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)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01403051

Enrollment

167

Registered

2011-07-27

Start date

2011-09-30

Completion date

2013-02-28

Last updated

2018-10-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV-1 Infection

Brief summary

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).

Interventions

DRUGEFV/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.

DRUGCalcium Carbonate

Calcium carbonate 500 mg tablet taken orally twice daily with food for 48 weeks.

DRUGVitamin D3

One Vitamin D3 4000 IU capsule taken orally once daily with food for 48 weeks.

DRUGPlacebo for calcium carbonate

A placebo for calcium carbonate twice daily taken orally as one x 0 mg tablets with food for 48 weeks

DRUGPlacebo for vitamin D3

A placebo for vitamin D3 once daily taken orally as one capsule with food for 48 weeks.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
The Percent Change From Baseline in Bone Mineral Density (BMD) at Total Hip	Weeks 0 and 48	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)

Secondary

Measure	Time frame	Description
Number of Participants With Primary Adverse Events	From first study treatment to week 48	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
The Change in Total 25-OH Vitamin D Level From Baseline to Weeks 24 and 48	Weeks 0, 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
The Changes From Baseline in IL-6 to Weeks 24 and 48	Weeks 0, 24 and 48	Interleukin 6 (IL-6) changes from baseline to weeks 24 and 48 ( \[week 24-baseline\] and \[week 48 - baseline\], respectively).
The Changes From Baseline in sCD14 to Weeks 24 and 48	Weeks 0, 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).
The Changes From Baseline in P1NP to Weeks 24 and 48	Weeks 0, 24 and 48	P1NP (marker of bone formation) changes from baseline to weeks 24 and 48 ( \[week 24-baseline\] and \[week 48 - baseline\], respectively).
The Changes From Baseline in CTX to Weeks 24 and 48	Weeks 0, 24 and 48	CTX (marker of bone resorption) changes from baseline to weeks 24 and 48 ( \[week 24-baseline\] and \[week 48 - baseline\], respectively).
The Percent Change From Baseline in Bone Mineral Density (BMD) at Spine	Weeks 0 and 48	The percent change from baseline to week 48 in bone mineral density (BMD) at spine as measured by DXA scan
The Changes From Baseline in Fasting Total Cholesterol to Weeks 24 and 48	Weeks 0, 24 and 48	Fasting total cholesterol changes from baseline to weeks 24 and 48 ( \[week 24-baseline\] and \[week 48 - baseline\], respectively).
The Changes From Baseline in Fasting LDL to Weeks 24 and 48	Weeks 0, 24 and 48	Fasting LDL cholesterol changes from baseline to weeks 24 and 48 ( \[week 24-baseline\] and \[week 48 - baseline\], respectively).
The Changes From Baseline in Urinary Phosphate Excretion to Weeks 24 and 48	Weeks 0, 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%
The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	Weeks 0, 4, 12, 24 and 48	Total CD4 count changes from baseline to weeks 4, 12, 24 and 48 \[week 4/12/24/48 - baseline\].
The Changes From Baseline in iPTH to Weeks 24 and 48	Weeks 0, 24 and 48	iPTH (Parathyroid Hormone, intact) changes from baseline to weeks 24 and 48 ( \[week 24-baseline\] and \[week 48 - baseline\], respectively).
The Changes From Baseline in HOMA-IR to Weeks 24 and 48	Weeks 0, 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).

Countries

Puerto Rico, United States

Participant flow

Recruitment details

A5280 opened under version 1.0 on September 15, 2011, and the first subject was randomized on September 26, 2011. Accrual to the study closed on March 2, 2012, with a total of 167 subjects enrolled from 39 sites within the US.

Pre-assignment details

Subjects were randomized with a 1:1 ratio at enrollment.

Participants by arm

Arm	Count
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF The participants were administered vitamin D3, calcium carbonate and FDC efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla). Vitamin D3: One Vitamin D3 4000 IU capsule taken orally once daily with food for 48 weeks. Calcium Carbonate: Calcium carbonate 500 mg tablet taken orally twice daily with food for 48 weeks. Atripla: FDC efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) 600 mg/200 mg/ 300 mg tablet taken orally once daily at bedtime on an empty stomach.	79
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF The participants were administered a placebo for vitamin D3, a placebo for calcium carbonate, and FDC efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla). Placebo for vitamin D3: A placebo for vitamin D3 once daily taken orally as one capsule with food for 48 weeks. Placebo for calcium carbonate: A placebo for calcium carbonate twice daily taken orally as one x 0 mg tablets with food for 48 weeks Atripla: FDC efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) 600 mg/200 mg/ 300 mg tablet taken orally once daily at bedtime on an empty stomach.	86
Total	165

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	1	0
Overall Study	Lost to Follow-up	5	5
Overall Study	Protocol Violation	2	0
Overall Study	Withdrawal by Subject	2	1

Baseline characteristics

Characteristic	Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	3 Participants	1 Participants	4 Participants
Age, Categorical Between 18 and 65 years	76 Participants	85 Participants	161 Participants
Age, Continuous	36 years	31 years	33 years
CD4 count	339 cells/mm3	342 cells/mm3	341 cells/mm3
HIV-1 RNA level	4.5 log10 copies/mL	4.5 log10 copies/mL	4.5 log10 copies/mL
Race/Ethnicity, Customized American Indian, Alaskan Native	2 participants	0 participants	2 participants
Race/Ethnicity, Customized Asian, Pacific Islander	2 participants	5 participants	7 participants
Race/Ethnicity, Customized Black Non-Hispanic	24 participants	30 participants	54 participants
Race/Ethnicity, Customized Hispanic (Regardless of Race)	23 participants	18 participants	41 participants
Race/Ethnicity, Customized White Non-Hispanic	28 participants	33 participants	61 participants
Region of Enrollment United States	79 participants	86 participants	165 participants
Sex: Female, Male Female	7 Participants	9 Participants	16 Participants
Sex: Female, Male Male	72 Participants	77 Participants	149 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	60 / 81	70 / 86
serious Total, serious adverse events	8 / 81	7 / 86

Outcome results

Primary

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)

Time frame: Weeks 0 and 48

Population: The primary analysis is intent-to-treat (ITT) which is limited to eligible subjects who have baseline and week 48 follow-up regardless of treatment change or discontinuation.

Arm	Measure	Value (MEDIAN)
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	The Percent Change From Baseline in Bone Mineral Density (BMD) at Total Hip	-1.46 percentage change
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	The Percent Change From Baseline in Bone Mineral Density (BMD) at Total Hip	-3.19 percentage change

Comparison: The study was sized to have 80% power to detect a 2 % difference in BMD of the hip from baseline to week 48.p-value: 0.001Stratified Wilcoxon rank sum test

Secondary

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

Time frame: From first study treatment to week 48

Population: All enrolled subjects including subjects excluded from efficacy analysis due to eligibility violation.

Arm	Measure	Value (NUMBER)
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	Number of Participants With Primary Adverse Events	50 participants
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	Number of Participants With Primary Adverse Events	53 participants

Secondary

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

Time frame: Weeks 0, 24, and 48

Population: Included all available data regardless of treatment change/discontinuation, but was limited to eligible subjects who had both baseline and follow-up data.~n=71 and 74 for changes at week 24, n=65 and 68 for changes at week 48.

Arm	Measure	Group	Value (MEDIAN)
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	The Change in Total 25-OH Vitamin D Level From Baseline to Weeks 24 and 48	change from baseline to week 24	27.5 ng/mL
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	The Change in Total 25-OH Vitamin D Level From Baseline to Weeks 24 and 48	change from baseline to week 48	24.2 ng/mL
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	The Change in Total 25-OH Vitamin D Level From Baseline to Weeks 24 and 48	change from baseline to week 24	-0.8 ng/mL
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	The Change in Total 25-OH Vitamin D Level From Baseline to Weeks 24 and 48	change from baseline to week 48	0.6 ng/mL

Secondary

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 \[week 4/12/24/48 - baseline\].

Time frame: Weeks 0, 4, 12, 24 and 48

Population: Included all available data regardless of treatment change/discontinuation, but was limited to eligible subjects who had both baseline and follow-up data.~n=78 and 86 for changes at week 4, n=77 and 85 for changes at week 4, n=76 and 84 for changes at week 24, n=69 and 80 for changes at week 48.

Arm	Measure	Group	Value (MEDIAN)
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	change from baseline to week 4	74 cells/mm^3
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	change from baseline to week 12	103 cells/mm^3
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	change from baseline to week 24	138 cells/mm^3
Arm A: Vitamin D3 and Calcium Carbonate Plus EFV/FTC/TDF	The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	change from baseline to week 48	192 cells/mm^3
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	change from baseline to week 48	201 cells/mm^3
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	change from baseline to week 4	60 cells/mm^3
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	change from baseline to week 24	136 cells/mm^3
Arm B: Vitamin D3 Placebo and Calcium Placebo Plus EFV/FTC/TDF	The Changes From Baseline in CD4 to Weeks 4, 12, 24 and 48	change from baseline to week 12	106 cells/mm^3

Secondary

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).