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

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)

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).

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: EFV/FTC/TDF; Drug: Calcium Carbonate; Drug: Vitamin D3; Drug: Placebo for calcium carbonate; Drug: Placebo for vitamin D3

• Study Type: Interventional
• Enrollment (Actual): 167
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • Puerto Rico-AIDS CRS (5401)
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Alabama Therapeutics CRS (5801)
  • California
    • Los Angeles, California, United States, 90095
      • UCLA CARE Center CRS (601)
    • Los Angeles, California, United States, 90033
      • Usc Crs (1201)
    • Palo Alto, California, United States, 94304
      • Stanford CRS (501)
    • San Diego, California, United States, 92103
      • Ucsd, Avrc Crs (701)
    • San Francisco, California, United States, 94110
      • Ucsf Aids Crs (801)
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS (603)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital CRS (6101)
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University CRS (GU CRS) (1008)
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • The Ponce de Leon Ctr. CRS (5802)
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS (2701)
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center (2702)
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • IHV Baltimore Treatment CRS (4651)
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ACTG CRS (101)
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hosp. ACTG CRS (107)
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Med. Ctr., ACTG CRS (103)
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University CRS (2101)
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School-Adult Clinical Research Ctr. CRS (31477)
  • New York
    • Bronx, New York, United States, 10457
      • Bronx-Lebanon Hosp. Ctr. CRS (31469)
    • New York, New York, United States, 10011
      • Cornell CRS (7804)
    • New York, New York, United States, 10032
      • HIV Prevention & Treatment CRS (30329)
    • New York, New York, United States, 10016
      • NY Univ. HIV/AIDS CRS (401)
    • Rochester, New York, United States, 14642
      • AIDS Care CRS (1108)
    • Rochester, New York, United States, 14642
      • University of Rochester ACTG CRS (1101)
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Unc Aids Crs (3201)
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center Adult CRS (1601)
    • Greensboro, North Carolina, United States, 27401
      • Regional Center for Infectious Disease, Wendover Medical Center CRS (3203)
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Univ. of Cincinnati CRS (2401)
    • Cleveland, Ohio, United States, 44106
      • Case CRS (2501)
    • Cleveland, Ohio, United States, 44109
      • MetroHealth CRS (2503)
    • Columbus, Ohio, United States, 43210
      • The Ohio State Univ. AIDS CRS (2301)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hosp. of the Univ. of Pennsylvania CRS (6201)
    • Pittsburgh, Pennsylvania, United States, 15213
      • Pittsburgh CRS (1001)
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hosp. ACTG CRS (2951)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Therapeutics CRS (3652)
  • Texas
    • Dallas, Texas, United States, 75208
      • Trinity Health and Wellness Center CRS (31443)
    • Houston, Texas, United States, 77030
      • Houston AIDS Research Team CRS (31473)
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington AIDS CRS (1401)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Edgar (Turner) Overton, MD, Alabama Therapeutics CRS; Study Chair: Michael T Yin, MD, MS, HIV Prevention & Treatment CRS

Publications and helpful links

General Publications

• Yin MT, Chan ES, Brown TT, Kinslow J, Martinson J, Landay A, Melbourne KM, Ribaudo HJ, Overton ET; A5280 Study Team. Vitamin D does not modulate immune-mediated bone loss during ART initiation. Antivir Ther. 2019;24(5):355-362. doi: 10.3851/IMP3316.
• Yin MT, Chan ES, Brown TT, Tebas P, McComsey GA, Melbourne KM, Napoli A, Hardin WR, Ribaudo HJ, Overton ET; A5280 Study Team. Racial differences in calculated bioavailable vitamin D with vitamin D/calcium supplementation. AIDS. 2017 Nov 13;31(17):2337-2344. doi: 10.1097/QAD.0000000000001621.
• Overton ET, Chan ES, Brown TT, Tebas P, McComsey GA, Melbourne KM, Napoli A, Hardin WR, Ribaudo HJ, Yin MT. Vitamin D and Calcium Attenuate Bone Loss With Antiretroviral Therapy Initiation: A Randomized Trial. Ann Intern Med. 2015 Jun 16;162(12):815-24. doi: 10.7326/M14-1409.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: July 25, 2011
• First Submitted That Met QC Criteria: July 25, 2011
• First Posted (Estimate): July 27, 2011

Study Record Updates

• Last Update Posted (Actual): October 12, 2018
• Last Update Submitted That Met QC Criteria: September 11, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antacids; Vitamin D; Cholecalciferol; Calcium; Vitamins; Calcium, Dietary; Ergocalciferols; Calcium Carbonate
• Other Study ID Numbers: ACTG A5280; 1U01AI068636 (U.S. NIH Grant/Contract)