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Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity

Primary Purpose

Acquired Immunodeficiency Syndrome

Status
Not yet recruiting
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Dolutegravir 50 MG plus lamivudine 300 MG; Dolutegravir/lamivudine (50 MG/300 MG)
Sponsored by
Shanghai Public Health Clinical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acquired Immunodeficiency Syndrome

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Female subjects were required to meet one of the following criteria: 1) Incapacitated, defined as postmenopausal (spontaneous amenorrhea at 12 months, age ≥45 years) or physically unable to conceive after tubal ligation, hysterectomy, or bilateral oophorectomy; 2) Have potential to have children, but are negative at screening and on day 1 pregnancy test, and agree to use appropriate contraceptive methods, including oral contraceptives, condoms and intrauterine devices;
  2. At least once plasma HIV-1 RNA<40 c/mL in the 6 months prior to screening and plasma HIV-1 RNA <40 c/mL at screening;
  3. Must be on uninterrupted TDF + 3TC/FTC-based regimen for ≥6 months prior to screening;
  4. Participants with pre-existing clinical manifestations of TDF related adverse reactions at the time of screening.

    TDF-related renal damage was defined as: meeting 1 of the 5 following conditions in the investigator's judgement, based upon the medical history and relevant examinations, likely to represent TDF toxicity:

    i. eGFR decrease by 5 mL/min per year for at least 3 consecutive years or confirmed 25% eGFR decline from baseline ii. Urine β2-microglobulin/Cr ≥300 μg/g iii. Urine microalbumin/creatinine >30 μg/mg iv. Non-diabetic glycosuria (urine glucose 1+ or above) v. Serum phosphate <0.8 mmol/L TDF - associated bone toxicity is defined as a T-value less than -1.0 or Z- value less than -2.0 or fragility fracture after TDF/XTC use and other factors is excluded according to the medical history and relevant examination.

  5. Sign the informed consent and be able to visit regularly according to the test requirements.

Exclusion Criteria:

  1. Women who are pregnant or breastfeeding or plan to become pregnant or breastfeed during the study;
  2. Participants with AIDS-related opportunistic infections or AIDS-related or unrelated neoplastic diseases;
  3. Patients with ALT >= 5 x ULN, or ALT >=3 x ULN and bilirubin >= 1.5xULN (with >35% direct bilirubin. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  4. Evidence of Hepatitis B virus (HBV) infection: Participants positive for HBsAg, negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.
  5. Hepatitis C virus (HCV) infection;
  6. Participants who are allergic or intolerant to lamivudine or dolutegravir;
  7. Participants with known previous episodes of virologic failure and known resistance mutations of 3TC or INSTI if resistance mutations had previously been identified;
  8. Taking medications that contraindicated with lamivudine or dolutegravir; Other conditions that the investigator considers unsuitable to participate in the study, including the risk of suicide, poor adherence, and interference with the evaluation of clinical study endpoints.
  9. Participants with creatinine clearance <30ml/min.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Other

    Arm Label

    DTG/3TC

    Arm Description

    Subjects will switch to dolutegravir (DTG) plus lamivudine (3TC) or fixed dose combination DTG/3TC for 48 weeks.

    Outcomes

    Primary Outcome Measures

    Virologic outcomes
    Percentage of participants with virologic failure after 48 weeks of treatment by FDA Snapshot algorithm.

    Secondary Outcome Measures

    HIV-RNA
    Percentage of participants with HIV-RNA <40 copies/mL at weeks 24 and 48
    CD4 counts
    Changes from Baseline in CD4+ Cell Counts at Week 24 and 48
    bone markers
    Median percentage improvement (±SD) of circulating bone markers (alkaline phosphatase, osteocalcin, 25-OH-vitamin D level) at 24 weeks and 48 weeks after switch vs baseline)
    DEXA
    Percentage change of T-score classification (normal, osteopenia and osteoporosis) or Z-score classification (normal, abnormal) of bone mineral density using DEXA at 48 weeks after switch vs baseline
    renal markers
    Median percentage improvement (±SD) of urine microalbumin , serum CysC, urine β2-microglobulin/creatinine, urine N-Acetyl-Beta-D-Glucosaminidase (NAG), serum retinol binding protein (RBP) at 24 weeks and 48 weeks after switch vs baseline
    eGFR
    Median percentage improvement (±SD) of eGFR and Percentage change of renal function (normal, mild, moderate and severe) at 24 weeks and 48 weeks after switch vs baseline

    Full Information

    First Posted
    August 5, 2022
    Last Updated
    August 6, 2022
    Sponsor
    Shanghai Public Health Clinical Center
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05493969
    Brief Title
    Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
    Official Title
    A Study Evaluating the Efficacy and Tolerability of Dolutegravir Plus Lamivudine in HIV Infected Adults Who Are Virologically Suppressed and With Evidence of TDF Toxicity
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2022
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    August 2022 (Anticipated)
    Primary Completion Date
    August 2025 (Anticipated)
    Study Completion Date
    June 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Shanghai Public Health Clinical Center

    4. Oversight

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

    5. Study Description

    Brief Summary
    To investigate the efficacy and tolerability of the regimen of dolutegravir plus lamivudine in HIV infected adults who are virologically suppressed and with evidence of TDF toxicity.
    Detailed Description
    This study is a single-center, prospective, uncontrolled, open-label and single-arm interventional study, and aim to investigate the efficacy and safety of dolutegravir plus lamivudine (DTG+3TC) for HIV-infected adults switching from TDF-based triple ART due to TDF toxicity. The study populations are : HIV-infected patients, irrespective of gender, aged 18-75 years old; At least one plasma HIV-1 RNA<40 c/mL in the 6 months prior to Screening and plasma HIV-1 RNA <40 c/mL at Screening; Must be on uninterrupted TDF + 3TC / FTC-based regimen for ≥ 6 months prior to Screening; There are clinical manifestations of TDF related adverse reactions. All enrolled subjects will receive DTG + 3TC once daily (DTG + 3TC) for up to 48 weeks. After stable switch indication approved in China mainland, it's allowed for subjects switch from DTG+3TC to fixed dose combination DTG/3TC. The primary endpoint is the percentage of participants with virologic failure at 48 weeks of treatment by FDA Snapshot algorithm. The secondary endpoints are immunologic outcomes and adverse events including bone and renal biomarkers.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Acquired Immunodeficiency Syndrome

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    100 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    DTG/3TC
    Arm Type
    Other
    Arm Description
    Subjects will switch to dolutegravir (DTG) plus lamivudine (3TC) or fixed dose combination DTG/3TC for 48 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    Dolutegravir 50 MG plus lamivudine 300 MG; Dolutegravir/lamivudine (50 MG/300 MG)
    Intervention Description
    Subjects will discontinue their TDF + 3TC/FTC-based regimen and will switch to DTG+3TC or fixed dose combination DTG/3TC.
    Primary Outcome Measure Information:
    Title
    Virologic outcomes
    Description
    Percentage of participants with virologic failure after 48 weeks of treatment by FDA Snapshot algorithm.
    Time Frame
    Week 48
    Secondary Outcome Measure Information:
    Title
    HIV-RNA
    Description
    Percentage of participants with HIV-RNA <40 copies/mL at weeks 24 and 48
    Time Frame
    Week 24 and Week 48
    Title
    CD4 counts
    Description
    Changes from Baseline in CD4+ Cell Counts at Week 24 and 48
    Time Frame
    Week 24 and Week 48
    Title
    bone markers
    Description
    Median percentage improvement (±SD) of circulating bone markers (alkaline phosphatase, osteocalcin, 25-OH-vitamin D level) at 24 weeks and 48 weeks after switch vs baseline)
    Time Frame
    Week 48
    Title
    DEXA
    Description
    Percentage change of T-score classification (normal, osteopenia and osteoporosis) or Z-score classification (normal, abnormal) of bone mineral density using DEXA at 48 weeks after switch vs baseline
    Time Frame
    Week 48
    Title
    renal markers
    Description
    Median percentage improvement (±SD) of urine microalbumin , serum CysC, urine β2-microglobulin/creatinine, urine N-Acetyl-Beta-D-Glucosaminidase (NAG), serum retinol binding protein (RBP) at 24 weeks and 48 weeks after switch vs baseline
    Time Frame
    Week 24 and Week 48
    Title
    eGFR
    Description
    Median percentage improvement (±SD) of eGFR and Percentage change of renal function (normal, mild, moderate and severe) at 24 weeks and 48 weeks after switch vs baseline
    Time Frame
    Week 24 and Week 48

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Female subjects were required to meet one of the following criteria: 1) Incapacitated, defined as postmenopausal (spontaneous amenorrhea at 12 months, age ≥45 years) or physically unable to conceive after tubal ligation, hysterectomy, or bilateral oophorectomy; 2) Have potential to have children, but are negative at screening and on day 1 pregnancy test, and agree to use appropriate contraceptive methods, including oral contraceptives, condoms and intrauterine devices; At least once plasma HIV-1 RNA<40 c/mL in the 6 months prior to screening and plasma HIV-1 RNA <40 c/mL at screening; Must be on uninterrupted TDF + 3TC/FTC-based regimen for ≥6 months prior to screening; Participants with pre-existing clinical manifestations of TDF related adverse reactions at the time of screening. TDF-related renal damage was defined as: meeting 1 of the 5 following conditions in the investigator's judgement, based upon the medical history and relevant examinations, likely to represent TDF toxicity: i. eGFR decrease by 5 mL/min per year for at least 3 consecutive years or confirmed 25% eGFR decline from baseline ii. Urine β2-microglobulin/Cr ≥300 μg/g iii. Urine microalbumin/creatinine >30 μg/mg iv. Non-diabetic glycosuria (urine glucose 1+ or above) v. Serum phosphate <0.8 mmol/L TDF - associated bone toxicity is defined as a T-value less than -1.0 or Z- value less than -2.0 or fragility fracture after TDF/XTC use and other factors is excluded according to the medical history and relevant examination. Sign the informed consent and be able to visit regularly according to the test requirements. Exclusion Criteria: Women who are pregnant or breastfeeding or plan to become pregnant or breastfeed during the study; Participants with AIDS-related opportunistic infections or AIDS-related or unrelated neoplastic diseases; Patients with ALT >= 5 x ULN, or ALT >=3 x ULN and bilirubin >= 1.5xULN (with >35% direct bilirubin. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, 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: Participants positive for HBsAg, negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded. Hepatitis C virus (HCV) infection; Participants who are allergic or intolerant to lamivudine or dolutegravir; Participants with known previous episodes of virologic failure and known resistance mutations of 3TC or INSTI if resistance mutations had previously been identified; Taking medications that contraindicated with lamivudine or dolutegravir; Other conditions that the investigator considers unsuitable to participate in the study, including the risk of suicide, poor adherence, and interference with the evaluation of clinical study endpoints. Participants with creatinine clearance <30ml/min.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Renfang Zhang
    Phone
    +86-18916051096
    Email
    zhangrenfang@shaphc.org
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Renfang Zhang
    Organizational Affiliation
    Shanghai Public Health Clinical Center
    Official's Role
    Study Chair

    12. IPD Sharing Statement

    Plan to Share IPD
    No

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