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Regimen Switch to Dolutegravir/Lamivudine Fixed Dose Combination From Current Antiretroviral Regimen in HIV-1 Infected and Virologically Suppressed Adults (SALSA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04021290
Recruitment Status : Active, not recruiting
First Posted : July 16, 2019
Last Update Posted : September 22, 2021
Sponsor:
Collaborators:
GlaxoSmithKline
PPD
Information provided by (Responsible Party):
ViiV Healthcare

Brief Summary:
The aim of this study is to determine if virologically suppressed Human Immunodeficiency Virus (HIV) Type 1 infected adults on a current antiretroviral regimen (CAR) (including 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus a third agent) remain suppressed upon switching to dolutegravir/lamivudine (DTG/3TC) fixed dose combination (FDC). The main objective of the study is to demonstrate the non-inferior antiviral activity of switching to DTG/3TC FDC once daily compared to continuation of CAR over 48 weeks in virologically suppressed adults living with HIV-1. The study will also evaluate information regarding the safety and health related quality of life. The study will include Screening Phase (up to 28 days), a Randomization Phase (up to Week 52) and a Continuation Phase (post Week 52). The Continuation Phase is not applicable for participants in Sweden and Denmark. Approximately 490 participants will be randomized in 1:1 ratio to receive DTG/3TC FDC once daily for up to 52 weeks or continue their CAR for 52 weeks. Participants in the DTG/3TC FDC arm who successfully complete up to 52 weeks of treatment will have the opportunity to continue receiving DTG/3TC FDC once daily in Continuation Phase.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: DTG/3TC FDC Drug: CAR Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 493 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 FDC will receive DTG/3TC FDC up to Week 52. Participants randomized to CAR will continue to take their current regimen up to Week 52. 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)
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Multicenter, Open-label, Non-inferiority Study Evaluating the Efficacy, Safety and Tolerability of Switching to Dolutegravir/Lamivudine Fixed Dose Combination in HIV-1 Infected Adults Who Are Virologically Suppressed
Actual Study Start Date : November 11, 2019
Actual Primary Completion Date : April 23, 2021
Estimated Study Completion Date : March 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Participants receiving DTG/3TC FDC
Eligible participants will be randomized to receive 50 milligrams (mg)/300 mg DTG/3TC FDC therapy from Day 1 up to 52 weeks. Participants who complete 52 weeks of treatment will have the opportunity to continue receiving DTG/3TC FDC once daily in the continuation phase.
Drug: DTG/3TC FDC
DTG/3TC FDC will be available as white, oval, film-coated tablets at a unit dose strength of 50 mg/300 mg. Participants will take DTG/3TC once daily via oral route.

Active Comparator: Participants receiving CAR
Eligible participants will continue to receive CAR from Day 1 up to 52 weeks.
Drug: CAR
Participants who are randomized to the CAR arm will continue to take the current treatment until Week 52. CAR will include 2 NTRIs plus either an INI, NNRTI, or boosted PI or atazanavir unboosted.




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


Secondary Outcome Measures :
  1. Number of participants with plasma HIV-1 Ribonucleic acid (RNA) <50 copies/milliliter (c/mL) using the Snapshot algorithm at Week 48 [ Time Frame: Week 48 ]
    Number of participants with plasma HIV-1 RNA <50 c/mL will be evaluated using the FDA snapshot algorithm at Week 48 to demonstrate the antiviral activity of switching to DTG/3TC FDC once daily compared to continuation of CAR over 48 weeks. Plasma samples for HIV-1 RNA will be collected at Week 48.

  2. Number of participants with virologic failure using the Snapshot algorithmat Week 24 [ Time Frame: Week 24 ]
    Number of participants with plasma HIV-1 RNA <50 c/mL will be evaluated using the FDA snapshot algorithm at Week 24 to demonstrate the antiviral activity of switching to DTG/3TC FDC once daily compared to continuation of CAR over 24 weeks. Plasma samples for HIV-1 RNA will be collected at Week 24.

  3. Number of participants with plasma HIV-1 RNA <50 c/mL using the Snapshot algorithm at Week 24 [ Time Frame: Week 24 ]
    Number of participants with plasma HIV-1 RNA <50 c/mL will be evaluated using the FDA snapshot algorithm at Week 24 to demonstrate the antiviral activity of switching to DTG/3TC FDC once daily compared to continuation of CAR over 24 weeks. Plasma samples for HIV-1 RNA will be collected at Week 24.

  4. Change from Baseline in cluster of differentiation 4 (CD4+) cell count for Week 24 [ Time Frame: Baseline and Week 24 ]
    Lymphocyte subsets will be collected for assessment by flow cytometry. Change from Baseline in CD4+ lymphocyte count will be assessed at Week 24 to evaluate the immune effects of DTG/3TC FDC once daily compared to continuation of CAR. Plasma samples for lymphocyte subsets will be collected.

  5. Change from Baseline in CD4+ cell count for Week 48 [ Time Frame: Baseline and Week 48 ]
    Lymphocyte subsets will be collected for assessment by flow cytometry. Change from Baseline in CD4+ lymphocyte count will be assessed at Week 48 to evaluate the immune effects of DTG/3TC FDC once daily compared to continuation of CAR. Plasma samples for lymphocyte subsets will be collected.

  6. Change from Baseline in CD4+/ cluster of differentiation 8 (CD8+) cell counts ratio for Week 24 [ Time Frame: Baseline and Week 24 ]
    Lymphocyte subsets will be collected for assessment by flow cytometry. Change from Baseline in CD4+/CD8+ cell count ratio will be assessed at Week 24 to evaluate the immune effects of DTG/3TC FDC once daily compared to continuation of CAR. Plasma samples for lymphocyte subsets will be collected.

  7. Change from Baseline in CD4+/CD8+ cell counts ratio for Week 48 [ Time Frame: Baseline and Week 48 ]
    Lymphocyte subsets will be collected for assessment by flow cytometry. Change from Baseline in CD4+/CD8+ cell count ratio will be assessed at Week 48 to evaluate the immune effects of DTG/3TC FDC once daily compared to continuation of CAR. Plasma samples for lymphocyte subsets will be collected.

  8. Number of participants with HIV-associated conditions, AIDS and death through Week 48 [ Time Frame: Up to 48 weeks ]
    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 FDC once daily compared to continuation of CAR.

  9. Number of participants with adverse events (AEs) and serious AEs (SAEs) and AEs leading to discontinuation [ Time Frame: Up to 52 weeks ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is defined as any untoward medical occurrence that, at any dose can result in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, it is a congenital anomaly/birth defect or any medical or surgical intervention to prevent one of the other outcomes listed in the above.

  10. Number of Participants With AEs by Maximum Severity Grades [ Time Frame: Up to 52 weeks ]
    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. AEs were evaluated by the investigator and graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) toxicity scales from Grade 1 to 5 (1=Mild, 2=Moderate, 3=Severe, 4=Potentially life threatening, 5=Death). The higher the grade, the more severe the symptoms.

  11. Number of participants with laboratory abnormalities through 52 weeks [ Time Frame: Up to 52 weeks ]
    Blood and urine samples will be collected to evaluate laboratory parameters. Laboratory parameters will include hematology, clinical chemistry and urinalysis.

  12. Number of participants with AEs and SAEs and AE leading to discontinuation based on creatinine clearance [ Time Frame: Up to 52 weeks ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is defined as any untoward medical occurrence that, at any dose can result in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, it is a congenital anomaly/birth defect or any medical or surgical intervention to prevent one of the other outcomes listed in the above. Number of participants with any AE, SAE, or AE leading to discontinuation through 52 weeks will be summarized to evaluate the safety and tolerability of DTG/3TC FDC once daily in those with creatinine clearance of between 30-49 milliliter (mL)/minute (min)/1.73 meter square (m^2) compared to those with a creatinine clearance of >=50 mL/min/1.73m^2.

  13. Number of Participants With AEs based on creatinine clearance by Maximum Severity Grades [ Time Frame: Up to 52 weeks ]
    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. AEs were evaluated by the investigator and graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) toxicity scales from Grade 1 to 5 (1=Mild, 2=Moderate, 3=Severe, 4=Potentially life threatening, 5=Death). The higher the grade, the more severe the symptoms.

  14. Number of participants with laboratory abnormalities through Week 52 based on creatinine clearance [ Time Frame: Up to 52 weeks ]
    Blood and urine samples will be collected to evaluate laboratory parameters. Laboratory parameters will include hematology, clinical chemistry and urinalysis.

  15. Change from Baseline in fasting lipids at Week 24 [ Time Frame: Baseline and Week 24 ]
    Lipid parameters will include total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides.

  16. Change from Baseline in fasting lipids at Week 48 [ Time Frame: Baseline and Week 48 ]
    Lipid parameters will include total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides.

  17. Number of participants with observed genotypic and phenotypic resistance to antiretrovirals (ARVs) for participants meeting Virologic Withdrawal Criteria [ Time Frame: Up to 52 weeks ]
    Blood samples will be collected 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 copies/mL will be used for this resistance testing.

  18. Change from Baseline in health status by HIV treatment satisfaction questionnaire (TSQ) at Week 24 [ Time Frame: Baseline and Week 24 ]
    The health status of participants will be evaluated using HIV TSQ. HIV TSQ is a 10-item self-reported scale that measures overall satisfaction with treatment and by specific domains

  19. Change from Baseline in health status by HIV TSQ at Week 48 [ Time Frame: Baseline and Week 48 ]
    The health status of participants will be evaluated using HIV TSQ. HIV TSQ is a 10-item self-reported scale that measures overall satisfaction with treatment and by specific domains

  20. Change from Baseline in health status by Symptom Distress Module (SDM) at Week 24 [ Time Frame: Baseline and Week 24 ]
    The health status of participants will be evaluated using SDM. It is also known as HIV Symptom Index or Symptoms Impact Questionnaire, which is 20-item self-reported measure that addresses the presence and perceived distress linked to symptoms commonly associated with HIV or its treatment.

  21. Change from Baseline in health status by SDM at Week 48 [ Time Frame: Baseline and Week 48 ]
    The health status of participants will be evaluated using SDM. It is also known as HIV Symptom Index or Symptoms Impact Questionnaire, which is 20-item self-reported measure that addresses the presence and perceived distress linked to symptoms commonly associated with HIV or its treatment.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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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:

  • Eligible participants must be able to understand and comply with protocol requirements, instructions, and restrictions; participant must be likely to complete the study as planned; participants should be considered appropriate candidates for participation in an investigative clinical trial with oral medication (example given [e.g.] no active problematic substance abuse, acute major organ disease, or potential long-term work assignments out of the country).
  • Participant should be aged 18 years or older (or older, if required by local regulatory agencies), at the time of signing the informed consent.
  • Participants living with HIV.
  • 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.
  • Participant must be on uninterrupted current regimen (either the initial or second Combination antiretroviral therapy [cART] regimen) for at least 3 months prior to Screening.

    i) Any prior switch, defined as a change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability and/or safety concerns or access to medications, or convenience/simplification and must not have been done for suspected or established treatment failure. The following switches, if they are the only switches, would not be considered a change in regimen. a) A switch from a PI boosted with ritonavir (RTV) to the same PI boosted with cobicistat is allowed (and vice versa). b) A switch from 3TC to emtricitabine (FTC) (and vice versa). c) A switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) (and vice versa).

ii) Acceptable stable cART regimens prior to Screening include 2 NRTIs plus a) INI (either the initial or second cART regimen) b) NNRTI (either the initial or second cART regimen) c) Boosted PI (or atazanavir [ATV] unboosted) (either the initial or second PI-based cART regimen).

  • A male or female participant.
  • 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 (a local serum hCG test at randomization is allowed if it can be done, and results obtained, within 24 hours prior to randomization)], not breastfeeding, and at least one of the following conditions applies; not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period from 28 days prior to the first dose of study medication and for at least 2 weeks after the last dose of study medication. All participants 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; The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
  • Participant must be capable of giving signed informed consent.
  • Participants enrolled in France must be affiliated to, or a beneficiary of, a social security category.

Exclusion Criteria:

  • Women who are pregnant or 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 per cubic millimeter (mm^3) are not exclusionary.
  • Participants with severe hepatic impairment (Class C) as determined by Child-Pugh classification.
  • Participants with unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Participants with the 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. Participant's 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 Immunoglobulin M (IgM). Participants with a documented history of chronic HBV and current undetectable HBV DNA while on a TAF/TDF regimen are excluded.
  • Participants with anticipated need for any hepatitis C virus (HCV) therapy during the randomized phase of the study, or anticipated need for HCV therapy with a potential for adverse drug-drug interactions with DTG or 3TC.
  • Participants with 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.
  • Participants with history or presence of allergy intolerance to the study interventions or their components or drugs of their class.
  • Participants with 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.
  • Participants with any pre-existing physical or mental condition which, in the opinion of the Investigator, may interfere with the participant's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participant.
  • Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study interventions or render the participant unable to take oral medication.
  • Use of any regimen consisting of single or dual ART (peri-partum treatment with single dose nevirapine is allowed).
  • Participants with current use of stavudine, didanosine, or nelfinavir.
  • Participants receiving any prohibited medication and who are unwilling or unable to switch to an alternate medication.
  • Participants receiving treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
  • Participants receiving treatment with any of the following agents within 28 days of Screening like radiation therapy; cytotoxic chemotherapeutic agents; any systemic immune suppressant.
  • Participants with 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).
  • Any evidence of major NRTI mutation or presence of any DTG resistance-associated mutation in any available prior resistance genotype assay test result, if known.
  • Participants with any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid abnormalities. A single repeat test is allowed during the Screening period to verify a result.
  • Participants with alanine aminotransferase (ALT) >= 5 times the upper limit of normal (ULN) or ALT >= 3 times ULN and bilirubin >= 1.5 times ULN (with >35 percent direct bilirubin).
  • Participants with creatinine clearance of <30 mL/min/1.73m^2 via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. Participants with creatinine clearance between 30 to 49 mL/min/1.73 m^2 are eligible after the medical monitor has provided approval after reviewing participant's current ART regimen.
  • Participants with any acute laboratory abnormality at Screening, which, in the opinion of the investigator, would preclude the participant'sparticipation in the study of an investigational compound.
  • Participants within the 12 month window prior to Screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.
  • Participants within the 12 month window prior to Screening and after confirmed suppression to <50 c/mL, 2 or more consecutive plasma HIV-1 RNA measurements >=50 c/mL. A single plasma HIV-1 RNA measurement >50 c/mL but less than 200 c/mL, with confirmation of return to <50 c/mL is allowed.
  • 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 with 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.
  • Participants who are currently participating in or anticipate to be selected for any other interventional study after randomization.
  • 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): NCT04021290


Locations
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Sponsors and Collaborators
ViiV Healthcare
GlaxoSmithKline
PPD
Investigators
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Study Director: GSK Clinical Trials ViiV Healthcare
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT04021290    
Other Study ID Numbers: 208090
First Posted: July 16, 2019    Key Record Dates
Last Update Posted: September 22, 2021
Last Verified: September 2021
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ViiV Healthcare:
Current antiretroviral regimen (CAR)
HIV-1
Long-term antiviral activity
Dolutegravir/lamivudine
Fixed dose combination
Additional relevant MeSH terms:
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HIV Infections
Blood-Borne Infections
Communicable Diseases
Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases