Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET)

Mass General Brigham

Status and phase: Completed; Phase 3

Conditions: Vitamin D Deficiency; Critical Illness; Acute Respiratory Distress Syndrome

Treatments: Drug: Placebo; Drug: Vitamin D3

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03096314

1U01HL123009 (U.S. NIH Grant/Contract)

PETAL02VIOLET

Details and patient eligibility

About

Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Patients screened as vitamin D deficient (<20 ng/mL) were randomized. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality.

Full description

Primary Objective: To assess the efficacy and safety of early administration of vitamin D3 (cholecalciferol) in reducing mortality and morbidity for vitamin D deficient patients at high risk for Acute Respiratory Distress Syndrome (ARDS) and mortality.

Primary Hypothesis: Early administration of vitamin D3 (cholecalciferol) will improve all-cause, all-location mortality to day 90 in vitamin D deficient patients at high risk for ARDS and mortality.

Methods: Patients were recruited from the emergency departments (EDs), hospital wards, operating rooms, intensive care unites (ICUs) and other acute care areas of the participating PETAL Network Clinical Centers. Screening included a test for Vitamin D (25OHD) levels using either the hospital's clinical laboratory or an FDA-approved point-of-care device (FastPack IP, Qualigen Inc). Patients screened as vitamin D deficient (<20 ng/mL) were randomized. Half of the randomized patients received an early administration of high-dose vitamin D3 and the other half received a placebo. Both active and placebo products were given orally or via naso/orogastric tube.

Rational: Vitamin D has pleiotropic roles in regulating immune function and maintaining epithelial surface integrity. Strong preclinical data support the protective role of vitamin D in regulating pulmonary inflammation and disruption of the alveolar-capillary membrane that are fundamental to ARDS pathogenesis.

Enrollment: 1,358 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age ≥ 18 years

2. Intention to admit to ICU from emergency department, hospital ward, operating room, or outside facility

3. One or more of the following acute risk factors for ARDS and mortality contributing directly to the need for ICU admission:

   Pulmonary

   1. Pneumonia
   2. Aspiration
   3. Smoke Inhalation
   4. Lung contusion
   5. Mechanical ventilation for acute hypoxemic or hypercarbic respiratory failure Extra-Pulmonary
   6. Shock
   7. Sepsis
   8. Pancreatitis

4. Vitamin D deficiency (screening 25OHD level <20 ng/mL)

Exclusion criteria

1. Inability to obtain informed consent
2. Unable to randomize within 12 hours of ICU admission decision
3. Unable to take study medication by mouth or enteral tube
4. Baseline serum calcium >10.2 mg/dL (2.54 mmol/L) or ionized calcium >5.2 mg/dL (1.30 mmol/L)
5. Known kidney stone in past year or history of multiple (>1) prior kidney stone episodes
6. Decision to withhold or withdraw life-sustaining treatment (patients are still eligible if they are committed to full support except cardiopulmonary resuscitation if a cardiac arrest occurs)
7. Expect <48 hour survival
8. If no other risk factors present, a) mechanical ventilation primarily for airway protection, pain/agitation control, or procedure; or b) elective surgical patients with routine postoperative mechanical ventilation; or c) anticipated mechanical ventilation duration <24 hours; or d) chronic/home mechanical ventilation for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion).
9. Prisoner
10. Pregnancy

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,358 participants in 2 patient groups, including a placebo group

High dose vitamin D formulation

Active Comparator group

Description:

A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time.

Treatment:

Drug: Vitamin D3

Placebo

Placebo Comparator group

Description:

A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time.

Treatment:

Drug: Placebo