CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Clinical trial on Vitamin D in diabetic patients

Introduction

Recent studies showed a significant association between diabetes and risk of fragility fractures (in particular hip, proximal humerus and foot fractures). It has been hypothesized that decreased bone strength in diabetes can contribute to fractures risk; however, the role of diabetes is controversial, since it's known that type 1 diabetes is associated with modest reduction in bone density, while type 2 diabetes is often characterized by elevated bone density. It can be supposed that increased fracture risk in type 2 diabetes is related to poorer bone quality that is not accounted for by lower bone density. Bone loss leads to decreased bone strength, beyond what can be predicted from bone density, and this can be in part explained by a greater weight loss in diabetic subjects. Vitamin D supplementation, either orally or with injected vit D, can increase bone strength. The hypothesis of the present study is that Vit D (300.000 IU, o.s.) to diabetic patients at "high risk", with vascular complications (diabetic foot), carries many advantages:

  1. it could represent an effective method for decreasing risk of vertebral and nonvertebral fractures, and improving bone quality.
  2. Poor muscle strength and weakness may be associated with vit D deficiency. Treating this deficiency in the elderly may improve muscular function and reduce falls and fractures.
  3. Vascular calcifications, as a consequence of processes culminating in extra cellular matrix deposition by osteoblast-like cells, seem to be induced by several factors including vit D deficiency. Diabetes mellitus is a process connected with a disregulation of the normal balance between promotion and inhibition of calcification, along with chronic kidney diseases, atherosclerosis and aging. Moreover, abdominal aortic calcification (AAC) is stronlgly associated with cardiovascular diseases including heart attacks and stroke. Vit D supplementation among diabetic subjects could reduce extra-skeletal calcification.
  4. 4. A recent study demonstrated that activated vitamin D has profound effects on human immunity, since it acts as an immune system modulator and stimulates the expression of potent anti-microbial peptides, lining the respiratory tract where they play a major role in protecting the lung from infection. The supply of vit D may therefore be related to infections reduction.
  5. Vit D receptor ligands have been shown to alter the activity of a number of proteins involved in the coagulation process. Some experiments demonstrated several mechanisms by which calcitriol (1,25-dihydroxyvitamin D) would be expected to reduce the activation of coagulation and the burden of thrombosis and its consequences.

Objectives

The objective of this trial is to assess the effects of Vit.D 300.000 IU supply on bone metabolism, muscolar function, vascular system and infection in patients with diabetic foot, at high cardiovascular (CV) and infections risk. The main endpoint is to determine if there is an improvement in bone metabolism by means of the comparison of change between baseline and after 13 and 26 weeks in osteocalcin. This parameter is a widely used marker of bone formation and it is showed to be correlated to diabetes mellitus severity, particularly to HbA1c. Moreover, it has been shown that osteocalcin is a predictor of hip fracture risk in elderly.

The secondary endpoint are as follows:

  • muscular improvement, measured by means muscular-adipose parameters (leptine, adiponectine, CPK)
  • risk reduction for progression of vascular calcifications (identified through Hologic DiscoveryTM DXA)
  • infections evaluated by means immune and clinical parameters (α-TNF)
  • thrombosis evaluated by means clinical and hemo-coagulation parameters (hemochromocitometric examination, fibrinogen, PT, PTT).

Trial design

The present study is a randomised, double-blind, between patients, placebo-controlled, monocentre clinical trial. The study includes three parts, screening, enrolment-treatment and follow up periods. Screening period will be performed within 15 days the entry in the study (V1). The enrolment and study treatment are at day 0 (V2). (Follow-up periods are at weeks 13 and weeks 26. The patients will be followed for 26 weeks and during this follow up period will be visited at week 13 (V3) and week 26 (V4).

Selection of patients

A total of 188 patients will be enrolled in 1 centre (the "Unità del Piede Diabetico" (Diabetic Foot Unit) of "Casa di Cura" located in Abano Terme (PD).

INCLUSION CRITERIA

  • out patients with type 2 diabetes mellitus, and diabetic foot complications;
  • age-range: = 60 years;
  • sex: both men and women;
  • patients agree to participate and give the written informed consent.

EXCLUSION CRITERIA

  • patients with previous or current tumoral disease, with less than 1 year quoad vitam prognosis;
  • patients with sever chronic or auto-immune inflammatory diseases;
  • contra-indications of Vit D (chronic renal failure, renal lithiasis, hypercalcemia, hypercalciuria, allergy to calciferole or excipients);
  • impossibility to perform follow up envisioned in the protocol of the study;
  • patients s treated with strontium ranelate;
  • treatments effective on bone turnover , including:
    • bisphosphonates by I.V. or by I.M. and rhPTH by S.C. within the previous 12 months
    • bisphosphonates, os, for more than 14 days in the previous 12 months
    • calcitonin, estrogens, ipriflavon, SERMs during the last 6 months
    • thyroid hormone, except for in case of stable dose for the last 6 months, together with a state of euthyroidism as documented by TSH test
    • systemic corticosteroids for more than 3 months, at doses greater than the equivalent of 5 mg of prednisone per day, in the previous 12 months;
  • patients treated with antithrombotic therapies;
  • gastrointestinal disorders which impair drug absorption;
  • participation to other clinical trials in the previous 12 months;
  • poor compliance.

WITHDRAWAL CRITERIA

Patients are free to discontinue their participation in the study at any time, and without prejudice to further treatment. A patient may be withdrawn from the study at any time at discretion of the investigator.

Date of and reason(s) for any premature discontinuation of patients from the trial should be recorded on the CRF as follow:

  1. Adverse Event;
  2. Serious Adverse Event;
  3. Unsatisfactory therapeutic effect;
  4. Patient's condition no longer requires trial treatment;
  5. Appearance of exclusion criteria;
  6. Patient non-compliance in returning for visits;
  7. Patient withdrew consent;
  8. Administrative reasons.

The monitor should be notified immediately to any patient discontinuing the study.

Treatment plan

TREATMENTS

Patients satisfying the inclusion/exclusion criteria will be randomly allocated to receive one of the two following treatments:

  1. Vit. D 300.000 IU, per os, in bolo (one vial)
  2. placebo, per os, in bolo (one vial)

TREATMENT SCHEDULE

Both the dose of Vit D and placebo will be given orally in bolo.

Grants

Grant:60,000.00 Euros from Abiogen (for study design and data analysis)

Collaborations

  • E. Brocco, Leonardo Foundation, Abano Terme General Hospital, Italy.
  • T. Harris, Clinical Epidemiology Unit, NIA, NIH, Bethesda, MD, USA.

 

PI photo

Gaetano Crepaldi

Contact information

email  E-mail

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Participating staff

S. Maggi

P. Siviero

G. Romanato