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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

Brief Summary:
Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Patients screened as vitamin D deficient (<20 ng/mL) were randomized. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality.

Condition or disease Intervention/treatment Phase
Acute Respiratory Distress Syndrome Vitamin D Deficiency Critical Illness Drug: Vitamin D3 Drug: Placebo Phase 3

Detailed Description:

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

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

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

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

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


Arm Intervention/treatment
Active Comparator: High dose vitamin D formulation
A single dose of 540,000 IU vitamin D3 will be administered within 2 hours of randomization time.
Drug: Vitamin D3
540,000 IU vitamin D3 delivered as a single, liquid enteral dose administered either orally or via naso/orogastric tube
Other Name: cholecalciferol

Placebo Comparator: Placebo
A single, liquid enteral placebo dose administered either orally or via naso/orogastric tube will be administered within 2 hours of randomization time.
Drug: Placebo
A single, liquid enteral dose identical in appearance and consistency to cholecalciferol administered either orally or via naso/orogastric tube.




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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).

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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


  15. 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).

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03096314


Locations
Show Show 47 study locations
Sponsors and Collaborators
Massachusetts General Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Boyd Taylor Thompson, MD Massachusetts General Hospital
  Study Documents (Full-Text)

Documents provided by Boyd Taylor Thompson, Massachusetts General Hospital:
Study Protocol  [PDF] September 12, 2017
Statistical Analysis Plan  [PDF] June 25, 2018


Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Boyd Taylor Thompson, Co-Prinicipal Investigator PETAL CCC, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03096314    
Other Study ID Numbers: PETAL02VIOLET
1U01HL123009 ( U.S. NIH Grant/Contract )
First Posted: March 30, 2017    Key Record Dates
Results First Posted: January 27, 2020
Last Update Posted: January 27, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Boyd Taylor Thompson, Massachusetts General Hospital:
ARDS
Vitamin D
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Vitamin D Deficiency
Critical Illness
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Disease Attributes
Pathologic Processes
Lung Injury
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders
Vitamin D
Ergocalciferols
Cholecalciferol
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents