Vitamin D Absorption in HIV Infected Young Adults Being Treated With Tenofovir Containing cART

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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HIV Infection

Intervention / Treatment
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* Dietary Supplement: Vitamin D3 50,000 IU
* Dietary Supplement: Vitamin D3 placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Vitamin D3 50,000 IU<br>Subjects randomized to Group A will receive Vitamin D3 50,000 IU orally every four weeks by directly observed therapy (DOT). In addition all subjects receive a multivitamin (MVI) that contains ingredients not to exceed 600 IU of vitamin D3 and 200 mg of Calcium (Ca). Subjects will self-administer one MVI tablet orally once daily. | Dietary Supplement: Vitamin D3 50,000 IU<br>* Group A: Vitamin D3 50,000 IU orally every four weeks by DOT<br>* Other names: Vitamin D3;|
| Placebo Comparator: Group B: Vitamin D3 placebo<br>Subjects randomized to Group B will receive Vitamin D3 placebo orally every four weeks by DOT. In addition all subjects receive a MVI that contains ingredients not to exceed 600 IU of vitamin D3 and 200 mg of Ca. Subjects will self-administer one MVI tablet orally once daily. | Dietary Supplement: Vitamin D3 placebo<br>* Group B: Vitamin D3 placebo orally every four weeks by DOT<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 48 in Dual Energy X-ray Absorptiometry (DXA)-Measured BMD at the Spine for the Randomized Study Groups | Percent change from baseline to week (wk) 48 in DXA-measured BMD at the spine for the randomized study groups. Lumbar spine BMD (L1 - L4) (g/cm2) change from Baseline to wk 48 visit. | Baseline and wk 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 24 of BMC of Whole Body for the Randomized Study Groups |  | Baseline and week 24 | 
| Percent Change From Baseline to Week 48 of BMC of Whole Body for the Randomized Study Groups |  | Baseline and week 48 | 
| Percent Change From Baseline to Week 24 of Lumbar Spine (L1-L4) BMD for the Randomized Study Groups |  | Baseline and week 24 | 
| Change From Baseline to Week 24 of Lumbar Spine (L1-L4) BMD Z-score for the Randomized Study Groups | The Z-score is the standard deviation around mean bone mineral density in the lumbar spine, adjusted for sex, age, and race/ethnicity. An average Z-score of zero would be expected to be seen in healthy populations. A negative Z-score indicates lower than average bone mineral density. Low bone mineral density is a frequent finding in HIV-infected individuals, including adolescents and young adults. | Baseline and week 24 | 
| Change From Baseline to Week 48 of Lumbar Spine (L1-L4) BMD Z-score for the Randomized Study Groups | The Z-score is the standard deviation around mean bone mineral density in the lumbar spine, adjusted for sex, age, and race/ethnicity. An average Z-score of zero would be expected to be seen in healthy populations. A negative Z-score indicates lower than average bone mineral density. Low bone mineral density is a frequent finding in HIV-infected individuals, including adolescents and young adults. | Baseline and week 48 | 
| Percent Change From Baseline to Week 24 of Femoral Neck BMD for the Randomized Study Groups |  | Baseline and week 24 | 
| Percent Change From Baseline to Week 48 of Femoral Neck BMD for the Randomized Study Groups |  | Baseline and week 48 | 
| Change From Baseline to Week 24 of Femoral Neck BMD Z-score for the Randomized Study Groups | The Z-score is the standard deviation around mean bone mineral density in the femoral neck, adjusted for sex, age, and race/ethnicity. An average Z-score of zero would be expected to be seen in healthy populations. A negative Z-score indicates lower than average bone mineral density. Low bone mineral density is a frequent finding in HIV-infected individuals, including adolescents and young adults. | Baseline and week 24 | 
| Change From Baseline to Week 48 of Femoral Neck BMD Z-score for the Randomized Study Groups | The Z-score is the standard deviation around mean bone mineral density in the femoral neck, adjusted for sex, age, and race/ethnicity. An average Z-score of zero would be expected to be seen in healthy populations. A negative Z-score indicates lower than average bone mineral density. Low bone mineral density is a frequent finding in HIV-infected individuals, including adolescents and young adults. | Baseline and week 48 | 
| Percent Change From Baseline to Week 24 of Total Hip BMD for the Randomized Study Groups |  | Baseline and week 24 | 
| Percent Change From Baseline to Week 48 of Total Hip BMD for the Randomized Study Groups |  | Baseline and week 48 | 
| Change From Baseline to Week 24 of Total Hip BMD Z-score for the Randomized Study Groups | The Z-score is the standard deviation around mean bone mineral density in the total hip, adjusted for sex, age, and race/ethnicity. An average Z-score of zero would be expected to be seen in healthy populations. A negative Z-score indicates lower than average bone mineral density. Low bone mineral density is a frequent finding in HIV-infected individuals, including adolescents and young adults. | Baseline and week 24 | 
| Change From Baseline to Week 48 of Total Hip BMD Z-score for the Randomized Study Groups | The Z-score is the standard deviation around mean bone mineral density in the total hip, adjusted for sex, age, and race/ethnicity. An average Z-score of zero would be expected to be seen in healthy populations. A negative Z-score indicates lower than average bone mineral density. Low bone mineral density is a frequent finding in HIV-infected individuals, including adolescents and young adults. | Baseline and week 48 | 
| Change in SCr From Baseline to Week 12. | To assess renal glomerular safety by measuring change in SCr from baseline to week 12 by randomized study group; | Baseline and week 12 | 
| Change in SCr From Baseline to Week 24. | To assess renal glomerular safety by measuring change in SCr from baseline to week 24 by randomized study group; | Baseline and week 24 | 
| Change in SCr From Baseline to Week 48. | To assess renal glomerular safety by measuring change in SCr from baseline to week 48 by randomized study group; | Baseline and week 48 | 
| Change From Baseline to Week 48 in Glucose Homeostasis (Fasting Insulin) |  | Baseline and 48 weeks | 
| Change From Baseline to Week 48 in Glucose Homeostasis (Fasting Glucose) |  | Baseline and week 48 | 
| Effect of Concurrent Treatment With Efavirenz on 25-OHD Serum Concentration: Concentration at Baseline by Efavirenz Use | Mean Vitamin D serum concentration (25-(OH)D) Total) in those with efavirenz use vs. those without efavirenz use | Baseline | 
| Effect of Concurrent Treatment With Efavirenz on 25-OHD Serum Concentration: Concentration at Week 48 by Efavirenz Use | Mean Vitamin D serum concentration (25-(OH)D) Total) in those with efavirenz use vs. those without efavirenz use | Week 48 | 
| Effect of Concurrent Treatment With Efavirenz on 25-OHD Serum Concentration: Change in Concentration From Baseline to Week 48 by Efavirenz Use | Mean Vitamin D serum concentration (25-(OH)D) Total) in those with efavirenz use vs. those without efavirenz use | Baseline and wk 48 | 
| Effect of Concurrent Treatment With Ritonavir on 25-OHD Serum Concentration: Concentration at Baseline by Ritonavir Use | Mean Vitamin D serum concentration (25-(OH)D) Total) in those with ritonavir use vs. those without ritonavir use | Baseline | 
| Effect of Concurrent Treatment With Ritonavir on 25-OHD Serum Concentration: Concentration at Week 48 by Ritonavir Use | Mean Vitamin D serum concentration (25-(OH)D) Total) in those with ritonavir use vs. those without ritonavir use | Week 48 | 
| Effect of Concurrent Treatment With Ritonavir on 25-OHD Serum Concentration: Change in Concentration From Baseline to Week 48 by Ritonavir Use | Mean Vitamin D serum concentration (25-(OH)D) Total) in those with ritonavir use vs. those without ritonavir use | Baseline and wk 48 | 
| 25-OHD Serum Concentration by Randomized Study Group at Week 24 |  | Week 24 | 
| 25-OHD Serum Concentration by Randomized Study Group at Week 48 |  | Week 48 | 
| Change From Baseline to Week 48 in Glucose Homeostasis (Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)) | HOMA-IR is calculated as fasting glucose (mg/dL) X fasting glucose (uIU/mL) / 405. An increase in HOMA-IR means that an individual has become more resistant (less sensitive) to the effects of insulin and thus would be a negative outcome. A reduction in HOMA-IR means that an individual has become more sensitive to the effects of insulin and would be considered a positive outcome.There are no set minimum or maximum scores for HOMA-IR, since it is based on measurements of insulin and glucose, the assays for which may vary. Several studies suggest a cut-off of >2 for any insulin resistance, but normal values appear to vary greatly by population (https://www.mdcalc.com/homa-ir-homeostatic-model-assessment-insulin-resistance). | Baseline and week 48 | 
| Change From Baseline to Week 12 in Serum Calcium (SCa) |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in Serum Calcium (SCa) |  | 24 weeks | 
| Change From Baseline to Week 48 in Serum Calcium (SCa) |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in CTX |  | Baseline and week 12 | 
| Change From Baseline to Week 24 in CTX |  | Baseline and week 24 | 
| Change From Baseline to Week 48 in CTX |  | Baseline and week 48 | 
| Change From Baseline to Week 12 in OC |  | Baseline and week 12 | 
| Change From Baseline to Week 24 in OC |  | Baseline and week 24 | 
| Change From Baseline to Week 48 in OC |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in BAP |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in BAP |  | Baseline and wk 24 | 
| Change From Baseline to Week 48 in BAP |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in FGF23 |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in FGF23 |  | Baseline and wk 24 | 
| Change From Baseline to Week 48 in FGF23 |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in PTH |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in PTH |  | Baseline and wk 24 | 
| Change From Baseline to Week 48 in PTH |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in Actual Free 1,25-OHD | Vitamin D serum concentration (1,25 (OH)DTotal) (pmol/L) multiplied by F times 1,000, where F is defined as F = 1/(1 + Kd * [VDBP] + Ka *[albumin]) where the binding constant for VDBP = Kd = 4.2 x 107 M-1, and for albumin is Ka = 5.4 x 104 M-1 and the concentrations of VDBP and albumin are in moles/L | Baseline and wk 12 | 
| Change From Baseline to Week 24 in Actual Free 1,25-OHD | Vitamin D serum concentration (1,25 (OH)DTotal) (pmol/L) multiplied by F times 1,000, where F is defined as F = 1/(1 + Kd * [VDBP] + Ka *[albumin]) where the binding constant for VDBP = Kd = 4.2 x 107 M-1, and for albumin is Ka = 5.4 x 104 M-1 and the concentrations of VDBP and albumin are in moles/L | Baseline and wk 24 | 
| Change From Baseline to Week 48 in Actual Free 1,25-OHD | Vitamin D serum concentration (1,25 (OH)DTotal) (pmol/L) multiplied by F times 1,000, where F is defined as F = 1/(1 + Kd * [VDBP] + Ka *[albumin]) where the binding constant for VDBP = Kd = 4.2 x 107 M-1, and for albumin is Ka = 5.4 x 104 M-1 and the concentrations of VDBP and albumin are in moles/L | Baseline and wk 48 | 
| Change From Baseline to Week 12 in 1,25-OHD |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in 1,25-OHD |  | Baseline and wk 24 | 
| Change From Baseline to Week 48 in 1,25-OHD |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in 25-OHD |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in 25-OHD |  | Baseline and wk 24 | 
| Change From Baseline to Week 48 in 25-OHD |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in TRP % |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in TRP % |  | Baseline and wk 24 | 
| Change From Baseline to Week 48 in TRP % |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in SPO4 |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in SPO4 |  | Baseline and wk 24 | 
| Change From Baseline to Week 48 in SPO4 |  | Baseline and wk 48 | 
| Change From Baseline to Week 12 in UCa/Ucr |  | Baseline and wk 12 | 
| Change From Baseline to Week 24 in UCa/Ucr |  | Baseline and wk 24 | 
| Change From Baseline to Week 48 in UCa/Ucr |  | Baseline and wk 48 | 
| Change in Estimated GFR From Baseline to Week 12. | To assess renal glomerular safety by measuring change in estimated GFR from baseline to week 12 by randomized study group. eGFR calculated by the CKD-Epi equation for subjects >=18 years of age, and by bedside Schwartz formula for subjects <18 years of age | Baseline and wk 12 | 
| Change in Estimated GFR From Baseline to Week 24. | To assess renal glomerular safety by measuring change in estimated GFR from baseline to week 24 by randomized study group; | Baseline and wk 24 | 
| Change in Estimated GFR From Baseline to Week 48. | To assess renal glomerular safety by measuring change in estimated GFR from baseline to week 48 by randomized study group; | Baseline and wk 48 | 
| Change in UGluc From Baseline to Week 48 | To assess renal tubular function by measuring change in urine glucose (UGluc) by randomized study group; | Baseline and wk 48 | 
| Change in URBP/UCr Ratio From Baseline to Week 48 | To assess renal tubular function by measuring change in urine retinol binding protein to urine creatinine (URBP/UCr) ratio by randomized study group; | Baseline and wk 48 | 
| Change in UB2MG From Baseline to Week 48 | To assess renal tubular function by measuring change in urine beta-2 microglobulin (UB2MG) by randomized study group; | Baseline and wk 48 | 
| Change in UProt/ UCr Ratio From Baseline to Week 48 | To assess renal tubular function by measuring change in urinary protein to creatinine ratio by randomized study group; | Baseline and wk 48 | 
| 25-OHD Serum Concentration by Randomized Study Group at Week 12 |  | Week 12 |