Clinical trial NCT01751646: Vitamin D Absorption in HIV Infected Young Adults Being Treated With Tenofovir Containing cART
Official title: A Randomized, Double-Blind, Placebo-Controlled Trial of the Safety and Effectiveness of Vitamin D3 50,000 IU Every 4 Weeks to Increase Bone Mineral Density and Decrease Tenofovir-Induced Hyperparathyroidism in Youth With HIV Infection Being Treated With Tenofovir-Containing Combination Antiretroviral Therapy (cART)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infection
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute on Drug Abuse (NIDA)
name: National Institute of Mental Health (NIMH)
First posted: 2012-12-18
Enrollment: 214
Sex: ALL
Minimum age (years): 16
Maximum age (years): 24
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: This is a 48 week randomized double-blind, placebo-controlled prospective cohort study of adolescents and young adults with HIV infection in the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) who are currently being treated with cART that includes tenofovir disoproxil fumarate (TDF) as one component of the regimen that includes at least three Food and Drug Administration (FDA)-approved antiretroviral (ARV) drugs for at least 180 days.

Detailed description: This is a 48 week randomized double-blind, placebo-controlled prospective cohort study of adolescents and young adults with HIV infection in the ATN who are currently being treated with cART that includes TDF as one component of the regimen that includes at least three Food and Drug Administration (FDA)-approved ARVs for at least 180 days. Subjects must have at least one documented viral load that is below 200 copies/mL that is collected following initiation of TDF containing cART and greater than 90 days prior to randomization; no viral load above 200 copies/mL if measured within the 90 days prior to randomization; and an HIV viral load obtained at screening that is below 200 copies/mL.

Treatment assignments will be balanced by subject sex at birth, age (\<20 years vs. \>=20 years), and race (African American vs. other). Enrolled subjects will be randomized to receive vitamin D3 50000 IU or matching placebo, given orally every four weeks by DOT. In addition to the randomized study agent, all subjects will receive a MVI to be taken orally once daily. This "standard" MVI will contain ingredients not to exceed 600 IU of vitamin D3 and 200 mg Ca.

Dual energy x-ray absorptiometry (DXA) measurement of bone mineral content (BMC)/bone mineral density (BMD) of whole body, spine, and hip, will be performed at baseline and study weeks 24 and 48. Blood and urine sampling to assess the Ca-phosphorous (PO4) axis, parathyroid hormone (PTH)-FGF23-vitamin D signaling, bone turnover, and renal glomerular and tubular function will occur at baseline and study weeks 12, 24, and 48. Blood samples to measure Gluc homeostasis will be drawn at baseline and week 48, and will be run by batch analysis.

Safety, measured by serum calcium (SCa) and serum creatinine (SCr), will be monitored by subject's record review at study sites since these labs will generally be measured as a part of routine clinical care. The Adolescent Medicine Trials Network for HIV/AIDS Interventions 109 (ATN 109) study will use the SCa and SCr values obtained within 10 weeks at the time of the visit beginning at the baseline visit. If these evaluations were not performed within the prior 10 weeks they will be drawn at the time of each visit. Viral load and cluster of differentiation 4 (CD4) cell count results will be recorded for this study, ATN 109, at screening, baseline and study weeks 12, 24, 48, and Post-Week 48 provided the evaluations were done within the protocol specified timeframe. If the evaluations were not performed within the protocol specified timeframes they will be drawn at the time of the visit.

Eligibility criteria: Inclusion Criteria:

To be considered eligible for enrollment, an individual must meet the criteria listed below at the time of randomization:

NOTE: If the DXA scan is scheduled prior to randomization, all eligibility criteria must be met prior to performing the DXA scan.

* Age 16 years and 0 days to 24 years and 364 days;
* Behaviorally infected with HIV (e.g., sexual contact, injection drug use; not infected by perinatal transmission, blood transfusion, or at age younger than 9 years);
* HIV-1 infection as documented in subject's medical record by at least one of the following criteria:

  * reactive HIV screening test result with an antibody based FDA-licensed assay followed by a positive supplemental assay (e.g., HIV-1 Western Blot, HIV-1 Indirect Immunofluorescence, Antibody Differentiation Assay (Multispot)); or
  * positive HIV-1 DNA polymerase chain reaction (PCR) assay; or
  * plasma HIV-1 quantitative RNA assay \>1,000 copies/mL; or
  * positive plasma HIV-1 RNA qualitative assay
* Subjects must have at least one documented HIV viral load that is below 200 copies/mL collected following initiation of TDF containing cART and greater than 90 days prior to randomization; no HIV viral load above 200 copies/mL if measured within the 90 days prior to randomization; and an HIV viral load obtained at screening that is below 200 copies/mL.
* Currently being treated for at least 180 days by the time of randomization with a TDF containing cART with at least 2 other FDA approved ARVs (NOTE: This may include a TDF-containing fixed drug combination medication);
* Negative serum hepatitis B surface antigen (HBsAg) at screening or by history within 4 weeks prior to screening (see section 7.1.3);
* Willingness and ability to remain on the same cART regimen for the duration of study participation;
* Willingness and ability to participate in the study, follow all study procedures for the duration of study participation, and provide written informed consent or assent with parental permission, if applicable; and
* For females of child-bearing potential, agreement to use a minimum of one proven-effective method of birth control and willingness to postpone pregnancy for the duration of study participation (see section 5.3.2 for permitted hormonal contraceptives)

Exclusion Criteria:

To be considered eligible for enrollment, an individual must not meet any of the criteria listed below at the time of randomization:

NOTE: If the DXA scan is scheduled prior to randomization, all eligibility criteria must be met prior to performing the DXA scan.

* Prior hypersensitivity to vitamin D;
* History of sarcoidosis, arteriosclerosis, renal stones, glomerulonephritis, interstitial kidney disease, nephrotic syndrome, hypercalcemia, osteoporosis and/or other bone diseases, clinical diagnosis of hypoparathyroidism or hyperparathyroidism;
* Lactation or pregnancy currently or within the past 24 weeks;
* Chemotherapy or radiation therapy for malignancy within the past 12 months;
* Known presence of GI disease that, in the opinion of the clinician, would interfere with study agent administration or absorption (e.g. Crohn's, Colitis);
* For subjects ≥ 18 years, confirmed creatinine clearance \< 70 ml/min (estimated glomerular filtration rate (GFR) from SCr using Cockcroft and Gault (CG) equation) and for subjects \<18 years, confirmed creatinine clearance \< 70ml/min/1.73m2 (estimated GFR from SCr using Schwartz formula (see section 3.5). (Estimated GFR may be calculated using the formulae programmed on the ATN website);
* SCa \> Upper Limit Normal (ULN) for local laboratory values (see section 7.1.3);
* Active Grade 3 or higher clinical or laboratory toxicity except atazanavir (ATV) associated indirect hyperbilirubinemia (see section 9.5.2.2);
* Weight is \> 350 pounds (lbs) or 159 kilograms (kgs);
* Positive hepatitis C antibody by history or at screening (see section 7.1.3); and
* Use of any medications as specified in sections 5.3.1, 5.3.3 and 5.4.
* Females Only: Use of certain hormonal contraceptives as specified in the protocol.

Primary outcomes:
measure: Percent Change From Baseline to Week 48 in Dual Energy X-ray Absorptiometry (DXA)-Measured BMD at the Spine for the Randomized Study Groups
timeFrame: Baseline and wk 48
Secondary outcomes:
measure: Percent Change From Baseline to Week 24 of BMC of Whole Body for the Randomized Study Groups
timeFrame: Baseline and week 24
measure: Percent Change From Baseline to Week 48 of BMC of Whole Body for the Randomized Study Groups
timeFrame: Baseline and week 48
measure: Percent Change From Baseline to Week 24 of Lumbar Spine (L1-L4) BMD for the Randomized Study Groups
timeFrame: Baseline and week 24
measure: Change From Baseline to Week 24 of Lumbar Spine (L1-L4) BMD Z-score for the Randomized Study Groups
timeFrame: Baseline and week 24
measure: Change From Baseline to Week 48 of Lumbar Spine (L1-L4) BMD Z-score for the Randomized Study Groups
timeFrame: Baseline and week 48
measure: Percent Change From Baseline to Week 24 of Femoral Neck BMD for the Randomized Study Groups
timeFrame: Baseline and week 24
measure: Percent Change From Baseline to Week 48 of Femoral Neck BMD for the Randomized Study Groups
timeFrame: Baseline and week 48
measure: Change From Baseline to Week 24 of Femoral Neck BMD Z-score for the Randomized Study Groups
timeFrame: Baseline and week 24
measure: Change From Baseline to Week 48 of Femoral Neck BMD Z-score for the Randomized Study Groups
timeFrame: Baseline and week 48
measure: Percent Change From Baseline to Week 24 of Total Hip BMD for the Randomized Study Groups
timeFrame: Baseline and week 24
measure: Percent Change From Baseline to Week 48 of Total Hip BMD for the Randomized Study Groups
timeFrame: Baseline and week 48
measure: Change From Baseline to Week 24 of Total Hip BMD Z-score for the Randomized Study Groups
timeFrame: Baseline and week 24
measure: Change From Baseline to Week 48 of Total Hip BMD Z-score for the Randomized Study Groups
timeFrame: Baseline and week 48
measure: Change in SCr From Baseline to Week 12.
timeFrame: Baseline and week 12
measure: Change in SCr From Baseline to Week 24.
timeFrame: Baseline and week 24
measure: Change in SCr From Baseline to Week 48.
timeFrame: Baseline and week 48
measure: Change From Baseline to Week 48 in Glucose Homeostasis (Fasting Insulin)
timeFrame: Baseline and 48 weeks
measure: Change From Baseline to Week 48 in Glucose Homeostasis (Fasting Glucose)
timeFrame: Baseline and week 48
measure: Change From Baseline to Week 48 in Glucose Homeostasis (Homeostasis Model Assessment of Insulin Resistance (HOMA-IR))
timeFrame: Baseline and week 48
measure: Change From Baseline to Week 12 in Serum Calcium (SCa)
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in Serum Calcium (SCa)
timeFrame: 24 weeks
measure: Change From Baseline to Week 48 in Serum Calcium (SCa)
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in CTX
timeFrame: Baseline and week 12
measure: Change From Baseline to Week 24 in CTX
timeFrame: Baseline and week 24
measure: Change From Baseline to Week 48 in CTX
timeFrame: Baseline and week 48
measure: Change From Baseline to Week 12 in OC
timeFrame: Baseline and week 12
measure: Change From Baseline to Week 24 in OC
timeFrame: Baseline and week 24
measure: Change From Baseline to Week 48 in OC
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in BAP
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in BAP
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in BAP
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in FGF23
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in FGF23
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in FGF23
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in PTH
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in PTH
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in PTH
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in Actual Free 1,25-OHD
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in Actual Free 1,25-OHD
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in Actual Free 1,25-OHD
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in 1,25-OHD
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in 1,25-OHD
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in 1,25-OHD
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in 25-OHD
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in 25-OHD
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in 25-OHD
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in TRP %
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in TRP %
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in TRP %
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in SPO4
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in SPO4
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in SPO4
timeFrame: Baseline and wk 48
measure: Change From Baseline to Week 12 in UCa/Ucr
timeFrame: Baseline and wk 12
measure: Change From Baseline to Week 24 in UCa/Ucr
timeFrame: Baseline and wk 24
measure: Change From Baseline to Week 48 in UCa/Ucr
timeFrame: Baseline and wk 48
measure: Change in Estimated GFR From Baseline to Week 12.
timeFrame: Baseline and wk 12
measure: Change in Estimated GFR From Baseline to Week 24.
timeFrame: Baseline and wk 24
measure: Change in Estimated GFR From Baseline to Week 48.
timeFrame: Baseline and wk 48
measure: Change in UGluc From Baseline to Week 48
timeFrame: Baseline and wk 48
measure: Change in URBP/UCr Ratio From Baseline to Week 48
timeFrame: Baseline and wk 48
measure: Change in UB2MG From Baseline to Week 48
timeFrame: Baseline and wk 48
measure: Change in UProt/ UCr Ratio From Baseline to Week 48
timeFrame: Baseline and wk 48
measure: 25-OHD Serum Concentration by Randomized Study Group at Week 12
timeFrame: Week 12
measure: 25-OHD Serum Concentration by Randomized Study Group at Week 24
timeFrame: Week 24
measure: 25-OHD Serum Concentration by Randomized Study Group at Week 48
timeFrame: Week 48
measure: Effect of Concurrent Treatment With Efavirenz on 25-OHD Serum Concentration: Concentration at Baseline by Efavirenz Use
timeFrame: Baseline
measure: Effect of Concurrent Treatment With Efavirenz on 25-OHD Serum Concentration: Concentration at Week 48 by Efavirenz Use
timeFrame: Week 48
measure: Effect of Concurrent Treatment With Efavirenz on 25-OHD Serum Concentration: Change in Concentration From Baseline to Week 48 by Efavirenz Use
timeFrame: Baseline and wk 48
measure: Effect of Concurrent Treatment With Ritonavir on 25-OHD Serum Concentration: Concentration at Baseline by Ritonavir Use
timeFrame: Baseline
measure: Effect of Concurrent Treatment With Ritonavir on 25-OHD Serum Concentration: Concentration at Week 48 by Ritonavir Use
timeFrame: Week 48
measure: Effect of Concurrent Treatment With Ritonavir on 25-OHD Serum Concentration: Change in Concentration From Baseline to Week 48 by Ritonavir Use
timeFrame: Baseline and wk 48
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hopsital of Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of Southern California - NICHD Westat Site
state: California
city: Washington
country: United States
facility: Childrens National Medical Center
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Children's Diagnostic and Treatment Center - NICHD Westat Site
state: Florida
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Stroger Hospital and the CORE Center
state: Illinois
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University - NICHD Westat Site
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Fenway Institute
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Childrens Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Juan
country: Puerto Rico
facility: San Juan City Hospital (Puerto Rico) - NICHD Westat Site
Study officials:
affiliation: MACC Fund Research Center
name: Peter Havens, MD
role: STUDY_CHAIR
References:
citation: Havens PL, Stephensen CB, Van Loan MD, Schuster GU, Woodhouse LR, Flynn PM, Gordon CM, Pan CG, Rutledge B, Harris DR, Price G, Baker A, Meyer WA 3rd, Wilson CM, Hazra R, Kapogiannis BG, Mulligan K; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 109 Study Team. Vitamin D3 Supplementation Increases Spine Bone Mineral Density in Adolescents and Young Adults With Human Immunodeficiency Virus Infection Being Treated With Tenofovir Disoproxil Fumarate: A Randomized, Placebo-Controlled Trial. Clin Infect Dis. 2018 Jan 6;66(2):220-228. doi: 10.1093/cid/cix753.
citation: Havens PL, Long D, Schuster GU, Gordon CM, Price G, Wilson CM, Kapogiannis BG, Mulligan K, Stephensen CB; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 117 and 109 study teams. Tenofovir disoproxil fumarate appears to disrupt the relationship of vitamin D and parathyroid hormone. Antivir Ther. 2018;23(7):623-628. doi: 10.3851/IMP3269. Epub 2018 Sep 27.