Clinical trial NCT03549689: Effect of Reducing Nucleotide Exposure on Bone Health (ReNew)
Official title: Effect of Reducing Nucleotide Exposure on Bone Health (ReNew)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: HIV/AIDS
HIV-1-infection
Osteopenia
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2018-06-08
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Percent change in lumbar spine Bone Mineral Density (BMD) at 96 weeks
timeFrame: Baseline and 96 weeks
Secondary outcomes:
measure: Percentage change in lumbar spine BMD at 48 weeks
timeFrame: Baseline and 48 weeks
measure: Percentage change in total hip BMD at 48 weeks
timeFrame: Baseline, 48 weeks
measure: Percentage change in total hip BMD at 96 weeks
timeFrame: Baseline, 96 weeks
measure: Change in CTX (a bone resorption marker)
timeFrame: Baseline, 12 weeks, 48 weeks, and 96 weeks
measure: Change in P1NP (a bone deposition marker)
timeFrame: Baseline, 12 weeks, 48 weeks, and 96 weeks
measure: Change in urine β2-microglobulin (renal tubular marker)
timeFrame: Baseline, 48 weeks, and 96 weeks
measure: Change in urine RBP (renal tubular marker)
timeFrame: Baseline, 48 weeks, and 96 weeks
measure: Change in urine protein
timeFrame: Baseline, 48 weeks, and 96 weeks
measure: Change in urine albumin
timeFrame: Baseline, 48 weeks, and 96 weeks
measure: Change in fractional excretion in phosphate
timeFrame: Baseline, 48 weeks, and 96 weeks
measure: Percentage change in total lean mass
timeFrame: Baseline, 48 weeks, and 96 weeks
measure: Percentage change in trunk fat
timeFrame: Baseline, 48 weeks, and 96 weeks
measure: Percentage change in limb fat
timeFrame: Baseline, 48 weeks, and 96 weeks
measure: Maintenance of HIV RNA level
timeFrame: 48 weeks and 96 weeks
measure: Grade 3 or 4 adverse events
timeFrame: 96 weeks
measure: Treatment discontinuation of study medication due to adverse effect
timeFrame: 96 weeks
measure: Change in fasting lipids
timeFrame: Entry, 48 weeks, and 96 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Atlanta
country: United States
facility: Emory
state: Georgia
city: Chicago
country: United States
facility: Northwestern
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: New York
country: United States
facility: Columbia
state: New York
city: Philadelphia
country: United States
facility: Penn
state: Pennsylvania
city: Dallas
country: United States
facility: Dallas VA Medical Center
state: Texas
city: Houston
country: United States
facility: UT Houston
state: Texas
Study officials:
affiliation: Stanford University
name: Philip Grant, MD
role: PRINCIPAL_INVESTIGATOR
References: