Trial Outcomes & Findings for Vitamin D to Improve Outcomes by Leveraging Early Treatment (NCT NCT03096314)

Last Updated: 2020-01-27

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1358 participants

Primary outcome timeframe

90 days after randomization

Results posted on

2020-01-27

Participant Flow

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.

Participant milestones

Participant milestones
Measure	High Dose Vitamin D Formulation 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.	Placebo 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.
Screened Vitamin D Deficient STARTED	690	668
Screened Vitamin D Deficient COMPLETED	681	656
Screened Vitamin D Deficient NOT COMPLETED	9	12
Confirmed Vitamin D Deficient STARTED	538	540
Confirmed Vitamin D Deficient COMPLETED	531	528
Confirmed Vitamin D Deficient NOT COMPLETED	7	12

Reasons for withdrawal

Reasons for withdrawal
Measure	High Dose Vitamin D Formulation 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.	Placebo 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.
Screened Vitamin D Deficient Lost to Follow-up	9	12

Baseline Characteristics

Data missing on some subjects prevented calculating index on total cohort.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	High Dose Vitamin D Formulation n=538 Participants 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	Placebo n=540 Participants 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 n=1078 Participants Total of all reporting groups
Age, Categorical <=18 years	1 Participants n=538 Participants	0 Participants n=540 Participants	1 Participants n=1078 Participants
Age, Categorical Between 18 and 65 years	368 Participants n=538 Participants	379 Participants n=540 Participants	747 Participants n=1078 Participants
Age, Categorical >=65 years	169 Participants n=538 Participants	161 Participants n=540 Participants	330 Participants n=1078 Participants
Sex: Female, Male Female	229 Participants n=538 Participants	238 Participants n=540 Participants	467 Participants n=1078 Participants
Sex: Female, Male Male	309 Participants n=538 Participants	302 Participants n=540 Participants	611 Participants n=1078 Participants
Race/Ethnicity, Customized Race/Ethnicity · Non-Hispanic White	280 Participants n=538 Participants	287 Participants n=540 Participants	567 Participants n=1078 Participants
Race/Ethnicity, Customized Race/Ethnicity · Black	130 Participants n=538 Participants	122 Participants n=540 Participants	252 Participants n=1078 Participants
Race/Ethnicity, Customized Race/Ethnicity · Non-Black Hispanic	33 Participants n=538 Participants	31 Participants n=540 Participants	64 Participants n=1078 Participants
Race/Ethnicity, Customized Race/Ethnicity · Other	15 Participants n=538 Participants	12 Participants n=540 Participants	27 Participants n=1078 Participants
Race/Ethnicity, Customized Race/Ethnicity · Not Available	80 Participants n=538 Participants	88 Participants n=540 Participants	168 Participants n=1078 Participants
Region of Enrollment United States	538 participants n=538 Participants	540 participants n=540 Participants	1078 participants n=1078 Participants
Facility residence prior to hospitalization (%)	33 Participants n=538 Participants	35 Participants n=540 Participants	68 Participants n=1078 Participants
Health-related quality of life by EuroQol (EQ-5D-5L)	0.7 score STANDARD_DEVIATION 0.3 • n=538 Participants	0.7 score STANDARD_DEVIATION 0.3 • n=540 Participants	0.7 score STANDARD_DEVIATION 0.3 • n=1078 Participants
Charlson co-morbidity index	4.0 index STANDARD_DEVIATION 2.9 • n=538 Participants	3.5 index STANDARD_DEVIATION 6.5 • n=540 Participants	3.7 index STANDARD_DEVIATION 2.9 • n=1078 Participants
Body mass index (BMI)	29.8 kg/m^2 STANDARD_DEVIATION 10.1 • n=524 Participants • Data missing on some subjects prevented calculating index on total cohort.	31.0 kg/m^2 STANDARD_DEVIATION 11.4 • n=529 Participants • Data missing on some subjects prevented calculating index on total cohort.	30.4 kg/m^2 STANDARD_DEVIATION 10.8 • n=1053 Participants • Data missing on some subjects prevented calculating index on total cohort.
Lung Injury risk factors number (%) Pneumonia	204 Participants n=538 Participants	181 Participants n=540 Participants	385 Participants n=1078 Participants
Lung Injury risk factors number (%) Shock	192 Participants n=538 Participants	197 Participants n=540 Participants	389 Participants n=1078 Participants
Lung Injury risk factors number (%) Sepsis	185 Participants n=538 Participants	174 Participants n=540 Participants	359 Participants n=1078 Participants
Lung Injury risk factors number (%) mechanical ventilation for acute resp failure	119 Participants n=538 Participants	121 Participants n=540 Participants	240 Participants n=1078 Participants
Lung Injury risk factors number (%) Aspiration	27 Participants n=538 Participants	35 Participants n=540 Participants	62 Participants n=1078 Participants
Lung Injury risk factors number (%) Lung contusion	15 Participants n=538 Participants	18 Participants n=540 Participants	33 Participants n=1078 Participants
Lung Injury risk factors number (%) Pancreatitis	17 Participants n=538 Participants	19 Participants n=540 Participants	36 Participants n=1078 Participants
Medical intensive care unit admission - (%)	447 Participants n=538 Participants	462 Participants n=540 Participants	909 Participants n=1078 Participants
Total Sequential Organ Failure Assessment (SOFA) Score	4.1 score STANDARD_DEVIATION 2.9 • n=538 Participants	4.0 score STANDARD_DEVIATION 3.1 • n=540 Participants	4 score STANDARD_DEVIATION 3 • n=1078 Participants
Lung injury prediction score (LIPS)	5.3 score STANDARD_DEVIATION 2.9 • n=538 Participants	5.3 score STANDARD_DEVIATION 3.1 • n=540 Participants	5.3 score STANDARD_DEVIATION 3 • n=1078 Participants
Mechanical Ventilation (%)	173 Participants n=538 Participants	184 Participants n=540 Participants	357 Participants n=1078 Participants
ARDS (%)	44 Participants n=538 Participants	44 Participants n=540 Participants	88 Participants n=1078 Participants
Vasopressor use at baseline (%)	169 Participants n=538 Participants	177 Participants n=540 Participants	346 Participants n=1078 Participants
Vitamin D supplement use in past week (%)	31 Participants n=538 Participants	24 Participants n=540 Participants	55 Participants n=1078 Participants
Multivitamin use in past week (%)	38 Participants n=538 Participants	37 Participants n=540 Participants	75 Participants n=1078 Participants
Estimated average daily vitamin D dose	3269 IU STANDARD_DEVIATION 13118 • n=57 Participants • This variable was analyzed in those participants that received a multivitamin/supplement within 30 days prior to current study hospitalization.	4252 IU STANDARD_DEVIATION 15094 • n=54 Participants • This variable was analyzed in those participants that received a multivitamin/supplement within 30 days prior to current study hospitalization.	3747.1 IU STANDARD_DEVIATION 14057.7 • n=111 Participants • This variable was analyzed in those participants that received a multivitamin/supplement within 30 days prior to current study hospitalization.
25-hydroxyvitamin D	11.2 ng/mL STANDARD_DEVIATION 4.8 • n=538 Participants	11 ng/mL STANDARD_DEVIATION 4.7 • n=540 Participants	11.1 ng/mL STANDARD_DEVIATION 4.7 • n=1078 Participants
Total serum calcium (mg/dL)	8.3 mg/dL STANDARD_DEVIATION 0.9 • n=528 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available serum calcium levels.	8.3 mg/dL STANDARD_DEVIATION 0.9 • n=526 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available serum calcium levels.	8.3 mg/dL STANDARD_DEVIATION 0.9 • n=1054 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available serum calcium levels.
Ionized calcium (mg/dL)	4.3 mg/dL STANDARD_DEVIATION 1.4 • n=210 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available ionized calcium levels.	4.3 mg/dL STANDARD_DEVIATION 0.9 • n=212 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available ionized calcium levels.	4.3 mg/dL STANDARD_DEVIATION 1.2 • n=422 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available ionized calcium levels.
Creatinine (mg/dL)	2.2 mg/dL STANDARD_DEVIATION 2.3 • n=535 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available serum creatinine levels.	2.0 mg/dL STANDARD_DEVIATION 2.0 • n=539 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available serum creatinine levels.	2.1 mg/dL STANDARD_DEVIATION 2.2 • n=1074 Participants • This outcome was analyzed in participants in the confirmed deficient cohort with available serum creatinine levels.
Estimated Glomerular Filtration Rate (eGFR)	60 ml/min/1.73m2 STANDARD_DEVIATION 39.3 • n=535 Participants • This variable was analyzed in participants in the confirmed deficient cohort and calculated based on available data.	60.9 ml/min/1.73m2 STANDARD_DEVIATION 36.9 • n=539 Participants • This variable was analyzed in participants in the confirmed deficient cohort and calculated based on available data.	60.5 ml/min/1.73m2 STANDARD_DEVIATION 38.1 • n=1074 Participants • This variable was analyzed in participants in the confirmed deficient cohort and calculated based on available data.

PRIMARY outcome

Timeframe: 90 days after randomization

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

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=531 Participants 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	Placebo n=528 Participants 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, All-location Mortality to Day 90	125 Participants	109 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=531 Participants 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	Placebo n=528 Participants 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, All Location Mortality to Day 28	92 participants	69 participants

SECONDARY outcome

Timeframe: Up to 90 days after randomization

Population: Participant count is based on available data.

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

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=538 Participants 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	Placebo n=539 Participants 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
Hospital Mortality to Day 90	92 participants	72 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=528 Participants 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	Placebo n=526 Participants 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
Alive and Home (Prior Level of Care) at Day 90	348 Participants	345 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=406 Participants 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	Placebo n=418 Participants 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
Hospital Length of Stay to Day 90	9.1 days Standard Deviation 9.2	10.4 days Standard Deviation 11.0

SECONDARY outcome

Timeframe: 90 days after randomization

Population: 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.

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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=402 Participants 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	Placebo n=416 Participants 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
Healthcare Facility Length of Stay to Day 90	6.0 days Standard Deviation 17.5	8.1 days Standard Deviation 20.4

SECONDARY outcome

Timeframe: 28 days after randomization

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

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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=523 Participants 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	Placebo n=534 Participants 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
Ventilator-free Days (VFDs) to Day 28	21.3 days Standard Deviation 11.3	22.1 days Standard Deviation 10.5

SECONDARY outcome

Timeframe: baseline to study day 90

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

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).

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=340 Participants 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	Placebo n=346 Participants 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
Health-related Quality of Life by EuroQol (EQ-5D-5L)	0.0 score on a scale Standard Deviation 0.2	-0.0 score on a scale Standard Deviation 0.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=411 Participants 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	Placebo n=412 Participants 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
Number of Participants Who Developed (New) ARDS to Day 7	20 Participants	17 Participants

SECONDARY outcome

Timeframe: 7 days after randomization

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

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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=20 Participants 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	Placebo n=17 Participants 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
Severity of Acute Respiratory Distress Syndrome (ARDS) Mild	6 Participants	4 Participants
Severity of Acute Respiratory Distress Syndrome (ARDS) Moderate	9 Participants	12 Participants
Severity of Acute Respiratory Distress Syndrome (ARDS) Severe	5 Participants	1 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=484 Participants 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	Placebo n=495 Participants 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
Worst Acute Kidney Injury (AKI) None	285 Participants	297 Participants
Worst Acute Kidney Injury (AKI) Mild	70 Participants	77 Participants
Worst Acute Kidney Injury (AKI) Moderate	48 Participants	52 Participants
Worst Acute Kidney Injury (AKI) Severe	81 Participants	69 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=489 Participants 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	Placebo n=500 Participants 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
New Renal Replacement Therapy (RRT)	20 Participants	18 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=518 Participants 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	Placebo n=528 Participants 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
Highest Creatinine Levels	2.2 mg/dL Standard Error 0.1	2.1 mg/dL Standard Error 0.1

SECONDARY outcome

Timeframe: Up to 7 days after randomization

Population: need info on this

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

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=357 Participants 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	Placebo n=360 Participants 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
New Vasopressor Use to Day 7	43 Participants	42 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=523 Participants 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	Placebo n=534 Participants 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
Highest Cardiovascular SOFA (Sepsis Related Organ Failure Assessment) Score	1.4 score on a scale Standard Error 0.1	1.3 score on a scale Standard Error 0.1

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=145 Participants 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	Placebo n=133 Participants 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
25OHD Levels at Day 3	46.9 ng/mL Standard Deviation 23.2	11.4 ng/mL Standard Deviation 5.6

SECONDARY outcome

Timeframe: 14 days after randomization

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

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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=507 Participants 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	Placebo n=513 Participants 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
Highest Total Calcium to Day 14	8.9 mg/dL Standard Deviation 0.8	8.8 mg/dL Standard Deviation 0.7

SECONDARY outcome

Timeframe: up to 14 days after randomization

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

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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=153 Participants 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	Placebo n=177 Participants 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
Highest Ionized Calcium to Day 14	4.7 mg/dL Standard Deviation 0.8	4.6 mg/dL Standard Deviation 0.8

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=513 Participants 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	Placebo n=523 Participants 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
Hypercalcemia to Day 14	14 Participants	11 Participants

SECONDARY outcome

Timeframe: 90 days after randomization

Population: Subjects discharged from the hospital prior to study day 90.

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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=507 Participants 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	Placebo n=507 Participants 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
Kidney Stones to Day 90	0 Participants	3 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=507 Participants 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	Placebo n=507 Participants 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
Fall-related Fractures to Day 90	4 Participants	2 Participants

SECONDARY outcome

Timeframe: 90 days post randomization

Population: need to give info

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.

Outcome measures

Outcome measures
Measure	High Dose Vitamin D Formulation n=507 Participants 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	Placebo n=507 Participants 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
Falls to Day 90	36 Participants	27 Participants

Adverse Events

High Dose Vitamin D Formulation

Serious events: 14 serious events

Other events: 10 other events

Deaths: 159 deaths

Placebo

Serious events: 18 serious events

Other events: 6 other events

Deaths: 137 deaths

Serious adverse events

Other adverse events

Additional Information

Nancy Ringwood, CCC Project Manager

Massachusetts General Hospital

Phone: 617-724-9836

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Measure	High Dose Vitamin D Formulation n=690 participants at risk 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	Placebo n=668 participants at risk 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
Blood and lymphatic system disorders Anemia Microcytic	0.14% 1/690 • Number of events 2 • 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.	0.00% 0/668 • 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.
Respiratory, thoracic and mediastinal disorders Aspiration Pneumonia	0.14% 1/690 • Number of events 1 • 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.	0.00% 0/668 • 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.
Cardiac disorders Atrial Fibrillation	0.00% 0/690 • 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.	0.15% 1/668 • Number of events 1 • 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.
Cardiac disorders Ventricular Tachycardia	0.00% 0/690 • 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.	0.15% 1/668 • Number of events 1 • 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.
General disorders Confidentiality	0.14% 1/690 • Number of events 1 • 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.	0.15% 1/668 • Number of events 1 • 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.
General disorders Fatigue	0.00% 0/690 • 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.	0.15% 1/668 • Number of events 1 • 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.
Renal and urinary disorders Discoloration Urine	0.00% 0/690 • 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.	0.15% 1/668 • Number of events 1 • 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.
Renal and urinary disorders Renal Failure Acute	0.14% 1/690 • Number of events 1 • 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.	0.00% 0/668 • 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.
Gastrointestinal disorders Emesis	0.00% 0/690 • 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.	0.15% 1/668 • Number of events 1 • 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.
Gastrointestinal disorders Nausea	0.29% 2/690 • Number of events 2 • 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.	0.15% 1/668 • Number of events 1 • 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.
Gastrointestinal disorders Nausea and Vomitting	0.14% 1/690 • Number of events 1 • 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.	0.00% 0/668 • 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.
Endocrine disorders Hypercalcemia	0.29% 2/690 • Number of events 2 • 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.	0.00% 0/668 • 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.
Investigations Platelets Decreased	0.14% 1/690 • Number of events 1 • 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.	0.00% 0/668 • 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.
Infections and infestations Pneumonia	0.14% 1/690 • Number of events 1 • 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.	0.00% 0/668 • 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.
Skin and subcutaneous tissue disorders Rash	0.14% 1/690 • Number of events 1 • 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.	0.00% 0/668 • 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.