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Effect of Reducing Nucleotide Exposure on Bone Health (ReNew) (ReNew)

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ClinicalTrials.gov Identifier: NCT03549689
Recruitment Status : Not yet recruiting
First Posted : June 8, 2018
Last Update Posted : April 5, 2019
Sponsor:
Information provided by (Responsible Party):
Philip Grant, Stanford University

Brief Summary:
This is an open-label, randomized pilot study to assess the effect on bone mineral density (BMD) of a switch from a tenofovir alafenamide-containing antiretroviral regimen to dolutegravir/lamivudine vs. a continuation of the tenofovir alafenamide-containing regimen.

Condition or disease Intervention/treatment Phase
HIV/AIDS HIV-1-infection Osteopenia Drug: Dolutegravir (DTG) 50MG/lamivudine (3TC) 300MG FIXED DOSE COMBINATION (FDC) Drug: Current tenofovir alafenamide (TAF)-containing ART regimen Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effect of Reducing Nucleotide Exposure on Bone Health (ReNew)
Estimated Study Start Date : August 1, 2019
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : July 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Switch
Dolutegravir (DTG) 50MG/ lamivuidne (3TC) 300MG FIXED_DOSE COMBINATION (FDC) DAILY at randomization for 96 weeks
Drug: Dolutegravir (DTG) 50MG/lamivudine (3TC) 300MG FIXED DOSE COMBINATION (FDC)
Participants randomized to the Switch Arm will take DTG 50mg/3TC 300mg FDC once daily with or without food at approximately the same time each day.

Active Comparator: Continuation
Continue current tenofovir alafenamide (TAF)-containing ART regimen from weeks 0 to 96.
Drug: Current tenofovir alafenamide (TAF)-containing ART regimen
Continuation of current TAF-containing ART for 96 weeks.




Primary Outcome Measures :
  1. Percent change in lumbar spine Bone Mineral Density (BMD) at 96 weeks [ Time Frame: Baseline and 96 weeks ]
    Compare the percentage change from entry to 96 weeks in lumbar spine BMD in those randomized to DTG/3TC vs. those continuing a TAF-based regimen


Secondary Outcome Measures :
  1. Percentage change in lumbar spine BMD at 48 weeks [ Time Frame: Baseline and 48 weeks ]
    Compare the percentage change from entry to 48 weeks in lumbar spine BMD in those randomized to DTG/3TC vs. those continuing a TAF-based regimen

  2. Percentage change in total hip BMD at 48 weeks [ Time Frame: Baseline, 48 weeks ]
    Compare the percentage change from entry to 48 weeks in total hip BMD in those randomized to DTG/3TC vs. those continuing a TAF-based regimen

  3. Percentage change in total hip BMD at 96 weeks [ Time Frame: Baseline, 96 weeks ]
    Compare the percentage change from entry to 96 weeks in total hip BMD in those randomized to DTG/3TC vs. those continuing a TAF-based regimen

  4. Change in CTX (a bone resorption marker) [ Time Frame: Baseline, 12 weeks, 48 weeks, and 96 weeks ]
    Compare the changes in CTX from entry to 12, 48, and 96 weeks

  5. Change in P1NP (a bone deposition marker) [ Time Frame: Baseline, 12 weeks, 48 weeks, and 96 weeks ]
    Compare the changes in P1NP from entry to 12, 48, and 96 weeks

  6. Change in urine β2-microglobulin (renal tubular marker) [ Time Frame: Baseline, 48 weeks, and 96 weeks ]
    Compare the changes in urine β2-microglobulin from entry to 48 weeks and 96 weeks.

  7. Change in urine RBP (renal tubular marker) [ Time Frame: Baseline, 48 weeks, and 96 weeks ]
    Compare the changes in RBP from entry to 48 weeks and 96 weeks.

  8. Change in urine protein [ Time Frame: Baseline, 48 weeks, and 96 weeks ]
    Compare the changes in protein from entry to 48 weeks and 96 weeks.

  9. Change in urine albumin [ Time Frame: Baseline, 48 weeks, and 96 weeks ]
    Compare the changes in urine albumin from entry to 48 weeks and 96 weeks.

  10. Change in fractional excretion in phosphate [ Time Frame: Baseline, 48 weeks, and 96 weeks ]
    Compare the changes in fractional excretion of phosphate from entry to 48 weeks and 96 weeks.

  11. Percentage change in total lean mass [ Time Frame: Baseline, 48 weeks, and 96 weeks ]
    Compare the percentage change from entry to 48 weeks and 96 weeks in total lean mass (as measured by whole body DXA)

  12. Percentage change in trunk fat [ Time Frame: Baseline, 48 weeks, and 96 weeks ]
    Compare the percentage change from entry to 48 weeks and 96 weeks in trunk fat (as measured by whole body DXA)

  13. Percentage change in limb fat [ Time Frame: Baseline, 48 weeks, and 96 weeks ]
    Compare the percentage change from entry to 48 weeks and 96 weeks in limb fat (as measured by DXA)

  14. Maintenance of HIV RNA level [ Time Frame: 48 weeks and 96 weeks ]
    Compare the levels of HIV RNA <50 copies/mL and below the limit of quantification (BLQ) at 48 weeks and 96 weeks using the FDA snapshot algorithm

  15. Grade 3 or 4 adverse events [ Time Frame: 96 weeks ]
    Compare rates of grade 3 or 4 adverse events experienced by participants through 96 weeks

  16. Treatment discontinuation of study medication due to adverse effect [ Time Frame: 96 weeks ]
    Compare treatment discontinuation of study medication due to adverse effect experienced by participants through 96 weeks

  17. Change in fasting lipids [ Time Frame: Entry, 48 weeks, and 96 weeks ]
    Compare changes in fasting lipids (total cholesterol, LDL, HDL, and triglycerides) at entry, 48 weeks, and 96 weeks



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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:

  1. HIV-1 infection, as documented by a positive 4th generation assay or by any licensed ELISA test kit confirmed by Western blot at any time prior to study entry.
  2. Age ≥18 years
  3. HIV-1 RNA BLQ (e.g., <20 copies/mL or other threshold based on the local viral load assay used) for at least 12 months prior to study entry excluding blips (i.e., a single measurement <200 copies/mL preceded and followed by measurements BLQ)
  4. On a stable TAF-containing ART that also includes at least 2 other antiretrovirals, with no changes in the 12 months prior to entry (except for a switch to a co-formulated tablet from the component tablets or a switch from ritonavir to cobicistat)
  5. Lumbar spine, femoral neck or total hip BMD T-score ≤-1.0 from a DXA scan within the past 48 weeks
  6. If receiving testosterone or estrogen replacement therapy, on a stable dose for ≥3 months prior to enrollment without plan to change dose during the study period.
  7. Acceptable blood laboratory values at screening visit:

    • CD4+ T-cell count ≥200 cells/µL
    • Phosphate ≥2mg/dL
    • 25-hydroxyvitamin D level ≥10 ng/ml
    • Calculated creatinine clearance (CrCl) ≥50 mL/min as estimated by the Cockcroft-Gault equation*:

      • For men = CrCl (mL/min) = (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72)

    For women, multiply the above result by 0.85

  8. For women of reproductive potential, negative serum or urine pregnancy test prior to screening and a negative urine pregnancy test at the entry visit prior to randomization and agreeable to using a contraceptive of choice during the study period.

"Women of reproductive potential" are defined as women who have not been post-menopausal for at least 24 consecutive months (i.e., who have had menses within the preceding 24 months) and have not undergone surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, or tubal ligation; participant report sufficient)

Exclusion Criteria:

  1. Current systemic glucocorticoid use
  2. Lumbar spine, femoral neck or total hip BMD T-score <-3.0
  3. Previous, current pharmacologic treatment, or plan for initiation of therapy for osteoporosis (i.e., bisphosphonates, teriparatide, denosumab, tamoxifen or raloxifene)
  4. Previous fragility fracture (i.e., any fall from a standing height or less that resulted in a fracture)
  5. History of genotypic resistance or phenotypic resistance to either DTG or 3TC. The interpretation of genotypic resistance is based on output from the Stanford HIV Resistance Database (available at https://hivdb.stanford.edu). Isolates with an interpretation of low-level resistance or higher are considered resistant.
  6. History of virologic failure (i.e., confirmed HIV-1 RNA level ≥200 copies/mL after over 6 months of therapy) while on an integrase inhibitor (i.e., raltegravir, elvitegravir, bictegravir, or dolutegravir) or on lamivudine/emtricitabine prior to study enrollment. Any antiretroviral history (even before routine virologic monitoring became standard of care) that would suggest the presence of the M184V mutation should be considered exclusionary
  7. ALT ≥5 X ULN, OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin)
  8. Severe hepatic impairment (Child Pugh Class C)
  9. Anticipated need for antiviral therapy for HCV
  10. Hepatitis B surface antigen positive or Hepatitis B DNA positive
  11. Weight >300 pounds, precluding safe DXA testing
  12. Breastfeeding, pregnancy, or plans to become pregnant during the study
  13. Known allergy/sensitivity to DTG or 3TC.
  14. Receipt or planned receipt of prohibited concomitant medications (See section 5.4)
  15. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study procedures and treatment.
  16. Any serious medical or psychiatric illness that, in the opinion of the site investigator, precludes safe participation or adherence to study procedures.

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): NCT03549689


Contacts
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Contact: Kevin M Morrison (650) 497-4057 kmmorris@stanford.edu
Contact: Philip Grant, MD pmgrant@stanford.edu

Locations
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United States, Alabama
University of Alabama Birmingham
Birmingham, Alabama, United States, 35233
United States, California
Stanford University Not yet recruiting
Palo Alto, California, United States, 94305
Contact: Philip Grant         
United States, Colorado
University of Colorado Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Kristine Erlandson         
United States, Georgia
Emory
Atlanta, Georgia, United States, 75440
United States, Illinois
Northwestern Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Babafemi Taiwo         
United States, Maryland
Johns Hopkins Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Todd Brown         
United States, New York
Columbia Not yet recruiting
New York, New York, United States, 10032
Contact: Michael Yin         
United States, Pennsylvania
Penn Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Pablo Tebas         
United States, Texas
Dallas VA Medical Center Not yet recruiting
Dallas, Texas, United States, 75216
Contact: Roger Bedimo, MD         
UT Houston Not yet recruiting
Houston, Texas, United States, 77030
Contact: Jordan Lake         
Sponsors and Collaborators
Philip Grant
Investigators
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Principal Investigator: Philip Grant, MD Stanford University

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Responsible Party: Philip Grant, Assistant Professor, Stanford University
ClinicalTrials.gov Identifier: NCT03549689     History of Changes
Other Study ID Numbers: 43453
First Posted: June 8, 2018    Key Record Dates
Last Update Posted: April 5, 2019
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:
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Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases
Tenofovir
Lamivudine
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