VIOLET: Vitamin D to Improve Outcomes by Leveraging Early Treatment

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03096314
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 1,358
• Locations: 47
• Arms: 2
• Actual Duration (Months): 19.5
• Patients Per Site: 28.9
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome; Vitamin D Deficiency; Critical Illness	Drug: Vitamin D3; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1358 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Vitamin D to Improve Outcomes by Leveraging Early Treatment
• Actual Study Start Date: Apr 27, 2017
• Actual Primary Completion Date: Dec 11, 2018
• Actual Study Completion Date: Dec 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: High dose vitamin D formulation A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time.	Drug: Vitamin D3; 540,000 IU vitamin D3 delivered as a single, liquid enteral dose administered either orally or via naso/orogastric tube; Other Names: cholecalciferol
Placebo Comparator: Placebo A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time.	Drug: Placebo; A single, liquid enteral dose identical in appearance and consistency to cholecalciferol administered either orally or via naso/orogastric tube.

Outcome Measures

Primary Outcome Measures

1. All-cause, All-location Mortality to Day 90 [90 days after randomization]

   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).

Secondary Outcome Measures

1. All-cause, All Location Mortality to Day 28 [Up to 28 days after randomization]

   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.

2. Hospital Mortality to Day 90 [Up to 90 days after randomization]

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

3. Alive and Home (Prior Level of Care) at Day 90 [90 days post randomization]

   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.

4. Hospital Length of Stay to Day 90 [90 days after randomization]

   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.

5. Healthcare Facility Length of Stay to Day 90 [90 days after randomization]

   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.

6. Ventilator-free Days (VFDs) to Day 28 [28 days after randomization]

   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.

7. Health-related Quality of Life by EuroQol (EQ-5D-5L) [baseline to study day 90]

   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).

8. Number of Participants Who Developed (New) ARDS to Day 7 [Up to 7 days after randomization]

   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.

9. Severity of Acute Respiratory Distress Syndrome (ARDS) [7 days after randomization]

   Severity of ARDS is determined using the PaO2/FiO2 ratio or SpO2/FiO2 ratio and confirmation of ARDS through chest x-ray reviews. The breakout of mild to severe was categorized as P/F or imputed P/F ratio of 201-300 (mild), 100-200 (moderate), or less than 100 (severe). This physiologic outcome is one of three key organ systems (respiratory, renal, and cardiovascular) used to assess change in organ failure severity from randomization up to study day 7.

10. Worst Acute Kidney Injury (AKI) [Up to 7 days after randomization]

    This physiologic outcome is one of three key organ systems (respiratory, renal, and cardiovascular) used to assess change in organ failure severity from randomization up to study day 7. Worst AKI was determined by using highest daily creatinine values or new use of dialysis/ renal replacement therapy (chronic dialysis participants were excluded). Mild: On-study creatinine levels 1.5 times greater than baseline value or 0.3 mg/dL over the prehospital value. Moderate: On-study creatinine levels 2 times greater than the baseline pre-hospital value. Severe: On-study creatinine creatinine levels are 3 times greater than baseline prehospital value, or the on-study creatinine level is over 4 mg/dL with an acute (1 day) 0.5 mg/dL rise, or participant is on new renal replacement therapy.

11. New Renal Replacement Therapy (RRT) [Up to 7 days after randomization]

    Participants who were on chronic dialysis at baseline were excluded from the analysis. Participants who started renal replacement therapy on a study day after day 0 and inclusive of day 7 were considered as having new renal replacement therapy. Those who have never started renal replacement therapy over days 0-7 were considered as not having new renal replacement therapy.

12. Highest Creatinine Levels [Up to 7 days after randomization]

    The highest recorded creatinine values is taken from available levels reported across the 7 study days for each patient.

13. New Vasopressor Use to Day 7 [Up to 7 days after randomization]

    The number of subjects in each arm that are started on a vasopressor after randomization up to study day 7.

14. Highest Cardiovascular SOFA (Sepsis Related Organ Failure Assessment) Score [Up to 7 days after randomization]

    Cardiovascular score of the Organ SOFA score was used: Score = 0: MAP* >= 70 mmHg and No Drug; Score = 1: MAP < 70 mmHg and No Drug; Score = 2: (Any MAP) ( dopamine<=5 OR any dobutamine ) AND no other drugs (include neosynephrine vasopressin); Score = 3: (Any MAP) 5 < dopamine <= 15 OR epinephrine <= 0.1 OR norepinephrine <= 0.1 OR neosynephrine <=0.22 OR any dose vasopressin; Score = 4: (Any MAP) dopamine > 15 OR epinephrine > 0.1 OR norepinephrine > 0.1 OR neosynephrine > 0.22 * MAP = mean arterial pressure

15. 25OHD Levels at Day 3 [3 days after randomization]

    Baseline levels will be measured using LC/MS/MS methods (all randomized participants) and at day 3 (the first 300 randomized participants only).

16. Highest Total Calcium to Day 14 [14 days after randomization]

    Clinically available serum or ionized Ca levels were obtained through day 14 for all randomized patients. This time frame was selected to align with the 25OHD half life of two weeks.

17. Highest Ionized Calcium to Day 14 [up to 14 days after randomization]

    Clinically available serum or ionized calcium levels through day 14 were collected for all randomized participants. This time frame was selected to align with the 25OHD half life of two weeks.

18. Hypercalcemia to Day 14 [up to 14 days after randomization]

    As the half-life of 25OHD is approximately 2 weeks, clinically available serum or ionized calcium levels through study day 14 were collected. The number of participants with hypercalcemia was reported.

19. Kidney Stones to Day 90 [90 days after randomization]

    Incident of kidney stones determined by chart review at the end of hospitalization and by self-report at day 90 phone call in those discharged from the hospital prior to day 90.

20. Fall-related Fractures to Day 90 [90 days after randomization]

    Incident of fall-related fractures will be determined by chart review at the end of hospitalization and by self-report at day 90 phone call for those discharged from the hospital prior to day 90. Most data suggest that high dose vitamin D in healthy outpatients may improve muscle function, balance, and bone mineral density, and thus decrease fall-related fractures, but other data suggest that high dose vitamin D supplementation may actually increase the incidence of falls/fractures. Because of this uncertainty and limited data in hospitalized patients, we assessed for incident of fall-related fractures.

21. Falls to Day 90 [90 days post randomization]

    We assessed for incidence of falls by chart review at the end of hospitalization and by self-report at the 90 day phone call. Most data suggest that high dose vitamin D in healthy outpatients may improve muscle function, balance, and bone mineral density, and thus decrease fall-related fractures, but other data suggest that high dose vitamin D supplementation may actually increase the incidence of falls/fractures.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

9. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Fresno	Fresno	California	United States	93701
2	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
3	UC Davis Medical Center	Sacramento	California	United States	95817
4	UCSF Medical Center	San Francisco	California	United States	94143
5	Stanford University	Stanford	California	United States	94305
6	Medical Center of Aurora	Aurora	Colorado	United States	80045
7	University of Colorado Hospital	Aurora	Colorado	United States	80045
8	St. Joseph Hospital	Del Norte	Colorado	United States	80218
9	Denver Health Medical Center	Denver	Colorado	United States	80204
10	Swedish Medical Center	Englewood	Colorado	United States	80113
11	IU Health Methodist Hospital	Indianapolis	Indiana	United States	46202
12	University of Kentucky	Lexington	Kentucky	United States	40506
13	University Medical Center	New Orleans	Louisiana	United States	70112
14	Maine Medical Center	Portland	Maine	United States	04102
15	Tufts Medical Center	Boston	Massachusetts	United States	02111
16	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
17	Massachusetts General Hospital	Boston	Massachusetts	United States	02214
18	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
19	Baystate Medical Center	Springfield	Massachusetts	United States	01199
20	St. Vincent's Hospital	Worcester	Massachusetts	United States	01608
21	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
22	Henry Ford Medical Center	Detroit	Michigan	United States	48025
23	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
24	Montefiore Medical Center	Bronx	New York	United States	10467
25	Mt. Sinai Hospital	New York	New York	United States	10029
26	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
27	Summa Akron City Hospital	Akron	Ohio	United States	44304
28	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
29	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
30	OSU Hospital East Campus	Columbus	Ohio	United States	43203
31	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
32	Providence Portland Medical Center	Portland	Oregon	United States	97213
33	Oregon Health and Science University	Portland	Oregon	United States	97239
34	Penn State Hershey Medical Center	Hershey	Pennsylvania	United States	17033
35	UPMC Presbyterian/Mercy/Shadyside	Pittsburgh	Pennsylvania	United States	15261
36	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37221
37	Intermountain Medical Center	Murray	Utah	United States	84107
38	McKay-Dee Hospital	Ogden	Utah	United States	84403
39	Utah Valley Regional Medical Center	Provo	Utah	United States	84604
40	University of Utah Hospital	Salt Lake City	Utah	United States	84132
41	LDS Hospital	Salt Lake City	Utah	United States	84143
42	University of Virginia Health System	Charlottesville	Virginia	United States	22903
43	VCU Medical Center	Richmond	Virginia	United States	23298
44	Harborview Medical Center	Seattle	Washington	United States	98104
45	University of Washington Medical Center	Seattle	Washington	United States	98104
46	Swedish Hospital Cherry Hill	Seattle	Washington	United States	98122
47	Swedish Hospital First Hill	Seattle	Washington	United States	98122

Sponsors and Collaborators

• Massachusetts General Hospital
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Boyd Taylor Thompson, MD, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol - Sep 12, 2017
• Statistical Analysis Plan - Jun 25, 2018

More Information

Additional Information:

• Website for the PETAL Network

Publications

None provided.

• Responsible Party: Boyd Taylor Thompson, Co-Prinicipal Investigator PETAL CCC, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT03096314
• Other Study ID Numbers: PETAL02VIOLET; 1U01HL123009
• First Posted: Mar 30, 2017
• Last Update Posted: Jan 27, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Boyd Taylor Thompson, Co-Prinicipal Investigator PETAL CCC, Massachusetts General Hospital: ARDS; Vitamin D
• Additional relevant MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Vitamin D Deficiency; Critical Illness; Vitamin D; Cholecalciferol

Study Results

Participant Flow

Pre-assignment Detail	After initial study screening, eligible patients were consented and received secondary screening for vitamin D deficiency; performed via an FDA-approved test (either hospital clinical laboratory or the FastPack IP device (Qualigen Inc., Carlsbad, CA). Participants with a screening 25OHD level <20 ng/mL were randomized for treatment assignment.

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	Patients at high risk for ARDS and mortality with initial screening 25OHD levels < 20 ng/mL randomized to receive 540,00 IU vitamin D3 (cholecalciferol) as a single, liquid enteral dose, administered either orally or via naso/orogastric tube within 2 hours of randomization.	Patients at high risk for ARDS and mortality with initial screening 25OHD levels < 20 ng/mL randomized to receive placebo (similar in appearance to the vitamin D3 treatment) as a single, liquid enteral dose, administered either orally or via naso/orogastric tube within 2 hours of randomization.
Period Title: Screened Vitamin D Deficient
STARTED	690	668
COMPLETED	681	656
NOT COMPLETED	9	12
Period Title: Screened Vitamin D Deficient
STARTED	538	540
COMPLETED	531	528
NOT COMPLETED	7	12

Baseline Characteristics

Arm/Group Title	High Dose Vitamin D Formulation	Placebo	Total
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube	Total of all reporting groups
Overall Participants	538	540	1078
Age (Count of Participants)
<=18 years	1 0.2%	0 0%	1 0.1%
Between 18 and 65 years	368 68.4%	379 70.2%	747 69.3%
>=65 years	169 31.4%	161 29.8%	330 30.6%
Sex: Female, Male (Count of Participants)
Female	229 42.6%	238 44.1%	467 43.3%
Male	309 57.4%	302 55.9%	611 56.7%
Race/Ethnicity, Customized (Count of Participants)
Non-Hispanic White	280 52%	287 53.1%	567 52.6%
Black	130 24.2%	122 22.6%	252 23.4%
Non-Black Hispanic	33 6.1%	31 5.7%	64 5.9%
Other	15 2.8%	12 2.2%	27 2.5%
Not Available	80 14.9%	88 16.3%	168 15.6%
Region of Enrollment (participants) [Number]
United States	538 100%	540 100%	1078 100%
Facility residence prior to hospitalization (%) (Count of Participants)
Count of Participants [Participants]	33 6.1%	35 6.5%	68 6.3%
Health-related quality of life by EuroQol (EQ-5D-5L) (score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score]	0.7 (0.3)	0.7 (0.3)	0.7 (0.3)
Charlson co-morbidity index (index) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [index]	4.0 (2.9)	3.5 (6.5)	3.7 (2.9)
Body mass index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.8 (10.1)	31.0 (11.4)	30.4 (10.8)
Lung Injury risk factors number (%) (Count of Participants)
Pneumonia	204 37.9%	181 33.5%	385 35.7%
Shock	192 35.7%	197 36.5%	389 36.1%
Sepsis	185 34.4%	174 32.2%	359 33.3%
mechanical ventilation for acute resp failure	119 22.1%	121 22.4%	240 22.3%
Aspiration	27 5%	35 6.5%	62 5.8%
Lung contusion	15 2.8%	18 3.3%	33 3.1%
Pancreatitis	17 3.2%	19 3.5%	36 3.3%
Medical intensive care unit admission - (%) (Count of Participants)
Count of Participants [Participants]	447 83.1%	462 85.6%	909 84.3%
Total Sequential Organ Failure Assessment (SOFA) Score (score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score]	4.1 (2.9)	4.0 (3.1)	4 (3)
Lung injury prediction score (LIPS) (score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score]	5.3 (2.9)	5.3 (3.1)	5.3 (3)
Mechanical Ventilation (%) (Count of Participants)
Count of Participants [Participants]	173 32.2%	184 34.1%	357 33.1%
ARDS (%) (Count of Participants)
Count of Participants [Participants]	44 8.2%	44 8.1%	88 8.2%
Vasopressor use at baseline (%) (Count of Participants)
Count of Participants [Participants]	169 31.4%	177 32.8%	346 32.1%
Vitamin D supplement use in past week (%) (Count of Participants)
Count of Participants [Participants]	31 5.8%	24 4.4%	55 5.1%
Multivitamin use in past week (%) (Count of Participants)
Count of Participants [Participants]	38 7.1%	37 6.9%	75 7%
Estimated average daily vitamin D dose (IU) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [IU]	3269 (13118)	4252 (15094)	3747.1 (14057.7)
25-hydroxyvitamin D (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	11.2 (4.8)	11 (4.7)	11.1 (4.7)
Total serum calcium (mg/dL) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	8.3 (0.9)	8.3 (0.9)	8.3 (0.9)
Ionized calcium (mg/dL) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	4.3 (1.4)	4.3 (0.9)	4.3 (1.2)
Creatinine (mg/dL) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	2.2 (2.3)	2.0 (2.0)	2.1 (2.2)
Estimated Glomerular Filtration Rate (eGFR) (ml/min/1.73m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/1.73m2]	60 (39.3)	60.9 (36.9)	60.5 (38.1)

Outcome Measures

1. Primary Outcome

Title	All-cause, All-location Mortality to Day 90
Description	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

Outcome Measure Data

Analysis Population Description

The primary analysis included subjects who had confirmed vitamin D deficiency by LC/MS/MS testing.

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	531	528
Count of Participants [Participants]	125 23.2%	109 20.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Generalized linear model
	Comments

2. Secondary Outcome

Title	All-cause, All Location Mortality to Day 28
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	531	528
Number [participants]	92 17.1%	69 12.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 95%; -0.1 to 8.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Hospital Mortality to Day 90
Description	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

Outcome Measure Data

Analysis Population Description

Participant count is based on available data.

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	538	539
Number [participants]	92 17.1%	72 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	3.7
	Confidence Interval	(2-Sided) 95%; -0.5 to 8.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	528	526
Count of Participants [Participants]	348 64.7%	345 63.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -5.4 to 6.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Hospital Length of Stay to Day 90
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	406	418
Mean (Standard Deviation) [days]	9.1 (9.2)	10.4 (11.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -2.7 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Healthcare Facility Length of Stay to Day 90
Description	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

Outcome Measure Data

Analysis Population Description

This outcome was 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.

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	402	416
Mean (Standard Deviation) [days]	6.0 (17.5)	8.1 (20.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -4.8 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Ventilator-free Days (VFDs) to Day 28
Description	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

Outcome Measure Data

Analysis Population Description

Excludes subjects who never required assisted breathing or who did not survive 28 days (considered zero vent free days).

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	523	534
Mean (Standard Deviation) [days]	21.3 (11.3)	22.1 (10.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -2.1 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Subjects alive and able to be contacted at study day 90 and who had a baseline EQ-5D-5L assessment were analyzed.

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	340	346
Mean (Standard Deviation) [score on a scale]	0.0 (0.2)	-0.0 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; 0 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Participants Who Developed (New) ARDS to Day 7
Description	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.
Time Frame	Up to 7 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	411	412
Count of Participants [Participants]	20 3.7%	17 3.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -2.1 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Severity of Acute Respiratory Distress Syndrome (ARDS)
Description	Severity of ARDS is determined using the PaO2/FiO2 ratio or SpO2/FiO2 ratio and confirmation of ARDS through chest x-ray reviews. The breakout of mild to severe was categorized as P/F or imputed P/F ratio of 201-300 (mild), 100-200 (moderate), or less than 100 (severe). This physiologic outcome is one of three key organ systems (respiratory, renal, and cardiovascular) used to assess change in organ failure severity from randomization up to study day 7.
Time Frame	7 days after randomization

Outcome Measure Data

Analysis Population Description

Those subjects that developed new ARDS after randomization were analyzed for severity.

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	20	17
Mild	6 1.1%	4 0.7%
Moderate	9 1.7%	12 2.2%
Severe	5 0.9%	1 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments	Mild ARDS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	6.5
	Confidence Interval	(2-Sided) 95%; -22.0 to 34.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments	Moderate ARDS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-25.6
	Confidence Interval	(2-Sided) 95%; -56.3 to 5.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments	Severe ARDS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	19.1
	Confidence Interval	(2-Sided) 95%; -2.9 to 41.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Worst Acute Kidney Injury (AKI)
Description	This physiologic outcome is one of three key organ systems (respiratory, renal, and cardiovascular) used to assess change in organ failure severity from randomization up to study day 7. Worst AKI was determined by using highest daily creatinine values or new use of dialysis/ renal replacement therapy (chronic dialysis participants were excluded). Mild: On-study creatinine levels 1.5 times greater than baseline value or 0.3 mg/dL over the prehospital value. Moderate: On-study creatinine levels 2 times greater than the baseline pre-hospital value. Severe: On-study creatinine creatinine levels are 3 times greater than baseline prehospital value, or the on-study creatinine level is over 4 mg/dL with an acute (1 day) 0.5 mg/dL rise, or participant is on new renal replacement therapy.
Time Frame	Up to 7 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	484	495
None	285 53%	297 55%
Mild	70 13%	77 14.3%
Moderate	48 8.9%	52 9.6%
Severe	81 15.1%	69 12.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments	No AKI
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -7.3 to 5.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments	Mild AKI
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -5.6 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments	Moderate AKI
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -4.4 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments	Severe AKI
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; -1.7 to 7.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	New Renal Replacement Therapy (RRT)
Description	Participants who were on chronic dialysis at baseline were excluded from the analysis. Participants who started renal replacement therapy on a study day after day 0 and inclusive of day 7 were considered as having new renal replacement therapy. Those who have never started renal replacement therapy over days 0-7 were considered as not having new renal replacement therapy.
Time Frame	Up to 7 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	489	500
Count of Participants [Participants]	20 3.7%	18 3.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -1.9 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Highest Creatinine Levels
Description	The highest recorded creatinine values is taken from available levels reported across the 7 study days for each patient.
Time Frame	Up to 7 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	518	528
Mean (Standard Error) [mg/dL]	2.2 (0.1)	2.1 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	New Vasopressor Use to Day 7
Description	The number of subjects in each arm that are started on a vasopressor after randomization up to study day 7.
Time Frame	Up to 7 days after randomization

Outcome Measure Data

Analysis Population Description

need info on this

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	357	360
Count of Participants [Participants]	43 8%	42 7.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -4.4 to 5.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Highest Cardiovascular SOFA (Sepsis Related Organ Failure Assessment) Score
Description	Cardiovascular score of the Organ SOFA score was used: Score = 0: MAP* >= 70 mmHg and No Drug; Score = 1: MAP < 70 mmHg and No Drug; Score = 2: (Any MAP) ( dopamine<=5 OR any dobutamine ) AND no other drugs (include neosynephrine vasopressin); Score = 3: (Any MAP) 5 < dopamine <= 15 OR epinephrine <= 0.1 OR norepinephrine <= 0.1 OR neosynephrine <=0.22 OR any dose vasopressin; Score = 4: (Any MAP) dopamine > 15 OR epinephrine > 0.1 OR norepinephrine > 0.1 OR neosynephrine > 0.22 * MAP = mean arterial pressure
Time Frame	Up to 7 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	523	534
Mean (Standard Error) [score on a scale]	1.4 (0.1)	1.3 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	25OHD Levels at Day 3
Description	Baseline levels will be measured using LC/MS/MS methods (all randomized participants) and at day 3 (the first 300 randomized participants only).
Time Frame	3 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	145	133
Mean (Standard Deviation) [ng/mL]	46.9 (23.2)	11.4 (5.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	35.5
	Confidence Interval	(2-Sided) 95%; 31.5 to 39.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Highest Total Calcium to Day 14
Description	Clinically available serum or ionized Ca levels were obtained through day 14 for all randomized patients. This time frame was selected to align with the 25OHD half life of two weeks.
Time Frame	14 days after randomization

Outcome Measure Data

Analysis Population Description

Subjects with a clinically available total calcium level up to study day 14

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	507	513
Mean (Standard Deviation) [mg/dL]	8.9 (0.8)	8.8 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	t-test, 2 sided
	Comments

18. Secondary Outcome

Title	Highest Ionized Calcium to Day 14
Description	Clinically available serum or ionized calcium levels through day 14 were collected for all randomized participants. This time frame was selected to align with the 25OHD half life of two weeks.
Time Frame	up to 14 days after randomization

Outcome Measure Data

Analysis Population Description

Subjects with a clinically available ionized calcium level up to study day 14

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	153	177
Mean (Standard Deviation) [mg/dL]	4.7 (0.8)	4.6 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	t-test, 2 sided
	Comments

19. Secondary Outcome

Title	Hypercalcemia to Day 14
Description	As the half-life of 25OHD is approximately 2 weeks, clinically available serum or ionized calcium levels through study day 14 were collected. The number of participants with hypercalcemia was reported.
Time Frame	up to 14 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	513	523
Count of Participants [Participants]	14 2.6%	11 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	Chi-squared
	Comments

20. Secondary Outcome

Title	Kidney Stones to Day 90
Description	Incident of kidney stones determined by chart review at the end of hospitalization and by self-report at day 90 phone call in those discharged from the hospital prior to day 90.
Time Frame	90 days after randomization

Outcome Measure Data

Analysis Population Description

Subjects discharged from the hospital prior to study day 90.

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	507	507
Count of Participants [Participants]	0 0%	3 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Fisher Exact
	Comments

21. Secondary Outcome

Title	Fall-related Fractures to Day 90
Description	Incident of fall-related fractures will be determined by chart review at the end of hospitalization and by self-report at day 90 phone call for those discharged from the hospital prior to day 90. Most data suggest that high dose vitamin D in healthy outpatients may improve muscle function, balance, and bone mineral density, and thus decrease fall-related fractures, but other data suggest that high dose vitamin D supplementation may actually increase the incidence of falls/fractures. Because of this uncertainty and limited data in hospitalized patients, we assessed for incident of fall-related fractures.
Time Frame	90 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	507	507
Count of Participants [Participants]	4 0.7%	2 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Chi-squared
	Comments

22. Secondary Outcome

Title	Falls to Day 90
Description	We assessed for incidence of falls by chart review at the end of hospitalization and by self-report at the 90 day phone call. Most data suggest that high dose vitamin D in healthy outpatients may improve muscle function, balance, and bone mineral density, and thus decrease fall-related fractures, but other data suggest that high dose vitamin D supplementation may actually increase the incidence of falls/fractures.
Time Frame	90 days post randomization

Outcome Measure Data

Analysis Population Description

need to give info

Arm/Group Title	High Dose Vitamin D Formulation	Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3	A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
Measure Participants	507	507
Count of Participants [Participants]	36 6.7%	27 5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose Vitamin D Formulation, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	Subjects were assessed for adverse events from enrollment (signing of the informed consent) through study day 14 or hospital discharge, whichever occurs first. Investigators will determine if the event is serious or related to the study drug. The rationale for this time window is the 2 week half-life of 25OHD, which helps to define the period at risk from vitamin D.
Arm/Group Title	High Dose Vitamin D Formulation		Placebo
Arm/Group Description	A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time. Vitamin D3: 540,000 IU vitamin D3		A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time. Placebo: A single, liquid enteral dose administered either orally or via naso/orogastric tube
All Cause Mortality
	High Dose Vitamin D Formulation		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	159/681 (23.3%)		137/656 (20.9%)
Serious Adverse Events
	High Dose Vitamin D Formulation		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/690 (2%)		18/668 (2.7%)
Blood and lymphatic system disorders
Heparin Induced Thrombocytopenia and Thrombosis	1/690 (0.1%)	1	0/668 (0%)	0
Cardiac disorders
Cardiac Arrest	1/690 (0.1%)	1	1/668 (0.1%)	1
Cardiomyopathy	1/690 (0.1%)	1	0/668 (0%)	0
Cardiopulmonary Arrest	0/690 (0%)	0	1/668 (0.1%)	1
Fluid Overload	0/690 (0%)	0	1/668 (0.1%)	1
PEA	0/690 (0%)	0	1/668 (0.1%)	1
Pulmonary Edema	0/690 (0%)	0	1/668 (0.1%)	2
Ventricular Tachycardia	1/690 (0.1%)	1	0/668 (0%)	0
Gastrointestinal disorders
Hemorrhage Jejunum	1/690 (0.1%)	1	0/668 (0%)	0
General disorders
Death	2/690 (0.3%)	2	0/668 (0%)	0
ED Visit	0/690 (0%)	0	1/668 (0.1%)	1
Readmission	2/690 (0.3%)	2	0/668 (0%)	0
Readmission to MICU	0/690 (0%)	0	1/668 (0.1%)	1
Weakness Left Sided	0/690 (0%)	0	1/668 (0.1%)	1
Infections and infestations
C Difficile Toxin	1/690 (0.1%)	1	0/668 (0%)	0
Colitis Pseudomembranous	0/690 (0%)	0	1/668 (0.1%)	1
Injury, poisoning and procedural complications
Fall	1/690 (0.1%)	1	0/668 (0%)	0
Hearing Impaired	0/690 (0%)	0	1/668 (0.1%)	1
Nervous system disorders
Altered Mental Status	1/690 (0.1%)	1	1/668 (0.1%)	1
Blindness	0/690 (0%)	0	1/668 (0.1%)	1
Cerebral Infarction	1/690 (0.1%)	1	0/668 (0%)	0
CVA	0/690 (0%)	0	1/668 (0.1%)	1
Seizure	1/690 (0.1%)	1	0/668 (0%)	0
Renal and urinary disorders
Renal Failure Acute	0/690 (0%)	0	1/668 (0.1%)	1
Ureteral Calculus	1/690 (0.1%)	1	0/668 (0%)	0
Ureteral Obstruction from Renal Stone	1/690 (0.1%)	1	0/668 (0%)	0
Respiratory, thoracic and mediastinal disorders
Breathing Kussmaul Type	0/690 (0%)	0	1/668 (0.1%)	1
Lung Disease Obstructive	1/690 (0.1%)	1	0/668 (0%)	0
Pneumothorax	0/690 (0%)	0	1/668 (0.1%)	1
Pulmonary Infarction	1/690 (0.1%)	1	0/668 (0%)	0
Shortness of Breath	0/690 (0%)	0	1/668 (0.1%)	1
Vascular disorders
Hemorrahge Retroperitoneal	0/690 (0%)	0	1/668 (0.1%)	1
Hypertension	0/690 (0%)	0	1/668 (0.1%)	1
Hypotension, Unresponsive	1/690 (0.1%)	1	0/668 (0%)	0
Other (Not Including Serious) Adverse Events
	High Dose Vitamin D Formulation		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/690 (1.4%)		6/668 (0.9%)
Blood and lymphatic system disorders
Anemia Microcytic	1/690 (0.1%)	2	0/668 (0%)	0
Cardiac disorders
Atrial Fibrillation	0/690 (0%)	0	1/668 (0.1%)	1
Ventricular Tachycardia	0/690 (0%)	0	1/668 (0.1%)	1
Endocrine disorders
Hypercalcemia	2/690 (0.3%)	2	0/668 (0%)	0
Gastrointestinal disorders
Emesis	0/690 (0%)	0	1/668 (0.1%)	1
Nausea	2/690 (0.3%)	2	1/668 (0.1%)	1
Nausea and Vomitting	1/690 (0.1%)	1	0/668 (0%)	0
General disorders
Confidentiality	1/690 (0.1%)	1	1/668 (0.1%)	1
Fatigue	0/690 (0%)	0	1/668 (0.1%)	1
Infections and infestations
Pneumonia	1/690 (0.1%)	1	0/668 (0%)	0
Investigations
Platelets Decreased	1/690 (0.1%)	1	0/668 (0%)	0
Renal and urinary disorders
Discoloration Urine	0/690 (0%)	0	1/668 (0.1%)	1
Renal Failure Acute	1/690 (0.1%)	1	0/668 (0%)	0
Respiratory, thoracic and mediastinal disorders
Aspiration Pneumonia	1/690 (0.1%)	1	0/668 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/690 (0.1%)	1	0/668 (0%)	0

Limitations/Caveats

The Data and Safety Monitoring Board recommended that the trial be stopped at the first interim analysis when the primary outcome of the study crossed a protocol specified futility boundary. This adaptive design element resulted in a completed study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.