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Switch Study to Evaluate Dolutegravir Plus Lamivudine in Virologically Suppressed Human Immunodeficiency Virus Type 1 Positive Adults (TANGO)

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ClinicalTrials.gov Identifier: NCT03446573
Recruitment Status : Active, not recruiting
First Posted : February 27, 2018
Last Update Posted : October 5, 2018
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:

The aim of the study is to establish if human immunodeficiency virus type 1 (HIV-1) infected adult participants with current virologic suppression on a ≥3-drug tenofovir alafenamide (TAF) based regimen (TBR) remain suppressed upon switching to a two-drug regimen of dolutegravir (DTG) 50 milligram (mg) + lamivudine (3TC) 300 mg. This study will also provide important information regarding the safety and participant satisfaction with this two-drug regimen. The primary objective of this trial is to demonstrate the non-inferior antiviral activity of switching to DTG + 3TC once daily compared to continuation of TBR over 48 weeks in HIV-1 infected, ART-experienced, virologically suppressed participants. This study also will characterize the long-term antiviral activity, tolerability and safety of DTG + 3TC through Week 100.

This will be a 100-week, Phase III, randomized, open-label, active-controlled, multicenter, parallel-group study. The study will include a screening phase (up to 28 days), a randomized early switch phase (Day 1 up to Week 52), a randomized late switch phase (Week 52 up to Week 100), and a continuation phase (post Week 100). Approximately 750 HIV-1 infected adults on stable TBR will be randomized 1:1 to switch to DTG + 3TC once daily for up to 100 weeks, or to continue their TBR for 52 weeks, at which time and if HIV-1 ribonucleic acid (RNA) <50 copies per milliliter (c/mL) at Week 48, these participants will switch to DTG + 3TC up to Week 100.


Condition or disease Intervention/treatment Phase
Infection, Human Immunodeficiency Virus Drug: DTG + 3TC Drug: TAF based regimen (TBR) Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 750 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a randomized study with parallel group assignment where participants will be randomized into one of the two treatment groups. Participants randomized to DTG + 3TC will receive DTG + 3TC up to Week 100. Participants randomized to TBR will continue to take their current regimen up to Week 52, at which time and if HIV-1 RNA <50 c/mL at Week 48, these participants will switch to DTG + 3TC up to Week 100. Randomization will be stratified by Baseline third agent class (protease inhibitor [PI], integrase inhibitor [INI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]).
Masking: None (Open Label)
Masking Description: This will be an open-label study and therefore no blinding is required. The Sponsor team aims to remain blinded to participant assignment, and will instruct sites to refrain from mentioning assignment when sending in queries (as the sites/participants will not be blinded). No summaries of the study data according to actual randomized treatment groups will be available to sponsor staff prior to the planned Week 24 preliminary analysis.
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Multicenter, Parallel-group, Non-inferiority Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Dolutegravir Plus Lamivudine in HIV-1 Infected Adults Who Are Virologically Suppressed
Actual Study Start Date : January 18, 2018
Estimated Primary Completion Date : June 14, 2019
Estimated Study Completion Date : January 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: DTG + 3TC 50 mg/300 mg
Participants will receive a single tablet of a two-drug regimen of DTG 50 mg + 3TC 300 mg once daily from Day 1 through Week 100 (Early and Late Switch Phase).
Drug: DTG + 3TC
DTG+3TC is supplied as white, oval, film-coated, fixed dose combination tablet. The tablets will be available in packed high density polyethylene (HDPE) bottles with induction seals and child-resistant closures.

Active Comparator: TAF based regimen (TBR)
Participants will continue their TBR from Day 1 to Week 52 (Early Switch Phase), and eligible participants will switch to DTG + 3TC once daily from Week 52 to 100 (Late Switch Phase).
Drug: TAF based regimen (TBR)
Participants will continue to receive their TBR.




Primary Outcome Measures :
  1. Number of participants with virologic failure endpoint as per Food and Drug Administration (FDA) snapshot category at Week 48 [ Time Frame: Week 48 ]
    Number of participants with virologic failure was evaluated using FDA snapshot algorithm at Week 48 to demonstrate the non-inferior antiviral activity of switching to DTG +3TC once daily compared to continuation of TBR over 48 weeks. Plasma samples for HIV-1 RNA was collected at Week 48.


Secondary Outcome Measures :
  1. Number of participants with plasma HIV-1 RNA <50 c/mL at Weeks 24 and 48 using the Snapshot algorithm [ Time Frame: Week 24 and Week 48 ]
    Number of participants with plasma HIV-1 RNA <50 c/mL were evaluated using the FDA snapshot algorithm at Weeks 24 and 48 to demonstrate the antiviral activity of switching to DTG + 3TC once daily compared to continuation of TBR over 24 and 48 weeks. Plasma samples for HIV-1 RNA were collected at Week 24 and Week 48.

  2. Number of participants with virologic failure endpoint as per FDA snapshot category at Week 24 [ Time Frame: Week 24 ]
    Number of participants with virologic failure was evaluated using FDA snapshot algorithm at Week 24 to demonstrate the antiviral activity of switching to DTG + 3TC once daily compared to continuation of TBR over 24 weeks. Plasma samples for HIV-1 RNA was collected at Week 24 .

  3. Change from Baseline in CD4+ lymphocyte count at Weeks 24 and 48 [ Time Frame: Baseline and up to Week 48 ]
    Lymphocyte subsets will be collected for assessment by flow cytometry. Change from Baseline in CD4+ lymphocyte count was assessed at Weeks 24 and 48 to evaluate the immune effects of DTG + 3TC once daily compared to continuation of TBR. Plasma samples for lymphocyte subsets were collected at Week 0 (Day 1) and at Weeks 4, 8, 12, 24, 36 and 48.

  4. Change from Baseline in CD4+/CD8+ cell count ratio [ Time Frame: Baseline and up to Week 48 ]
    Lymphocyte subsets will be collected for assessment by flow cytometry. Change from Baseline in CD4+/CD8+ cell count ratio was assessed at Weeks 24 and 48 to evaluate the immune effects of DTG + 3TC once daily compared to continuation of TBR. Plasma samples for lymphocyte subsets were collected at Week 0 (Day 1) and at Weeks 4, 8, 12, 24, 36 and 48.

  5. Number of participants with HIV-associated conditions, acquired immunodeficiency syndrome (AIDS) and death through Weeks 24 and 48 [ Time Frame: Up to Week 48 ]
    HIV-associated conditions will be assessed according to the 2014 CDC Classification System for HIV Infection in Adults to evaluate the immune effects of DTG + 3TC once daily compared to continuation of TBR.

  6. Number of participants with any adverse event (AE), serious AE (SAE), SAE and AE leading to discontinuation through 24 and 48 weeks [ Time Frame: Up to Week 48 ]
    An AE is any untoward medical occurrence in a clinical investigation participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward event that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. An SAE may also include any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the safety of the participant or may require medical or surgical intervention. Number of participant with any AE, SAE, or AE leading to discontinuation through 24 and 48 weeks will be summarized.

  7. Number of participants with laboratory abnormalities through 24 and 48 weeks [ Time Frame: Up to Week 48 ]
    Blood samples will be collected at Week 0 (Day 1) and at Weeks 4, 8, 12, 24, 36 and 48 to evaluate laboratory parameters.

  8. Time to first Adverse Event (AE) [ Time Frame: Up to Week 48 ]
    Time to first AE will be assessed to evaluate the safety and tolerability of DTG + 3TC once daily compared to TBR over time.

  9. Change from Baseline in total cholesterol at Weeks 24 and 48 [ Time Frame: Up to Week 48 ]
    Blood samples will be collected at Week 0 (Day 1), 24 and 48 to assess total cholesterol.

  10. Change from Baseline in low density lipoprotein (LDL) cholesterol at Weeks 24 and 48 [ Time Frame: Up to Week 48 ]
    Blood samples will be collected at Week 0 (Day 1), 24 and 48 to assess low density lipoprotein (LDL) cholesterol.

  11. Change from Baseline in high density lipoprotein (HDL) cholesterol at Weeks 24 and 48 [ Time Frame: Up to Week 48 ]
    Blood samples will be collected at Week 0 (Day 1), 24 and 48 to assess high density lipoprotein (HDL) cholesterol.

  12. Change from Baseline in triglycerides at Weeks 24 and 48 [ Time Frame: Up to Week 48 ]
    Blood samples will be collected at Week 0 (Day 1), 24 and 48 to assess triglycerides.

  13. Number of participants with observed genotypic and phenotypic resistance to antiretrovirals (ARVs) for participants meeting Virologic Withdrawal Criteria [ Time Frame: Up to Week 48 ]
    Blood samples will be collected at Week 0 (Day 1) and at Weeks 4, 8, 12, 24, 36 and 48 for potential viral genotypic and phenotypic analyses to assess viral resistance. Participants meeting Confirmed Virologic Withdrawal (CVW) or Precautionary Virologic Withdrawal (PVW) criteria will have plasma samples tested for HIV-1 protease (PRO), reverse transcriptase (RT), and integrase (IN) genotypic and phenotypic resistance. The earliest plasma sample with HIV-1 RNA ≥200 c/mL will be used for this resistance testing.

  14. Change from Baseline in Cystatin C [ Time Frame: Baseline and up to Week 48 ]
    Blood and urine samples will be collected for Cystatin C at Week 0 (Day 1) and at Weeks 24 and 48.

  15. Change from Baseline in Beta-2-Microglobulin [ Time Frame: Baseline and up to Week 48 ]
    Blood and urine samples will be collected for Beta-2-Microglobulin at Week 0 (Day 1) and at Weeks 24 and 48

  16. Change from Baseline in Retinol Binding Protein [ Time Frame: Baseline and up to Week 48 ]
    Blood and urine samples will be collected for Retinol Binding Protein at Week 0 (Day 1) and at Weeks 24 and 48

  17. Change from Baseline in bone specific alkaline phosphatase at Weeks 24 and 48 [ Time Frame: Baseline and up to Week 48 ]
    Blood samples will be collected for bone specific alkaline phosphatase at Week 0 (Day 1) and at Weeks 24 and 48.

  18. Change from Baseline in procollagen type 1-N-propeptide at Weeks 24 and 48 [ Time Frame: Baseline and up to Week 48 ]
    Blood samples will be collected for procollagen type 1-N-propeptide at Week 0 (Day 1) and at Weeks 24 and 48.

  19. Change from Baseline in type 1 collagen cross-linked C-telopeptide at Weeks 24 and 48 [ Time Frame: Baseline and up to Week 48 ]
    Blood samples will be collected for type 1 collagen cross-linked C-telopeptide at Week 0 (Day 1) and at Weeks 24 and 48.

  20. Change from Baseline in osteocalcin at Weeks 24 and 48 [ Time Frame: Baseline and up to Week 48 ]
    Blood samples will be collected for osteocalcin at Week 0 (Day 1) and at Weeks 24 and 48.

  21. Change from Baseline in 25 hydroxy-Vitamin D at Weeks 24 and 48 [ Time Frame: Baseline and up to Week 48 ]
    Blood samples will be collected for 25 hydroxy-Vitamin D at Week 0 (Day 1) and at Weeks 24 and 48.

  22. Change from Baseline in health status using European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Weeks 24 and 48 (or Withdrawal from the study) [ Time Frame: Baseline and up to Week 48 ]
    The EQ-5D-5L is a standardized, generic questionnaire that provides a profile of participant function and a global health state rating. The five-item measure has one question assessing each of five dimensions: 1) mobility, 2) self-care, 3) usual activities, 4) pain/discomfort, and 5) anxiety/depression, and 5 levels for each dimension (no problems, slight problems, moderate problems, severe problems and extreme problems). The EQ-5D-5L also includes a visual analog scale (VAS) that assesses overall health. EQ-5D-5L will be conducted at Week 0 (Day 1) and at Week 4, 24 and 48.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant must be able to understand and comply with protocol requirements, instructions, and restrictions;
  • Participant must be likely to complete the study as planned;
  • Participant must be considered an appropriate candidate for participation in an investigative clinical trial with medication (e.g. no active substance abuse, acute major organ disease, or planned long-term work assignments out of the country).
  • Aged 18 years or older (older where required by local regulatory agencies), at the time of signing the informed consent.
  • HIV-1 infected men or women.
  • Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening.
  • Plasma HIV-1 RNA <50 c/mL at Screening.
  • Must be on uninterrupted ART for at least 6 months prior to screening. Only the following regimens are allowed:

    • Participant on a TAF-based regimen for at least 6 months, or
    • Participant who switched from tenofovir disoproxil fumarate (TDF) (as part of first-line regimen) to tenofovir alafenamide (TAF), without any changes to the other drugs in their regimen, and have been on the TAF-based regimen for at least 3 months immediately prior to Screening. The switch must have occurred due to tolerability/safety, access to medications, or convenience/simplification, and must NOT have been done for suspected or established treatment failure.
  • A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at screen and a negative urine hCG test at randomization), not lactating, and at least one of the following conditions applies:

    a. Non-reproductive potential defined as:

  • Pre-menopausal females with one of the following:

    • Documented tubal ligation
    • Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
    • Hysterectomy
    • Documented bilateral oophorectomy
  • Post-menopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

    b. Reproductive potential and agrees to follow highly effective methods for avoiding pregnancy in females of reproductive potential (FRP) from 30 days prior to the first dose of study medication and for at least 2 weeks after the last dose of study medication.

  • The investigator is responsible for ensuring that Participants understand how to properly use these methods of contraception. All participants participating in the study should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to an uninfected partner.
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions of the consent form and the protocol. Eligible participants or their legal guardians must sign a written informed consent form before any protocol-specified assessments are conducted.

Participants enrolled in France must be 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, EXCEPT cutaneous Kaposi's sarcoma not requiring systemic therapy. Historical or current CD4 cell counts less than 200 cells/millimeter (mm)^3 are NOT exclusionary.
  • 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 based on the results of testing at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B surface antigen antibody (anti-HBs) and HBV deoxyribonucleic acid (DNA) as follows: participants positive for HBsAg are excluded; participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.

Note: Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded. Anti-HBc must be either total anti-HBc or anti-HBc immunoglobulin G (IgG), and NOT anti-HBc IgM.

  • Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of the study, for HCV therapy based on interferon or for any drugs that have a potential for adverse drug-drug interactions with study treatment throughout the entire study period.
  • Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of treatment). Participants who are at least 7 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.
  • Participants who in the investigator's judgment, poses a significant suicidality 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.
  • 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 investigational product (IP).
  • Use of any regimen consisting of single or dual ART.
  • Any evidence of major nucleoside reverse transcriptase inhibitor (NRTI) mutation or presence of any major INSTI resistance-associated mutation in any available prior resistance genotype assay test result, if known.
  • Any verified Grade 4 laboratory abnormality.
  • Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN) or ALT ≥3 times ULN and bilirubin ≥1.5 times ULN (with >35% direct bilirubin).
  • Creatinine clearance of <50 mL/minute/1.73 meter^2 via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method.
  • Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.
  • Within the 6 to 12 month window prior to Screening and after confirmed suppression to <50 c/mL, 2 or more plasma HIV-1 RNA measurements ≥50 c/mL.
  • Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement ≥50 c/mL.
  • Any drug holiday during the 6 months prior to Screening, except for brief periods (less than 1 month) where all ART was stopped due to tolerability and/or safety concerns.
  • Any history of switch to another regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV-1 RNA ≥400 c/mL.
  • Participants enrolled in France (or in other countries as required by local regulations or Ethics Committee/Institutional Review Board [IRB]) who:

    • Participated in any study using an investigational drug or vaccine 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
    • Participate simultaneously in another clinical study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03446573


  Show 155 Study Locations
Sponsors and Collaborators
ViiV Healthcare
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials ViiV Healthcare

Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT03446573     History of Changes
Other Study ID Numbers: 204862
First Posted: February 27, 2018    Key Record Dates
Last Update Posted: October 5, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request Site
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ViiV Healthcare:
Switch study
non-inferiority
HIV-1
tenofovir alafenamide
dolutegravir plus lamivudine

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
Lamivudine
Dolutegravir
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents
HIV Integrase Inhibitors
Integrase Inhibitors