The VALIDATE-D Study (VALIDATE-D)

Evaluating Hormonal Mechanisms for Vitamin D Receptor Agonist Therapy in Diabetes: The VALIDATE-D Study

The purpose of this study is to evaluate whether vitamin D receptor agonist therapy lowers renin-angiotensin system activity.

Study Overview

• Status: Completed
• Conditions: Obesity; Type 2 Diabetes
• Intervention / Treatment: Drug: Calcitriol; Drug: Placebo

Detailed Description

This study aims to evaluate whether vitamin D receptor agonist therapy (calcitriol) in diabetes lowers renin-angiotensin system (RAS) activity in a manner similar to an ACE inhibitor. This is a physiology study, focused on evaluating hormonal changes in the circulating and tissue RAS when compared to placebo.

Subjects with type 2 diabetes and obesity and normal kidney function will undergo evaluation of their circulating and renal-vascular RAS activity and urinary protein at baseline, after withdrawing interfering medications, while on a controlled electrolyte diet, and in controlled posture settings. They will then randomly receive a study medication (calcitriol or placebo) for 3 weeks followed by a re-assessment of their RAS parameters. The main outcomes that will be evaluated following calcitriol/placebo include measures of the circulating renin activity (primary), as well as measures of the renal-vascular RAS (renal plasma flow) and urine protein (secondary)

The primary outcome is the change in the plasma renin activity when sodium restricted, before and after intervention. Secondary outcomes include the change in renal plasma flow and urine protein when sodium loaded, before and after intervention.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Type-Two Diabetes (treated with diet alone, with oral hypoglycemic agents, or with a single injection of basal insulin daily)
2. Normal blood pressure, or Mild (Stage 1) Hypertension that is either untreated, or adequately treated with a single anti-hypertensive drug.
3. Age >18 years and <70 years
4. Estimated GFR > 60ml/min
5. Normal laboratory values for: Complete blood count, sodium, potassium, glucose, liver enzymes, urinalysis
6. Electrocardiogram without any signs of prior infarction, ventricular conduction abnormality, or supraventricular arrhythmia.

Exclusion Criteria:

1. Chronic Kidney Disease or eGFR<60
2. History of nephrolithiasis (kidney stones)
3. Multiple (more than one) insulin injections daily (since insulin can alter the RAS)
4. Poorly controlled type 2 diabetes (That may require more aggressive therapy) as defined by an HbA1c>8.5%
5. Type 1 diabetes
6. Stage 2 or Stage 3 hypertension or the use of more than 1 antihypertensive drug
7. Chronic inflammatory conditions (such as inflammatory bowel disease or arthritis) that are treated with prescribed doses of NSAIDs by a physician.
8. The use of prescribed doses of potassium supplements.
9. History of liver failure
10. History of parathyroid or granulomatous disorders
11. History of heart failure, cerebrovascular disease or coronary heart disease
12. History of known microvascular complications of diabetes (including retinopathy, neuropathy, nephropathy)
13. Illness requiring overnight hospitalization in the past 6 months
14. Active tobacco or recreational drug use
15. Pregnancy or current breast feeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: calcitriol; Subjects will receive calcitriol (titrated up to 0.75 mcg daily) for 3 weeks.	Drug: Calcitriol; Subjects will receive calcitriol (up to 0.75 mcg daily) for 3 weeks.; Other Names: 1,25-dihydroxyvitamin D3
Placebo Comparator: placebo; Subjects will receive placebo for 3 weeks.	Drug: Placebo; Subjects will receive placebo for 3 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change in Circulating RAS Activity After Calcitriol/Placebo Therapy	The below results represent the change in Plasma Renin Activity.	baseline and 2 weeks following calcitriol/placebo therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Renal Plasma Flow After Calcitriol/Placebo Therapy	Subjects had their renal plasma flow assessed at baseline while sodium loaded, and again after 3 weeks of randomized therapy with either calcitriol (up to 0.75 mcg daily) or placebo.	baseline and 3 weeks following calcitriol/placebo therapy
Change in Urine Protein After Calcitriol/Placebo Therapy	Subjects have their urine protein assessed at baseline while sodium loaded and again 3 weeks after randomized therapy with calcitriol or placebo.	baseline and 3 weeks following calcitriol/placebo therapy

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital

Publications and helpful links

General Publications

• Brown JM, Secinaro K, Williams JS, Vaidya A. Evaluating hormonal mechanisms of vitamin D receptor agonist therapy in diabetic kidney disease: the VALIDATE-D study. BMC Endocr Disord. 2013 Aug 23;13:33. doi: 10.1186/1472-6823-13-33.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: July 2, 2012
• First Submitted That Met QC Criteria: July 3, 2012
• First Posted (Estimate): July 6, 2012

Study Record Updates

• Last Update Posted (Actual): April 11, 2017
• Last Update Submitted That Met QC Criteria: February 28, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Micronutrients; Membrane Transport Modulators; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vasoconstrictor Agents; Calcium Channel Agonists; Calcitriol; Dihydroxycholecalciferols
• Other Study ID Numbers: 2012P000905