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.
Brief Title
Vitamin D to Improve Outcomes by Leveraging Early Treatment
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Acute Respiratory Distress Syndrome
Vitamin D Deficiency
Critical Illness
Eligibility Criteria
Inclusion Criteria:
1. Age ≥ 18 years
2. Intention to admit to ICU from emergency department, hospital ward, operating room, or outside facility
3. One or more of the following acute risk factors for ARDS and mortality contributing directly to the need for ICU admission:
Pulmonary
1. Pneumonia
2. Aspiration
3. Smoke Inhalation
4. Lung contusion
5. Mechanical ventilation for acute hypoxemic or hypercarbic respiratory failure Extra-Pulmonary
6. Shock
7. Sepsis
8. Pancreatitis
4. Vitamin D deficiency (screening 25OHD level \<20 ng/mL)
Exclusion Criteria:
1. Inability to obtain informed consent
2. Unable to randomize within 12 hours of ICU admission decision
3. Unable to take study medication by mouth or enteral tube
4. Baseline serum calcium \>10.2 mg/dL (2.54 mmol/L) or ionized calcium \>5.2 mg/dL (1.30 mmol/L)
5. Known kidney stone in past year or history of multiple (\>1) prior kidney stone episodes
6. Decision to withhold or withdraw life-sustaining treatment (patients are still eligible if they are committed to full support except cardiopulmonary resuscitation if a cardiac arrest occurs)
7. Expect \<48 hour survival
8. If no other risk factors present, a) mechanical ventilation primarily for airway protection, pain/agitation control, or procedure; or b) elective surgical patients with routine postoperative mechanical ventilation; or c) anticipated mechanical ventilation duration \<24 hours; or d) chronic/home mechanical ventilation for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion).
9. Prisoner
10. Pregnancy
1. Age ≥ 18 years
2. Intention to admit to ICU from emergency department, hospital ward, operating room, or outside facility
3. One or more of the following acute risk factors for ARDS and mortality contributing directly to the need for ICU admission:
Pulmonary
1. Pneumonia
2. Aspiration
3. Smoke Inhalation
4. Lung contusion
5. Mechanical ventilation for acute hypoxemic or hypercarbic respiratory failure Extra-Pulmonary
6. Shock
7. Sepsis
8. Pancreatitis
4. Vitamin D deficiency (screening 25OHD level \<20 ng/mL)
Exclusion Criteria:
1. Inability to obtain informed consent
2. Unable to randomize within 12 hours of ICU admission decision
3. Unable to take study medication by mouth or enteral tube
4. Baseline serum calcium \>10.2 mg/dL (2.54 mmol/L) or ionized calcium \>5.2 mg/dL (1.30 mmol/L)
5. Known kidney stone in past year or history of multiple (\>1) prior kidney stone episodes
6. Decision to withhold or withdraw life-sustaining treatment (patients are still eligible if they are committed to full support except cardiopulmonary resuscitation if a cardiac arrest occurs)
7. Expect \<48 hour survival
8. If no other risk factors present, a) mechanical ventilation primarily for airway protection, pain/agitation control, or procedure; or b) elective surgical patients with routine postoperative mechanical ventilation; or c) anticipated mechanical ventilation duration \<24 hours; or d) chronic/home mechanical ventilation for chronic lung or neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing is not an exclusion).
9. Prisoner
10. Pregnancy
Inclusion Criteria
Inclusion Criteria:
1. Age ≥ 18 years
2. Intention to admit to ICU from emergency department, hospital ward, operating room, or outside facility
3. One or more of the following acute risk factors for ARDS and mortality contributing directly to the need for ICU admission:
Pulmonary
1. Pneumonia
2. Aspiration
3. Smoke Inhalation
4. Lung contusion
5. Mechanical ventilation for acute hypoxemic or hypercarbic respiratory failure Extra-Pulmonary
6. Shock
7. Sepsis
8. Pancreatitis
4. Vitamin D deficiency (screening 25OHD level \<20 ng/mL)
1. Age ≥ 18 years
2. Intention to admit to ICU from emergency department, hospital ward, operating room, or outside facility
3. One or more of the following acute risk factors for ARDS and mortality contributing directly to the need for ICU admission:
Pulmonary
1. Pneumonia
2. Aspiration
3. Smoke Inhalation
4. Lung contusion
5. Mechanical ventilation for acute hypoxemic or hypercarbic respiratory failure Extra-Pulmonary
6. Shock
7. Sepsis
8. Pancreatitis
4. Vitamin D deficiency (screening 25OHD level \<20 ng/mL)
Gender
All
Gender Based
false
Keywords
ARDS
Vitamin D
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT03096314
Org Class
Other
Org Full Name
Massachusetts General Hospital
Org Study Id
PETAL02VIOLET
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Vitamin D to Improve Outcomes by Leveraging Early Treatment
Primary Outcomes
Outcome 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).
Outcome Measure
All-cause, All-location Mortality to Day 90
Outcome Time Frame
90 days after randomization
Secondary Ids
Secondary Id
1U01HL123009
Secondary Outcomes
Outcome 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.
Outcome Time Frame
Up to 28 days after randomization
Outcome Measure
All-cause, All Location Mortality to Day 28
Outcome Description
Analysis of the number of participants who died prior to hospital discharge up to study day 90.
Outcome Time Frame
Up to 90 days after randomization
Outcome Measure
Hospital Mortality to Day 90
Outcome 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.
Outcome Time Frame
90 days post randomization
Outcome Measure
Alive and Home (Prior Level of Care) at Day 90
Outcome 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.
Outcome Time Frame
90 days after randomization
Outcome Measure
Hospital Length of Stay to Day 90
Outcome 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.
Outcome Time Frame
90 days after randomization
Outcome Measure
Healthcare Facility Length of Stay to Day 90
Outcome 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.
Outcome Time Frame
28 days after randomization
Outcome Measure
Ventilator-free Days (VFDs) to Day 28
Outcome 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).
Outcome Time Frame
baseline to study day 90
Outcome Measure
Health-related Quality of Life by EuroQol (EQ-5D-5L)
Outcome 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.
Outcome Time Frame
Up to 7 days after randomization
Outcome Measure
Number of Participants Who Developed (New) ARDS to Day 7
Outcome 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.
Outcome Time Frame
7 days after randomization
Outcome Measure
Severity of Acute Respiratory Distress Syndrome (ARDS)
Outcome 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.
Outcome Time Frame
Up to 7 days after randomization
Outcome Measure
Worst Acute Kidney Injury (AKI)
Outcome 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.
Outcome Time Frame
Up to 7 days after randomization
Outcome Measure
New Renal Replacement Therapy (RRT)
Outcome Description
The highest recorded creatinine values is taken from available levels reported across the 7 study days for each patient.
Outcome Time Frame
Up to 7 days after randomization
Outcome Measure
Highest Creatinine Levels
Outcome Description
The number of subjects in each arm that are started on a vasopressor after randomization up to study day 7.
Outcome Time Frame
Up to 7 days after randomization
Outcome Measure
New Vasopressor Use to Day 7
Outcome 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
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 Time Frame
Up to 7 days after randomization
Outcome Measure
Highest Cardiovascular SOFA (Sepsis Related Organ Failure Assessment) Score
Outcome Description
Baseline levels will be measured using LC/MS/MS methods (all randomized participants) and at day 3 (the first 300 randomized participants only).
Outcome Time Frame
3 days after randomization
Outcome Measure
25OHD Levels at Day 3
Outcome 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.
Outcome Time Frame
14 days after randomization
Outcome Measure
Highest Total Calcium to Day 14
Outcome 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.
Outcome Time Frame
up to 14 days after randomization
Outcome Measure
Highest Ionized Calcium to Day 14
Outcome 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.
Outcome Time Frame
up to 14 days after randomization
Outcome Measure
Hypercalcemia to Day 14
Outcome 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.
Outcome Time Frame
90 days after randomization
Outcome Measure
Kidney Stones to Day 90
Outcome 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.
Outcome Time Frame
90 days after randomization
Outcome Measure
Fall-related Fractures to Day 90
Outcome 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.
Outcome Time Frame
90 days post randomization
Outcome Measure
Falls to Day 90
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Michelle Gong
Investigator Email
mgong@montefiore.org
Investigator Phone
718-920-5464