Effect of Reducing Nucleotide Exposure on Bone Health (ReNew)
Study Details
Study Description
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 |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| 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.
|
Outcome Measures
Primary Outcome Measures
- Percent change in lumbar spine Bone Mineral Density (BMD) at 96 weeks [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
- Percentage change in lumbar spine BMD at 48 weeks [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
- Percentage change in total hip BMD at 48 weeks [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
- Percentage change in total hip BMD at 96 weeks [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
- Change in CTX (a bone resorption marker) [Baseline, 12 weeks, 48 weeks, and 96 weeks]
Compare the changes in CTX from entry to 12, 48, and 96 weeks
- Change in P1NP (a bone deposition marker) [Baseline, 12 weeks, 48 weeks, and 96 weeks]
Compare the changes in P1NP from entry to 12, 48, and 96 weeks
- Change in urine β2-microglobulin (renal tubular marker) [Baseline, 48 weeks, and 96 weeks]
Compare the changes in urine β2-microglobulin from entry to 48 weeks and 96 weeks.
- Change in urine RBP (renal tubular marker) [Baseline, 48 weeks, and 96 weeks]
Compare the changes in RBP from entry to 48 weeks and 96 weeks.
- Change in urine protein [Baseline, 48 weeks, and 96 weeks]
Compare the changes in protein from entry to 48 weeks and 96 weeks.
- Change in urine albumin [Baseline, 48 weeks, and 96 weeks]
Compare the changes in urine albumin from entry to 48 weeks and 96 weeks.
- Change in fractional excretion in phosphate [Baseline, 48 weeks, and 96 weeks]
Compare the changes in fractional excretion of phosphate from entry to 48 weeks and 96 weeks.
- Percentage change in total lean mass [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)
- Percentage change in trunk fat [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)
- Percentage change in limb fat [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)
- Maintenance of HIV RNA level [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
- Grade 3 or 4 adverse events [96 weeks]
Compare rates of grade 3 or 4 adverse events experienced by participants through 96 weeks
- Treatment discontinuation of study medication due to adverse effect [96 weeks]
Compare treatment discontinuation of study medication due to adverse effect experienced by participants through 96 weeks
- Change in fasting lipids [Entry, 48 weeks, and 96 weeks]
Compare changes in fasting lipids (total cholesterol, LDL, HDL, and triglycerides) at entry, 48 weeks, and 96 weeks
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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.
-
Age ≥18 years
-
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)
-
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)
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Lumbar spine, femoral neck or total hip BMD T-score ≤-1.0 from a DXA scan within the past 48 weeks
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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.
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Acceptable blood laboratory values at screening visit:
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CD4+ T-cell count ≥200 cells/µL
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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
- 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:
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Current systemic glucocorticoid use
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Lumbar spine, femoral neck or total hip BMD T-score <-3.0
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Previous, current pharmacologic treatment, or plan for initiation of therapy for osteoporosis (i.e., bisphosphonates, teriparatide, denosumab, tamoxifen or raloxifene)
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Previous fragility fracture (i.e., any fall from a standing height or less that resulted in a fracture)
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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.
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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
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ALT ≥5 X ULN, OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin)
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Severe hepatic impairment (Child Pugh Class C)
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Anticipated need for antiviral therapy for HCV
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Hepatitis B surface antigen positive or Hepatitis B DNA positive
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Weight >300 pounds, precluding safe DXA testing
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Breastfeeding, pregnancy, or plans to become pregnant during the study
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Known allergy/sensitivity to DTG or 3TC.
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Receipt or planned receipt of prohibited concomitant medications (See section 5.4)
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Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study procedures and treatment.
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Any serious medical or psychiatric illness that, in the opinion of the site investigator, precludes safe participation or adherence to study procedures.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama Birmingham | Birmingham | Alabama | United States | 35233 |
| 2 | Stanford University | Palo Alto | California | United States | 94305 |
| 3 | University of Colorado | Aurora | Colorado | United States | 80045 |
| 4 | Emory | Atlanta | Georgia | United States | 75440 |
| 5 | Northwestern | Chicago | Illinois | United States | 60611 |
| 6 | Johns Hopkins | Baltimore | Maryland | United States | 21287 |
| 7 | Columbia | New York | New York | United States | 10032 |
| 8 | Penn | Philadelphia | Pennsylvania | United States | 19104 |
| 9 | Dallas VA Medical Center | Dallas | Texas | United States | 75216 |
| 10 | UT Houston | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Philip Grant
Investigators
- Principal Investigator: Philip Grant, MD, Stanford University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 43453