The VALIDATE-D Study

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

Detailed Description
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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.

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

Conditions
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Type 2 Diabetes, Obesity

Intervention / Treatment
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* Drug: Calcitriol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type-Two Diabetes (treated with diet alone, with oral hypoglycemic agents, or with a single injection of basal insulin daily) Normal blood pressure, or Mild (Stage 1) Hypertension that is either untreated, or adequately treated with a single anti-hypertensive drug. Age >18 years and <70 years Estimated GFR > 60ml/min Normal laboratory values for: Complete blood count, sodium, potassium, glucose, liver enzymes, urinalysis Electrocardiogram without any signs of prior infarction, ventricular conduction abnormality, or supraventricular arrhythmia. Exclusion Criteria: Chronic Kidney Disease or eGFR<60 History of nephrolithiasis (kidney stones) Multiple (more than one) insulin injections daily (since insulin can alter the RAS) Poorly controlled type 2 diabetes (That may require more aggressive therapy) as defined by an HbA1c>8.5% Type 1 diabetes Stage 2 or Stage 3 hypertension or the use of more than 1 antihypertensive drug Chronic inflammatory conditions (such as inflammatory bowel disease or arthritis) that are treated with prescribed doses of NSAIDs by a physician. The use of prescribed doses of potassium supplements. History of liver failure History of parathyroid or granulomatous disorders History of heart failure, cerebrovascular disease or coronary heart disease History of known microvascular complications of diabetes (including retinopathy, neuropathy, nephropathy) Illness requiring overnight hospitalization in the past 6 months Active tobacco or recreational drug use Pregnancy or current breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |