Clinical trial NCT01306656
Conditions: Primary Hyperparathyroidism Vitamin D Deficiency
Keywords: Endocrinology Metabolic Bone Disease Primary Hyperparathyroidism PHPT Vitamin D Deficiency Bone Mineral Density Hyper-calcemia
Sponsor: Columbia University
Start date: 2011-10-01; Completion date: 2017-02-01
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will look at the effect of 2 treatment regimens that contain vitamin D in a six-month treatment trial of patients with PHPT who are vitamin D deficient. Patients will be assigned randomly to one of 2 regimens, and will be followed with tests of their blood, urine and bones. This study should provide important information on the effect of vitamin D therapy in patients with PHPT. In addition, data from this study will guide physicians as to how best to treat their patients who have PHPT and vitamin D deficiency.

Detailed description:
Primary hyperparathyroidism (PHPT) is a common disease in which the parathyroid glands produce excessive amounts of parathyroid hormone (PTH), which regulates calcium levels. In primary hyperparathyroidism, high levels of PTH remove too much calcium from bones and deposit the excess calcium in the blood, which is then filtered into the urine by the kidneys. Bone health is threatened by the excess calcium loss which weakens the structure of the bones.

Many patients with primary hyperparathyroidism also have low vitamin D (25OHD) levels which is thought to further impair bone health. Recent medical guidelines recommend treating patients with primary hyperparathyroidism who have low vitamin D levels with oral vitamin D but the optimal vitamin D dose and rate of repletion is unclear. It is, therefore, important to determine if replenishing Vitamin D will improve bone health in primary hyperparathyroidism, and if so, to assess the impact of the rate of vitamin D repletion.

Arms: arm 1: 10,000 IU Vitamin D3 plus a multivitamin with 400 IU vitamin D arm 2: Placebo plus a multivitamin with 400 IU vitamin D
Interventions: intervention 1: 10,000 IU Vitamin D3 intervention 2: Placebo intervention 3: Vitamin D
Intervention descriptions: intervention 1: Month 1: 20,000 IU vitamin D3 once a week

Months 2-6: 10,000 IU vitamin D3 once a week intervention 2: Month 1: Placebo once a week

Months 2-6: Placebo once a week intervention 3: Daily multivitamin with 400 IU vitamin D.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol: AAAF1797 
Principal Investigator: Silverberg, Shonni Joy 
Title: Randomized controlled trial of Vitamin D Repletion Regimens in Primary Hyperparathyroidism 
Study Purpose and Rationale: 
Vitamin D deficiency is very common in the setting of PHPT, and leads to higher PTH levels. In this study, 
we will investigate the impact of two different vitamin D repletion regimens over a six month period in 
patients with PHPT and concurrent vitamin D deficiency. We hypothesize that vitamin D repletion 
ameliorates the extent of hyperparathyroidism and improves biochemical, microarchitectural and 
biomechanical features of the disease. In addition, we will show that vitamin D can be repleted safely in 
patients with PHPT. This would be of great importance to the many physicians treating patients with 
PHPT today, who are being advised to replete vitamin D in these patients without any clear guidelines as 
to how best to do so. 
Study Design: 
40 patients with PHPT and vitamin D deficiency (25OHD less than 30 ng/ml) will be enrolled and 
randomized 4:1 to two different vitamin D repletion regimens. Randomization to treatment will use 
randomly permuted blocks. Our first group will receive 2 capsules of 10,000 IU of vitamin D once per 
week for the first month and then 1 capsule of 10,000 IU of vitamin D once per week for the remaining 
five months which should replete vitamin D deficiency and decrease PTH (our primary end-point). 
Control subjects (Group 2) will take 2 capsules of the placebo once per week for the first month and 
then 1 capsule of the placebo once per week for the remaining five months. All subjects will receive 400 
IU of vitamin D each day, either in the form of a multivitamin or by itself, for the entire study. Our 
protocol provides 400 IU of vitamin D per day for control subjects because we felt that ethically it would 
not be appropriate to withhold all vitamin D from this group. A 400 IU dose is expected to raise serum 
25-OHD levels minimally (2-3 ng/ml) thus allowing this cohort to serve as a valid control group 1.  
Study drug will be dispensed at the first visit as appropriate to randomization. Participants will be 
instructed on and receive a printed medication administration schedule. They will be advised to begin 
taking their study drug immediately, and up to 500 mg of supplemental calcium but no additional 
vitamin D. They will be instructed about events that could be related to hypercalcemia or hypercalciuria: 
nephrolithiasis, nausea, vomiting, polyuria/polydipsia, or fractures.  
The study will have a 6 month design, which will allow us to capture our treatment groups before and 
during the process of becoming vitamin D replete. Many PHPT patients are monitored without surgery 
for years and thus determining the safety and effect of maintaining adequate 25-OHD levels is 
imperative. 
No vitamin D toxicity data exist in patients with PHPT. Available data in normal subjects are of limited 
applicability to patients with PHPT who are hypercalcemic and often hypercalciuric at the outset. 
However, in normal subjects hypercalcemia does not occur unless serum 25-OHD levels are above 150-
200 ng/ml. The Food and Nutrition Board has set a safe tolerable upper intake level of 2000 IU daily for 
vitamin D3 and 2400 IU as the no-observed adverse-effect level. More recent clinical trial data suggest 
that these assessments are extremely conservative 2. It should be noted that none of the patients 
ClinicalTrials.gov ID: NCT01306656 
Date: December 2, 2015


treated by Grey et al. achieved a 25-OHD level above 50 ng/ml, and their mean increment in 25-OHD 
was 19 (range 6-37 ng/ml). However, because PHPT patients may be more susceptible to adverse effects 
due to their baseline elevations in serum and urinary calcium, the careful monitoring we propose is 
essential to allow conclusions about safety of repleting vitamin D in PHPT. In addition, because of this 
concern, we will exclude any patient with: serum calcium greater than 11.5 mg/dL; urine calcium greater 
than 350 mg/dL per day; active nephrolithiasis or nephrocalcinosis. We will also compare the 
percentage of participants who achieve a 25-OHD level above 30 ng/ml in each group, and assess the 
changes in serum and urinary calcium, 25-OHD and 1,25-OH2D among groups. We will describe the time 
course of the normalization of 25-OHD levels in the treatment group and evaluate whether the level of 
vitamin D or acuity of the change in vitamin D is predictive of adverse events. We plan to analyze the 
data on an intent-to-treat basis, but will also do a secondary per protocol analysis based upon final 
vitamin D level in order to estimate achievable PTH reduction in regimen compliant subjects. Finally, we 
will assess patients for the development of safety outcomes. Participants whose serum calcium 
concentration rise above 12 mg/dL or develop nephrolithiasis (evaluation of clinical complaint) will be 
withdrawn. Although we will also monitor and compare the number of participants in each group whose 
urinary calcium level exceeds 400 mg/day, these individuals will not be withdrawn as explained in the 
Data and Safety Monitoring section. The frequency of patients with these outcomes at each time point 
will be compared among groups. We expect that the treatment regimen will be effective in achieving a 
vitamin D level above 30 ng/ml, while the 400 IU control group will not reach this threshold. The issues 
assessed here will therefore be of great value in formulating recommendations for vitamin D treatment, 
a key research goal of the new Consensus Guidelines, and an imperative for clinicians treating PHPT 
patients. 
Describe how participants will be recruited:  
Patients with primary hyperparathyroidism will be recruited by physician referral from the population of 
patients seen in the Metabolic Bone Diseases Unit, Endocrine Clinic, and the Surgical Endocrine Unit. 
During a medical visit, eligible patients will receive information about the study and study procedures by 
their physician. Those patients interested in the study will give their permission to have their contact 
information sent to the study coordinator and PI for follow-up. Patients who do not want to hear more 
information about the study will not be contacted. Those patients who agree to hear more information 
about the study will be contacted by the PI or the study coordinator. The patient will learn more about 
the study, study procedures, and the consent form. Those who agree to participate will have the 
consent form mailed to them for further review. During their first visit, the study coordinator, or the 
physician, will go over the consent form and answer any other study related questions, the participant 
will then sign the consent form. The availability of patients from both the medical and surgical services 
at Columbia University Medical Center (CUMC) over the funding period should provide ample 
opportunity for us to enroll patients. 
Statistical Procedures: 
The primary statistical analysis of the 6-month endpoint will be an intent-totreat (ITT), "as prescribed", 
ANCOVA assessment of between group differences in log-transformed serum PTH level adjusted for 
baseline serum PTH and the covariates listed below. The primary ITT analysis will be repeated with 
actual cumulative vitamin D intake entered as a continuous time-dependent covariate to estimate the 
time course of the "as treated" decrease in PTH level. Analysis of the longitudinal growth curve of each 


measure will use linear mixed models for repeated measures to assess the fixed effects of vitamin-D 
repletion regimen, time, regimen time interaction, random effects for intercept and standard covariates; 
and a covariance structure fit prior to the hypothesis test. Average time to achieve a 25-OHD level of 30 
for the two vitamin-D repletion regimens will be estimated with a Cox proportional hazards model. 
Power and sample size calculations assume PTH is analyzed in log units, unequal sample sizes in the two 
groups, unequal variances in the two groups, a type I error rate of 0.05, 80% power and a two-tailed T-
Test of the post-treatment PTH levels. A reduction in the treated group from 149 ± 64 ng/ml to 85 ± 48 
pg/ml is larger than our original estimated effect size but consistent with the data available from our 
cross-sectional study for patients with 25OHD 30 ng/ml, respectively. Given the above assumptions and 
a desired 4:1 treatment allocation ratio, a sample size of 40 distributed 32 vs 8 meets our power goal 
(calculated with harmonic mean sample size of 13 per group). The analysis of safety event rates will 
include Fisher's Exact comparisons of between-group differences in the number of patients with 
hypercalcemia and/or hypercalciuria; and a Cox proportional hazards assessment of time to first AE 
adjusted for standard timeindependent covariates and time-dependent cumulative vitamin D dosage 
will be used to estimate the contribution of vitamin D to the development of the safety events. 
Assessments of safety events will be conducted to relate the onset of safety events to baseline vitamin-
D levels, to the ramp of vitamin-D level increase and peak available vitamin-D level at time of event (to 
the extent known). Standard covariates for all analyses include season, weight, serum calcium and age. 
All power and sample size calculations based on SAS Power and Sample Size 3.1 (SAS Institute, Cary, NC). 
References: 
1. Hatcheck JN, Shao A, Vieth R, Heaney R 2007 Risk assessment for vitamin D. Am J Clin Nutr 85:6-
18 
2. Ambrogini E, Cetani F, Cianferotti L, Vignali E, Banti C, Viccica G, Oppo A, Miccoli P, Berti P, 
Bilezikian JP, Pinchera A, Marcocci C 2007 Surgery or surveillance for mild asymptomatic primary 
hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab 92:3114-
3121