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Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03096314
Recruitment Status : Completed
First Posted : March 30, 2017
Results First Posted : January 27, 2020
Last Update Posted : January 27, 2020
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Boyd Taylor Thompson, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE February 21, 2017
First Posted Date  ICMJE March 30, 2017
Results First Submitted Date  ICMJE December 10, 2019
Results First Posted Date  ICMJE January 27, 2020
Last Update Posted Date January 27, 2020
Actual Study Start Date  ICMJE April 27, 2017
Actual Primary Completion Date December 11, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
All-cause, All-location Mortality to Day 90 [ Time Frame: 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).
Original Primary Outcome Measures  ICMJE
 (submitted: March 23, 2017)
All-cause, All-location Mortality to Day 90 [ Time Frame: 90 days after randomization ]
Vital status of the patient at day 90 will be 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).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
  • All-cause, All Location Mortality to Day 28 [ Time Frame: 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.
  • Hospital Mortality to Day 90 [ Time Frame: Up to 90 days after randomization ]
    Analysis of the number of participants who died prior to hospital discharge up to study day 90.
  • Alive and Home (Prior Level of Care) at Day 90 [ Time Frame: 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.
  • Hospital Length of Stay to Day 90 [ Time Frame: 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.
  • Healthcare Facility Length of Stay to Day 90 [ Time Frame: 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.
  • Ventilator-free Days (VFDs) to Day 28 [ Time Frame: 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.
  • Health-related Quality of Life by EuroQol (EQ-5D-5L) [ Time Frame: 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).
  • Number of Participants Who Developed (New) ARDS to Day 7 [ Time Frame: 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.
  • Severity of Acute Respiratory Distress Syndrome (ARDS) [ Time Frame: 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.
  • Worst Acute Kidney Injury (AKI) [ Time Frame: 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.
  • New Renal Replacement Therapy (RRT) [ Time Frame: 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.
  • Highest Creatinine Levels [ Time Frame: 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.
  • New Vasopressor Use to Day 7 [ Time Frame: 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.
  • Highest Cardiovascular SOFA (Sepsis Related Organ Failure Assessment) Score [ Time Frame: 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
  • 25OHD Levels at Day 3 [ Time Frame: 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).
  • Highest Total Calcium to Day 14 [ Time Frame: 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.
  • Highest Ionized Calcium to Day 14 [ Time Frame: 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.
  • Hypercalcemia to Day 14 [ Time Frame: 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.
  • Kidney Stones to Day 90 [ Time Frame: 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.
  • Fall-related Fractures to Day 90 [ Time Frame: 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.
  • Falls to Day 90 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 23, 2017)
  • Hospital length of stay among survivors to day 90 [ Time Frame: 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.
  • Healthcare facility length of stay among survivors to day 90 [ Time Frame: 90 days after randomization ]
    Number of days spent in another hospital or healthcare facility following study hospital discharge until discharge home to day 90. This is calculated only for patients that survived through day 90 and were discharged to another healthcare facility after initial hospitalization at the study hospital.
  • Number of participants home alive at day 90. [ Time Frame: 90 days after randomization ]
    Home is defined as pre-hospitalization level of care.
  • Mean ventilator-free days to day 28 [ Time Frame: 28 days after randomization ]
    Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days.
  • Time to mortality to day 90 [ Time Frame: 90 days after randomization ]
    Calculated using best available data on vital status and date of death.
  • Number of participants who develop ARDS by day 7 [ Time Frame: 7 days after randomization ]
    Presence of ARDS determined using the PaO2/FiO2 ratio or SpO2/FiO2 ratio and chest x-ray confirmation.
  • 25OHD levels to day 3 [ Time Frame: 3 days after randomization ]
    Baseline levels will be measured using LC/MS/MS methods for all randomized participants. Day 3 levels will only be measured for the first 300 randomized patients.
  • IL-6 levels to day 3 [ Time Frame: 3 days after randomization ]
    Baseline and Day 3 levels will be measured in only the first 300 randomized patients.
  • Calcium levels to day 14 [ Time Frame: 14 days after randomization ]
    Clinically available serum or ionized Ca levels are obtained through day 14 for all randomized patients. Baseline and Day 3 levels will be measured in the first 300 randomized patients as part of routine clinical care or as a research procedure if not available.
  • Kidney Stones to Day 90 [ Time Frame: 90 days after randomization ]
    Incident of kidney stones will be 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.
  • Fall-related Fractures to Day 90 [ Time Frame: 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.
  • Severity of ARDS to day 7 [ Time Frame: 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.
  • Mean change in acute hypoxemic respiratory failure severity through day 7. [ Time Frame: 7 days after randomization ]
    Hypoxemic respiratory failure will be assessed by lowest daily PaO2/FiO2 or SpO2/FiO2 ratio.
  • Mean change in acute kidney injury severity through day 7 [ Time Frame: 7 days after randomization ]
    kidney injury will be assessed by highest daily creatinine and new dialyisis.
  • Mean change in acute cardiovascular failure severity through day 7. [ Time Frame: 7 days after randomization ]
    Cardiovascular failure will be assessed by highest daily rate of vasopressors.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vitamin D to Improve Outcomes by Leveraging Early Treatment
Official Title  ICMJE Vitamin D to Improve Outcomes by Leveraging Early Treatment
Brief Summary Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Patients screened as vitamin D deficient (<20 ng/mL) were randomized. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality.
Detailed Description

Primary Objective: To assess the efficacy and safety of early administration of vitamin D3 (cholecalciferol) in reducing mortality and morbidity for vitamin D deficient patients at high risk for Acute Respiratory Distress Syndrome (ARDS) and mortality.

Primary Hypothesis: Early administration of vitamin D3 (cholecalciferol) will improve all-cause, all-location mortality to day 90 in vitamin D deficient patients at high risk for ARDS and mortality.

Methods: Patients were recruited from the emergency departments (EDs), hospital wards, operating rooms, intensive care unites (ICUs) and other acute care areas of the participating PETAL Network Clinical Centers. Screening included a test for Vitamin D (25OHD) levels using either the hospital's clinical laboratory or an FDA-approved point-of-care device (FastPack IP, Qualigen Inc). Patients screened as vitamin D deficient (<20 ng/mL) were randomized. Half of the randomized patients received an early administration of high-dose vitamin D3 and the other half received a placebo. Both active and placebo products were given orally or via naso/orogastric tube.

Rational: Vitamin D has pleiotropic roles in regulating immune function and maintaining epithelial surface integrity. Strong preclinical data support the protective role of vitamin D in regulating pulmonary inflammation and disruption of the alveolar-capillary membrane that are fundamental to ARDS pathogenesis.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Respiratory Distress Syndrome
  • Vitamin D Deficiency
  • Critical Illness
Intervention  ICMJE
  • Drug: Vitamin D3
    540,000 IU vitamin D3 delivered as a single, liquid enteral dose administered either orally or via naso/orogastric tube
    Other Name: cholecalciferol
  • Drug: Placebo
    A single, liquid enteral dose identical in appearance and consistency to cholecalciferol administered either orally or via naso/orogastric tube.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Vitamin D3
  • 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.
    Intervention: Drug: Placebo
Publications * National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Ginde AA, Brower RG, Caterino JM, Finck L, Banner-Goodspeed VM, Grissom CK, Hayden D, Hough CL, Hyzy RC, Khan A, Levitt JE, Park PK, Ringwood N, Rivers EP, Self WH, Shapiro NI, Thompson BT, Yealy DM, Talmor D. Early High-Dose Vitamin D(3) for Critically Ill, Vitamin D-Deficient Patients. N Engl J Med. 2019 Dec 26;381(26):2529-2540. doi: 10.1056/NEJMoa1911124. Epub 2019 Dec 11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 24, 2020)
1358
Original Estimated Enrollment  ICMJE
 (submitted: March 23, 2017)
3000
Actual Study Completion Date  ICMJE December 11, 2018
Actual Primary Completion Date December 11, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03096314
Other Study ID Numbers  ICMJE PETAL02VIOLET
1U01HL123009 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be collected electronically and stored at the Clinical Coordinating Center at Massachusetts General Hospital (MGH). A de-identified database of all data will be available for use 3 years after the primary publication. Data can be accessed at that point via the National Heart Lung Blood Institute (NHLBI) BioLINCC data and biospecimen repository.
Responsible Party Boyd Taylor Thompson, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Boyd Taylor Thompson, MD Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP