Vitamin D to Improve Outcomes by Leveraging Early Treatment

Massachusetts General Hospital1,358 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (47)

UCSF Fresno

Fresno, California, United States

Ronald Reagan UCLA Medical Center

Los Angeles, California, United States

UC Davis Medical Center

Sacramento, California, United States

UCSF Medical Center

San Francisco, California, United States

Stanford University

Stanford, California, United States

Outcomes

Primary Outcomes

All-cause, All-location Mortality to Day 90

Vital status of the patient at day 90 was determined using any of the following methods: medical record review, phone calls to patient, proxy or healthcare facility, review of obituaries, or information from the Centers for Disease Control and Prevention's National Death Index (NDI).

Time frame: 90 days after randomization

Secondary Outcomes

All-cause, All Location Mortality to Day 28

This variable was calculated in participants who were reported alive at day 28. Vital status of the patient at day 28 was determined using any of the following methods: medical record review, phone calls to patient, proxy or healthcare facility, or review of obituaries.

Time frame: Up to 28 days after randomization

Hospital Mortality to Day 90

Analysis of the number of participants who died prior to hospital discharge up to study day 90.

Time frame: Up to 90 days after randomization

Alive and Home (Prior Level of Care) at Day 90

This endpoint is the count of participants who have survived and are present at home, defined as pre-hospitalization level of care, at day 90.

Time frame: 90 days post randomization

Hospital Length of Stay to Day 90

Number of days from enrollment to the day of study hospital discharge up to day 90. Only calculated for patients that survived through day 90.

Time frame: 90 days after randomization

Healthcare Facility Length of Stay to Day 90

Healthcare facility length of stay is the time spent in another hospital or healthcare facility (e.g. long-term acute care \[LTAC\] hospitals or acute rehabilitation/skilled nursing facility), for the subgroup of participants that were discharged to another healthcare facility after the initial hospitalization. This measure is defined as the number of days from initial hospital discharge to the first facility discharge to home (pre-hospitalization level of care) up to day 90. Healthcare facility LOS is zero for patients discharged to home (pre-hospitalization level of care) from the study hospital. This endpoint will be analyzed only in survivors using SACE methods because healthcare facility length of stay in those who die during the follow-up period is non-informative for this endpoint.

Time frame: 90 days after randomization

Ventilator-free Days (VFDs) to Day 28

In participants who survive 28 days, ventilator free days (VFDs) is defined as 28 minus duration of ventilation. Duration of ventilation is counted from the first study day of assisted breathing through the last day of assisted breathing provided the last day is prior to day 28. Or it is counted from the first study day of assisted breathing through day 28. For participants discharged with assisted ventilation prior to day 28, a phone call will be required to assess ventilator status at day 28. Participants discharged prior to day 28 (but not to home) on unassisted breathing will be assumed to remain on unassisted breathing through day 28. Isolated periods of ventilation briefer than 24 hours for surgical procedures and ventilation solely for sleep disordered breathing do not count towards duration of ventilation. In participants who never require assisted breathing, duration of ventilation is zero. Participants who do not survive 28 days will be assigned zero VFD.

Time frame: 28 days after randomization

Health-related Quality of Life by EuroQol (EQ-5D-5L)

Changes in Quality of life score by EuroQol from baseline to day 90. Change was calculated as the value at day 90 minus the value at baseline. The EuroQol score is based on 5 dimensions of perceived problems: Mobility, Self-Care, Anxiety/Depression, Pain/discomfort, and Usual Activities. Problems with each area are assigned a level from 1-5 with level 1 being no problem and level 5 indicating extreme problems. A unique health state score is defined by combining 1 level from each of the 5 dimensions. Responses can be used to calculate a health utility score55 associated with the given health state that ranges from -0.11 to 1.00 (higher scores are better; 1.00 is perfect health).

Time frame: baseline to study day 90

Number of Participants Who Developed (New) ARDS to Day 7

Presence of ARDS determined using the PaO2/FiO2 ratio or SpO2/FiO2 ratio (i.e., imputed P/F ratio) and chest x-ray confirmation. PaO2 = partial pressure of arterial oxygen; FiO2 = percentage of inspired oxygen; SpO2 = peripheral capillary oxygen saturation, an estimate of the amount of oxygen in the blood. For participants with P/F \<300 or imputed P/F \<300, FiO2 ≥40%, and PEEP ≥5 cm H2O, we determined if hypoxemia was valid, acute, and not fully explained by congestive heart failure (CHF) or fluid overload. PEEP = positive end expiatory pressure.