 3TC regimen to that of DTG + TDF/FTC FDC and will characterise the long term antiviral activity, tolerability and safety of DTG plus 3TC through Week 148. Approximately, 700 participants will be randomised 1:1 to receive DTG + 3TC or DTG + TDF/FTC FDC. Participants will be stratified by screening HIV 1 ribonucleotide nucleic acid (RNA) levels and by screening CD4+ (cluster of differentiation 4) cell count.

Enrollment: 722 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Must be an HIV 1 infected adult >=18 years of age (or older, if required by local regulations) at the time of signing the informed consent

• An eligible female participant should not be pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at Screening and negative urine test at Baseline), not lactating, and at least one of the following conditions applies

  • Non reproductive premenopausal women are those that have undergone documented tubal ligation or documented hysteroscopic tubal occlusion procedure with follow up confirmation of bilateral tubal occlusion or documented bilateral oophorectomy or hysterectomy
  • Non reproductive premenopausal women are those with 12 months of spontaneous amenorrhea and >=45 years of age
  • Women with reproductive potential agree to follow one of the protocol-defined methods for avoiding pregnancy

• Should have screening plasma HIV 1 RNA levels of 1000 c/mL to <=100,000 c/mL. If an independent review of accumulated data from other clinical trials investigating the DTG plus 3TC dual regimen is supportive of the DTG plus 3TC treatment regimen, enrolment will be opened to participants with Screening plasma HIV 1 RNA of 1000 c/mL to <=500,000 c/mL

• Participant should be antiretroviral naïve (defined as <=10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV 1 infection). Participants who received HIV post exposure prophylaxis (PEP) or pre exposure prophylaxis (PrEP) in the past are allowed as long as the last PEP/PrEP dose was >1 year from HIV diagnosis or there is documented HIV seronegativity between the last prophylactic dose and the date of HIV diagnosis

• Participants or the participants legal representative capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and the protocol

• Participants enrolled in France: a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria

• Women who are breastfeeding or plan to become pregnant or breastfeed during the study
• Any evidence of an active centers for disease control and prevention (CDC) Stage 3 disease (CDC, 2014), except cutaneous Kaposi's sarcoma not requiring systemic therapy and historical or current CD4 cell counts less than 200 cells/mm^3
• Participants with severe hepatic impairment (Class C) as determined by Child Pugh classification
• Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones
• Evidence of hepatitis B virus (HBV) infection or HBV surface antibody (anti-HBs or HBsAb) based on:

Participants positive for HBV surface antigen (HBsAg) at screening will be excluded Participants negative for HBV core antibody (anti HBs) but positive for anti HBc (negative HBsAg status) and positive for HBV deoxyribose nucleic acid (DNA) will be excluded; however, participants positive for anti HBc (negative HBsAg status) and positive for anti HBs (past and/or current evidence) are immune to HBV and will not be excluded

• Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of the study and for HCV therapy based on interferon or any drugs that have a potential for adverse drug:drug interactions with study treatment throughout the entire study period

• Untreated syphilis infection positive RPR at Screening without clear documentation of treatment. Participants who are at least 14 days post completed treatment are eligible

• History or presence of allergy or intolerance to the study drugs or their components or drugs of their class

• Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; other localised malignancies require agreement between the investigator and the Study Medical Monitor for inclusion of the participant

• Participants who in the Investigator's judgment, poses a significant suicidality risk. Recent history of suicidal behaviour and/or suicidal ideation may be considered as evidence of serious suicide risk

• Treatment with an HIV 1 immunotherapeutic vaccine within 90 days of Screening

• Treatment with any of the following agents within 28 days of Screening:

  • Radiation therapy,
  • Cytotoxic chemotherapeutic agents,
  • Any systemic immune suppressant

• Treatment with any agent, except recognised ART as allowed above, with documented activity against HIV 1 in vitro within 28 days of first dose of study treatment

• Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of study treatment

• Participants enrolled in France: the participant has participated in any study using an investigational drug during the previous 60 days or 5 half lives, or twice the duration of the biological effect of the experimental drug or vaccine, whichever is longer, prior to screening for the study or the participant will participate simultaneously in another clinical study

• Any evidence of pre existing viral resistance based on the presence of any major resistance associated mutation in the Screening result or, if known, in any historical resistance test result

• Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening period to verify a result

• Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the participants participation in the study of an investigational compound

• Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN) or ALT >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin)

• Creatinine clearance of <50 mL/min per 1.73 m^2 via the chronic kidney disease epidemiology collaboration (CKD EPI) method

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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722 participants in 2 patient groups

DTG + 3TC (50 mg+300 mg

Experimental group

Description:

Eligible participants will receive one 50 mg tablet of DTG plus one overencapsulated 300 mg 3TC tablet orally once daily upto 96 weeks; thereafter will receive DTG plus 3TC tablet upto Week 148 and will continue to receive this schedule until (i) DTG and 3TC are both locally approved for use as part of a dual regimen, and the single entities of DTG and 3TC are available to patients (e.g. through public health services), or (ii) the DTG/3TC FDC tablet, if required by local regulations, is available, , or (iii) the participant no longer derives clinical benefit, or (iv) the participant meets a protocol defined reason for discontinuation, or (v) development of the DTG plus 3TC dual regimen is terminated.

Treatment:

Drug: Lamivudine (3TC)

Drug: Dolutegravir (DTG)

DTG + TDF/FTC FDC (50 mg+300/200 mg)

Active Comparator group

Description:

Eligible participants will receive one 50 mg tablet of DTG plus one overencapsulated TDF/ FTC FDC (300/200 mg) tablet orally once daily upto 96 weeks; thereafter will receive DTG plus TDF/FTC FDC tablets upto Week 148 (open-label randomised phase).

Treatment:

Drug: Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC FDC)

Drug: Dolutegravir (DTG)