High Dose Vitamin D and Calcium for Bone Health in Individuals Initiating HAART

Study Overview
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Brief Summary
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This study was done with people who were infected with HIV and needed to start treatment for their HIV disease. The purpose of this study is to see if taking vitamin D and calcium will help prevent the bone loss that sometimes happens when people start HIV treatment. For this study, the following HIV treatment (or HAART) were provided in the form of a single tablet that contains three different drugs: efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). These drugs are approved by the FDA to treat HIV infection. The HIV treatment provided is common for people who are taking HIV drugs for the first time. The risks seen with this HIV treatment are the same that you would encounter when taking these drugs outside of the study. The lists of risks of this HIV treatment are included in this document because the drugs are provided by the study, not because the drugs are being tested. The purpose of the study is only to look at the impact of high doses of vitamin D and calcium in preventing bone loss. There are no study objectives related to HIV treatment (EFV/FTC/TDF).

Official Title
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A Prospective, Randomized, Double-Blind Phase II Trial of High-Dose Vitamin D and Calcium for Bone Health in HIV-Infected Individuals Initiating Highly Active Antiretroviral Therapy (HAART)

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: EFV/FTC/TDF
* Drug: Calcium Carbonate
* Drug: Vitamin D3
* Drug: Placebo for calcium carbonate
* Drug: Placebo for vitamin D3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection No evidence of any exclusionary resistance mutations based on results from any genotype assay from any laboratory that has a CLIA (Clinical Laboratory Improvement Amendments) certification or its equivalent. Results must be available from testing any time in the past or must be obtained prior to entry and reviewed by the site investigator. ARV drug-naïve (<=10 days of ART at any time prior to entry) and no ARV drugs taken within the past 30 days. CD4+ cell count of any value obtained within 90 days prior to study entry at any laboratory that has a CLIA certification or its equivalent. HIV-1 RNA >1000 copies/mL obtained within 90 days prior to study entry at any laboratory that has a CLIA certification or its equivalent. Certain laboratory values obtained within 30 days prior to entry (as indicated in section 4.1.6 of the protocol. Serum calcium < 10.5 mg/dL within 30 days prior to entry. For women of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to initiating study medications. Subjects must refrain from participating in a conception process (i.e., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) and if participating in sexual activity that could lead to pregnancy, the subject/partner must use at least two of the reliable forms of contraceptive listed in section 4.1.9 of the protocol. 25-OH vitamin D >=10 ng/mL and <75 ng/mL. Ability and willingness of subject or legally authorized representative to provide informed consent. Exclusion Criteria: Current or prior use of bisphosphonate therapy. Use of vitamin D supplements greater than 800 IU/day within 30 days prior to entry. Use of calcium supplements greater than 500 mg/day within 30 days prior to entry. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulations. Any oral, intravenous, or inhaled steroids within the 30 days prior to enrollment(intranasal steroid use is allowed). Use of androgenic hormones or growth hormones. Receipt of systemic cytotoxic chemotherapy within 30 days prior to entry. Pregnancy or currently breastfeeding. Documentation of acute opportunistic infections within 30 days prior to entry. Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to entry. Weight >300 lbs (exceeds weight limit of DXA scanners). History of nephrolithiasis (kidney stones). History of osteoporosis (as documented by DXA scan) or fragility fracture. Clinically active thyroid disease (use of thyroid hormone replacement therapy permitted but TSH must be in normal range). Current imprisonment or involuntary incarceration in a medical facility for psychiatric illness. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Any condition that, in the opinion of the site investigator, would compromise the subject's ability to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: EFV/FTC/TDF plus vitamin D3 and calcium carbonate<br>Participants were administered FDC efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla), calcium carbonate and vitamin D3 4000 IU. | Drug: EFV/FTC/TDF<br>* FDC efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla) 600 mg/200 mg/ 300 mg tablet taken orally once daily at bedtime on an empty stomach.<br>* Other names: Atripla;Drug: Calcium Carbonate<br>* Calcium carbonate 500 mg tablet taken orally twice daily with food for 48 weeks.<br>Drug: Vitamin D3<br>* One Vitamin D3 4000 IU capsule taken orally once daily with food for 48 weeks.<br>|
| Experimental: Arm B: EFV/FTC/TDF plus vitamin D placebo and calcium placebo<br>Participants were administered FDC efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla), a placebo for calcium carbonate, and a placebo for vitamin D3. | Drug: EFV/FTC/TDF<br>* FDC efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla) 600 mg/200 mg/ 300 mg tablet taken orally once daily at bedtime on an empty stomach.<br>* Other names: Atripla;Drug: Placebo for calcium carbonate<br>* A placebo for calcium carbonate twice daily taken orally as one x 0 mg tablets with food for 48 weeks<br>Drug: Placebo for vitamin D3<br>* A placebo for vitamin D3 once daily taken orally as one capsule with food for 48 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percent Change From Baseline in Bone Mineral Density (BMD) at Total Hip | The efficacy endpoint is the percent change from baseline to week 48 in bone mineral density (BMD) at total hip (as measured by DXA scan) | Weeks 0 and 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percent Change From Baseline in Bone Mineral Density (BMD) at Spine | The percent change from baseline to week 48 in bone mineral density (BMD) at spine as measured by DXA scan | Weeks 0 and 48 | 
| Number of Participants With Primary Adverse Events | Primary adverse events include all SAEs defined according to ICH guidelines and targeted protocol events, which include all diagnoses of hypercalcemia, hypophoatemia, and nephrolithiasis as well as signs and symptoms grade 2 or higher that may be associated with hypercalcemia and all laboratory toxicities grade 2 or higher defined by the 2004 DAIDS grading table | From first study treatment to week 48 | 
| The Change in Total 25-OH Vitamin D Level From Baseline to Weeks 24 and 48 | Changes in total 25-OH vitamin D from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). Total 25-OH vitamin D is the sum of vitamin 25-OH D2 and D3 levels. All 25-OH vitamin D2 or D3 values below the lower limit of 1.25 ng/mL were imputed to 0 ng/mL | Weeks 0, 24, and 48 | 
| The Changes From Baseline in IL-6 to Weeks 24 and 48 | Interleukin 6 (IL-6) changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). | Weeks 0, 24 and 48 | 
| The Changes From Baseline in sCD14 to Weeks 24 and 48 | Soluble cluster of differentiation 14 (sCD14) changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). | Weeks 0, 24 and 48 | 
| The Changes From Baseline in P1NP to Weeks 24 and 48 | P1NP (marker of bone formation) changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). | Weeks 0, 24 and 48 | 
| The Changes From Baseline in CTX to Weeks 24 and 48 | CTX (marker of bone resorption) changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). | Weeks 0, 24 and 48 | 
| The Changes From Baseline in HOMA-IR to Weeks 24 and 48 | Homeostatic model assessment insulin resistance (HOMA-IR) changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). | Weeks 0, 24 and 48 | 
| The Changes From Baseline in Fasting Total Cholesterol to Weeks 24 and 48 | Fasting total cholesterol changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). | Weeks 0, 24 and 48 | 
| The Changes From Baseline in Fasting LDL to Weeks 24 and 48 | Fasting LDL cholesterol changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). | Weeks 0, 24 and 48 | 
| The Changes From Baseline in Urinary Phosphate Excretion to Weeks 24 and 48 | Fractional excretion of phosphate changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). Fractional Excretion of Phosphate (in %) is defined as: [Urine Phosphate x Serum Creatinine] / [Urine Creatinine x Serum Phosphate] x 100% | Weeks 0, 24 and 48 | 
| The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48 | Total CD4 count changes from baseline to weeks 4, 12, 24 and 48 [week 4/12/24/48 - baseline]. | Weeks 0, 4, 12, 24 and 48 | 
| The Changes From Baseline in iPTH to Weeks 24 and 48 | iPTH (Parathyroid Hormone, intact) changes from baseline to weeks 24 and 48 ( [week 24-baseline] and [week 48 - baseline], respectively). | Weeks 0, 24 and 48 |