Clinical trial NCT03096314: Vitamin D to Improve Outcomes by Leveraging Early Treatment
Official title: Vitamin D to Improve Outcomes by Leveraging Early Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Respiratory Distress Syndrome
Vitamin D Deficiency
Critical Illness
Keywords: ARDS
Vitamin D
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2017-03-30
Enrollment: 1358
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: All-cause, All-location Mortality to Day 90
timeFrame: 90 days after randomization
Secondary outcomes:
measure: All-cause, All Location Mortality to Day 28
timeFrame: Up to 28 days after randomization
measure: Hospital Mortality to Day 90
timeFrame: Up to 90 days after randomization
measure: Alive and Home (Prior Level of Care) at Day 90
timeFrame: 90 days post randomization
measure: Hospital Length of Stay to Day 90
timeFrame: 90 days after randomization
measure: Healthcare Facility Length of Stay to Day 90
timeFrame: 90 days after randomization
measure: Ventilator-free Days (VFDs) to Day 28
timeFrame: 28 days after randomization
measure: Health-related Quality of Life by EuroQol (EQ-5D-5L)
timeFrame: baseline to study day 90
measure: Number of Participants Who Developed (New) ARDS to Day 7
timeFrame: Up to 7 days after randomization
measure: Severity of Acute Respiratory Distress Syndrome (ARDS)
timeFrame: 7 days after randomization
measure: Worst Acute Kidney Injury (AKI)
timeFrame: Up to 7 days after randomization
measure: New Renal Replacement Therapy (RRT)
timeFrame: Up to 7 days after randomization
measure: Highest Creatinine Levels
timeFrame: Up to 7 days after randomization
measure: New Vasopressor Use to Day 7
timeFrame: Up to 7 days after randomization
measure: Highest Cardiovascular SOFA (Sepsis Related Organ Failure Assessment) Score
timeFrame: Up to 7 days after randomization
measure: 25OHD Levels at Day 3
timeFrame: 3 days after randomization
measure: Highest Total Calcium to Day 14
timeFrame: 14 days after randomization
measure: Highest Ionized Calcium to Day 14
timeFrame: up to 14 days after randomization
measure: Hypercalcemia to Day 14
timeFrame: up to 14 days after randomization
measure: Kidney Stones to Day 90
timeFrame: 90 days after randomization
measure: Fall-related Fractures to Day 90
timeFrame: 90 days after randomization
measure: Falls to Day 90
timeFrame: 90 days post randomization
Other outcomes:
Locations:
city: Fresno
country: United States
facility: UCSF Fresno
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: Medical Center of Aurora
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Del Norte
country: United States
facility: St. Joseph Hospital
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: Englewood
country: United States
facility: Swedish Medical Center
state: Colorado
city: Indianapolis
country: United States
facility: IU Health Methodist Hospital
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: University Medical Center
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: St. Vincent's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Medical Center
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Mt. Sinai Hospital
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Akron
country: United States
facility: Summa Akron City Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: OSU Hospital East Campus
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian/Mercy/Shadyside
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Ogden
country: United States
facility: McKay-Dee Hospital
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Richmond
country: United States
facility: VCU Medical Center
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Hospital Cherry Hill
state: Washington
city: Seattle
country: United States
facility: Swedish Hospital First Hill
state: Washington
Study officials:
affiliation: Massachusetts General Hospital
name: Boyd Taylor Thompson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Ginde AA, Brower RG, Caterino JM, Finck L, Banner-Goodspeed VM, Grissom CK, Hayden D, Hough CL, Hyzy RC, Khan A, Levitt JE, Park PK, Ringwood N, Rivers EP, Self WH, Shapiro NI, Thompson BT, Yealy DM, Talmor D. Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients. N Engl J Med. 2019 Dec 26;381(26):2529-2540. doi: 10.1056/NEJMoa1911124. Epub 2019 Dec 11.