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An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects (Gemini 1)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
PPD
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT02831673
First received: July 8, 2016
Last updated: August 14, 2017
Last verified: August 2017
  Purpose
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 [TDF]/Emtricitabine [FTC] fixed dose combination [FDC]) administered once daily in human immunodeficiency virus (HIV) 1 infected adult subjects that have not previously received antiretroviral therapy. The study is designed to demonstrate the non-inferior antiviral activity of DTG plus 3TC regimen to that of DTG plus TDF/FTC FDC and will characterise the long term antiviral activity, tolerability and safety of DTG plus 3TC through Week 148. Approximately, 700 subjects will be randomised 1:1 to receive DTG + 3TC or DTG + TDF/FTC FDC. Subjects will be stratified by screening HIV 1 ribonucleotide nucleic acid (RNA) levels and by screening CD4+ (cluster of differentiation 4) cell count.

Condition Intervention Phase
Infection, Human Immunodeficiency Virus Drug: Dolutegravir (DTG) Drug: Lamivudine (3TC) Drug: Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC FDC) Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Randomised, Double Blind, Multicentre, Parallel Group, Non Inferiority Study Evaluating the Efficacy, Safety, and Tolerability of Dolutegravir Plus Lamivudine Compared to Dolutegravir Plus Tenofovir/Emtricitabine in Human Immunodeficiency Virus 1 Infected Treatment naïve Adults

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Percentage of subjects with plasma HIV 1 RNA <50 copies/milliliter at Week 48 [ Time Frame: Week 48 ]
    The proportion of responders (HIV-1 RNA <50 copies/mL) among randomized subjects who received at least one dose of study medication (ITT-E population) will be assessed at Week 48 according to the FDA's Snapshot algorithm.


Secondary Outcome Measures:
  • Percentage of subjects with plasma HIV 1 RNA <50 copies/milliliter at Weeks 24, 96, and 144 [ Time Frame: Week 24, 96, and 144 ]
    The proportion of responders (HIV-1 RNA <50 copies/mL) among randomized subjects in the ITT-E population will be assessed at Weeks 24, 96 and 144 according to the FDA's Snapshot algorithm

  • Time to viral suppression (HIV 1 RNA <50 copies/milliliter) over time [ Time Frame: Up to Week 144 ]
    Time to HIV-1 RNA <50 copies/mL

  • Absolute values in CD4+ cell counts at Weeks 24, 48, 96 and 144 [ Time Frame: Weeks 24, 48, 96 and 144 ]
    Blood samples will be collected for assessment of lymphocytes by flow cytometry

  • Changes from Baseline in CD4+ cell counts at Weeks 24, 48, 96 and 144 [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
    Blood samples will be collected for assessment of lymphocytes by flow cytometry

  • Number of subjects with disease progression (HIV associated conditions, acquired immunodeficiency syndrome, and death) over time [ Time Frame: Up to Week 144 ]
    Antiviral and immunological activity evaluated by incidence of disease progression (HIV-associated conditions, Acquired immune deficiency syndrome and death) over time

  • Incidence of treatment-emergent genotypic resistance to DTG and 3TC or TDF/FTC in subjects meeting confirmed virologic withdrawal criteria [ Time Frame: Up to Week 148 and then every 12 week post Week 148 (assessed Upto a maximum of 3.5 years) ]
    Viral genotype for both Baseline samples and from samples collected at the time of meeting a virologic withdrawal criterion may be analysed

  • Number of subjects with adverse events and serious adverse events over time [ Time Frame: Up to end of study (Approximately 7 years) ]
    Serious adverse event (SAE) is any untoward medical occurrence that, at any dose can result in death, or is life threatening or requires hospitalisation or prolongation of existing hospitalization or results in disability/incapacity or is a congenital anomaly/birth defect or is associated with liver injury and impaired liver function. An adverse event (AE) can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.

  • Incidence of treatment-emergent phenotypic resistance to DTG and 3TC or TDF/FTC in subjects meeting confirmed virologic withdrawal criteria [ Time Frame: Up to end of study (Approximately 7 years) ]
    Viral phenotype for both Baseline samples and from samples collected at the time of meeting a virologic withdrawal criterion may be analysed

  • Number of subjects with adverse events (AEs), severity of AEs and treatment discontinuations due to AEs over time [ Time Frame: Up to end of study (Approximately 7 years)Baseline and up to Week 144 ]
    Safety and tolerability of DTG + 3TC will be compared to DTG + TDF/FTC over time. An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  • Change from Baseline in renal biomarkers [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
    Safety will be assessed in terms of biomarkers. Blood and urine samples will be collected for renal biomarker assessments.

  • Change from Baseline in bone biomarkers [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
    Safety will be assessed in terms of biomarkers. Blood samples will be collected for bone biomarker assessments

  • Change from Baseline in fasting lipids [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
    Samples for lipid measurements will be obtained in a fasted state. Effects of DTG + 3TC on fasting lipids will be compared to DTG + TDF/FTC.

  • Number of subjects with Grade 2 or greater laboratory abnormalities in fasting low density lipoprotein cholesterol over time [ Time Frame: Weeks 24, 48, 96 and 144 ]
    Samples for lipid measurements will be obtained in a fasted state. Grade 2 or 3 low density lipoprotein cholesterol (as per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events).

  • Percentage of subjects with plasma HIV 1 RNA <50 c/mL by subgroups based on age, gender, Baseline CD4+ cell count [ Time Frame: Weeks 24, 48, 96 and 144 ]
    Impact of age, gender, Baseline CD4+ cell count on antiviral activity of DTG + 3TC compared to DTG + TDF/FTC

  • Change from Baseline in CD4+ cell count by patient subgroups based on age, gender, Baseline CD4+ cell count [ Time Frame: Baseline (Day 1), Weeks 24, 48, 96 and 144 ]
    Impact of age, gender, Baseline CD4+ cell count on immunological activity of DTG + 3TC compared to DTG + TDF/FTC

  • Change from Baseline in health related quality of life [ Time Frame: Baseline (Day 1), Weeks 4, 24, 48, 96 and 144 ]
    The European quality of life 5 dimensions 5 levels (EQ-5D-5L), is a self-reported scale that provides a profile of patient function (including mobility, self care, usual activities, pain/discomfort, and anxiety/depression) and a global health state rating.


Estimated Enrollment: 700
Actual Study Start Date: July 21, 2016
Estimated Study Completion Date: February 3, 2024
Estimated Primary Completion Date: April 27, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DTG + 3TC (50 mg+300 mg)
Eligible subjects 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 subject no longer derives clinical benefit, or (iv) the subject meets a protocol defined reason for discontinuation, or (v) development of the DTG plus 3TC dual regimen is terminated.
Drug: Dolutegravir (DTG)
DTG is available as 50 mg white, round, biconvex, film coated tablet debossed on one side with 'SV 572' and on the other side with '50'. The tablets are packaged into high density polyethylene (HDPE) bottles with induction seals and child resistant closures. Each 45 ml bottle contains 30 tablets and a desiccant. DTG 50 mg tablet will be orally administered once daily with or without food upto 148 weeks.
Drug: Lamivudine (3TC)
Lamivudine is available as swedish orange, 'AA' sized elongated double blind HPMC capsules containing 300 mg lamivudine to visually match overencapsulated TDF/FTC FDC tablet. The capsules are packaged into HDPE bottles with induction seals and child resistant closures. Each 150 mL bottle contains 30 capsules and a desiccant. Overencapsulated 3TC 300 mg tablet will be orally administered once daily with or without food upto 96 weeks. From Week 96 to Week 148, lamivudine will be dispensed as 300 mg white, diamond shaped, scored, film coated tablets debossed with 'GX CJ7' on both sides, packed in over labelled HDPE bottles with child-resistant closures each containing 30 tablets.
Active Comparator: DTG + TDF/FTC FDC (50 mg+300/200 mg)
Eligible subjects 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).
Drug: Dolutegravir (DTG)
DTG is available as 50 mg white, round, biconvex, film coated tablet debossed on one side with 'SV 572' and on the other side with '50'. The tablets are packaged into high density polyethylene (HDPE) bottles with induction seals and child resistant closures. Each 45 ml bottle contains 30 tablets and a desiccant. DTG 50 mg tablet will be orally administered once daily with or without food upto 148 weeks.
Drug: Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC FDC)
Tenofovir disoproxil fumarate and Emtricitabine are available as swedish orange, 'AA' sized elongated double blind HPMC capsules containing 300 mg TDF and 200 mg FTC to visually match overencapsulated 3TC tablet. The capsules are packaged into HDPE bottles with induction seals and child resistant closures. Each 150 mL bottle contains 30 capsules and a desiccant. Overencapsulated tenofovir disoproxil fumarate/emtricitabine tablet will be orally administered once daily with or without food upto 96 weeks. From Week 96 to Week 148, tenofovir disoproxil fumarate/emtricitabine will be dispensed as 300/200 mg white, blue, capsule shaped, film coated tablets debossed with 'GILEAD' on one side and '701' on another side, packed in overlabelled HDPE bottles with polypropylene childresistant closures each containing 30 tablets and a desiccant.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 subject 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 subjects with Screening plasma HIV 1 RNA of 1000 c/mL to <=500,000 c/mL
  • Subject should be antiretroviral naïve (defined as <=10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV 1 infection). Subjects 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
  • Subject or the subject's legal representative capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and the protocol
  • Subjects enrolled in France: a subject 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
  • Subjects 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:

Subjects positive for HBV surface antigen (HBsAg) at screening will be excluded Subjects 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, subjects 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 B 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. Subjects 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 subject
  • Subjects 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
  • Subjects enrolled in France: the subject 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 subject 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 subject's 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02831673

  Show 92 Study Locations
Sponsors and Collaborators
ViiV Healthcare
PPD
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare
  More Information

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT02831673     History of Changes
Other Study ID Numbers: 204861
Study First Received: July 8, 2016
Last Updated: August 14, 2017

Keywords provided by ViiV Healthcare:
safety
treatment naïve
HIV 1
dolutegravir plus lamivudine
non inferiority
tolerability
dolutegravir plus tenofovir/emtricitabine
efficacy

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Tenofovir
Lamivudine
Emtricitabine
Dolutegravir
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
HIV Integrase Inhibitors
Integrase Inhibitors

ClinicalTrials.gov processed this record on August 17, 2017