Clinical trial NCT02868827: Cholecalciferol Supplementation in Critically Ill Patients With Severe Vitamin D Deficiency.
Official title: Cholecalciferol Supplementation in Critically Ill Patients With Severe Vitamin D Deficiency in Intensive Care Unit- A Randomized Controlled Trial.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Vitamin D Deficiency
Critical Illness
Keywords: cholecalciferol and critical illness
Mortality and cholecalciferol supplementation
Lead sponsor: King Abdullah Medical City
Sponsor class: OTHER_GOV
First posted: 2016-08-16
Enrollment: 127
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of the research study is to determine whether a single high dose of vitamin D is helpful in reducing critical illness related complications in intensive care patients who are having sever vitamin D deficiency.

Vitamin D deficiency is quite common in critically ill patients ranging from 81.5% to 99%. A number of scientific studies have documented a strong correlation between low levels of vit.D and increased rate of adverse outcomes including infection, acute kidney injury and mortality in ICU patients. A recent randomized controlled trial (RCT) has demonstrated a 50% reduction in hospital mortality in severe vit.D deficient patients following a single high dose of cholecalciferol (Vitamin D3). However, the role of Vit.D supplementation to boost up host immune system and eventually reduction of mortality has yet to be determined by large randomized controlled trials in humans. Hence the study aims to run a randomized controlled trial (RCT) in order to study the role of Vitamin D in critically ill patients.

Detailed description: DETAILED DESCRIPTION

Introduction: Vitamin D is a fat soluble vitamin and it affects multiple systems of our body. It not only plays a key role in musculoskeletal system but also works on our immune and cardiovascular systems. Because of its wide range of anti-inflammatory and metabolic properties, vitamin D, recently, has gained an immense importance among the intensivists.

Most of the critically ill patients have vitamin D deficiency and are at high risk of complications ranging from systemic inflammatory response syndrome (SIRS), sepsis, septic shock, multi-organ dysfunction, multi-organ failure and finally death. Immune system dysregulation has been thought to play a pivotal role in the development of sepsis. Onset and progression of sepsis are dependent upon a fine balance between pro-inflammatory and anti-inflammatory mediators of the immune system. Massive and uncontrolled release of pro-inflammatory cytokines leads to widespread tissue damage and multi-organ failure. It has been found that the cells of the immune system (both innate and acquired) express receptors for vitamin D. Low levels of it renders the immune system regulatory cells dysfunctional and in turn, increases the risk of infections and other adverse outcomes. It has been estimated that even with optimal treatment anywhere from 16% to more than 80% of patients with sepsis don't survive.

To improve the survival of critically ill patients, several research studies have been focused on the identification of various biomarkers and their correlation with disease severity. Timely supplementation of cholecalciferol has been demonstrated as one of the mortality reduction interventions. In recent studies, vitamin D has been identified as an important regulator of our immune system and its deficiency is quite common in ICU patients ranging from 81.5% to 99%.

A number of scientific studies have documented a strong correlation between low levels of vit.D and increased rate of adverse outcomes including infection with multi drug resistant organisms, acute kidney injury, decreased left ventricular ejection fraction and mortality in ICU patients. It has been found that the emergence of acinetobacter baumannii infections in significantly more common in vit D deficient critically ill patients and vit D deficiency is an independent risk factor for the development of Acinetobacter baumannii infections in intensive care unit.

A recent RCT has demonstrated 50% reduction in hospital mortality in patients with severe vit.D deficiency following a single high dose of cholecalciferol (Vitamin D3). However, the role of Vit.D supplementation to boost up host immune system and eventually reduction of mortality has yet to be determined by large randomized controlled trials.

In patients with severe vitamin D deficiency, gastrointestinal absorption of vit.D, after enteral supplementation could be variable depending upon the patient's gastrointestinal functions, critical illness and the activity of hepatic cytochrome P 450 system. In order to restore optimal vit.D level in critically ill patients (possibly within first 48 hours), a single high dose of it has been suggested on admission to ICU. As in critically ill patients, it is highly unlikely to restore Vitamin D within a reasonable period of time by supplementing 400-4000 international units/day (recommended daily allowance). Moreover, a single large dose of vit.D through the enteral route is highly unlikely to cause vit.D toxicity. The acutely toxic level of vit.D is considered to be more than 150 ng/ml. Furthermore, this high loading dose of cholecalciferol has been justified based on the safety findings of previous studies.

In addition, during a pilot study followed by a large randomized controlled trial conducted by Karen A et al, no serious adverse events were noted with a single high dose (540,000 I.U) of cholecalciferol. The highest 25-hydroxyvitamin D level measured was 107 ng/ml which is far below the currently suggested toxic level of vit.D (that is more than 150 ng/ml). Moreover, one patient in vitamin D3 group was found to have a total serum calcium level of 12 mg/dl and an ionized serum calcium level of 6 mg/dl but that patient had primary hyperparathyroidism (although normocalcemic at study inclusion). However, the incidence of falls and fracture was similar in vitamin D3 and placebo groups for a follow-up period of six months. So a single high dose of cholecalciferol is less likely to increase the incidence of hypocalcemia, hypercalciuria, falls and fractures which have been found to be increased with annual high doses of vitamin D3.

Hence the investigator intends to use a single high dose of cholecalciferol in order to restore it deficiency quickly, hopefully within 1 to 2 days in order to give maximum benefits to our critically ill patients right from the start of their illness.

The aim of our RCT is to study the role of Vit.D supplementation in critically ill patients. By boosting up the already struggling immune system of critically ill patients, the investigator assumes a significant reduction in mortality and other adverse outcomes.

Hypothesis: A single high dose of cholecalciferol supplementation improves survival in critically ill patients with severe vitamin D deficiency.

Null Hypothesis: A single high dose of Cholecalciferol supplementation in critically ill patients will not reduce the mortality and adverse outcomes.

Recruitment and randomization: Patients or their surrogates will be contacted on admission to ICU and study information will be provided to them by the research staff members. Consented patients will be randomized. Randomization list will be prepared by King Abdullah Medical City (KAMC) research center. The list will be used to prepare sealed envelopes each containing the assigned treatment. These envelopes will be stored in the pharmacy and opened up by the research pharmacist who will prepare medication/placebo for the randomized patients.

Blinding: Blinding will be done by research pharmacist in KAMC pharmacy. Fresh milk will be used as a placebo. The study medication (a white-colored, powdered form of cellulose based vit.D) will be dissolved in fresh milk so that both interventional drug and placebo will have the same color, odor, consistency, taste, and amount as that of interventional medication.

For all vit. D deficient patients, supplement 50,000 IU of cholecalciferol per week through the enteral route as a part of routine ICU treatment plan. As our recruited patients will be having severe vitamin D deficiency (Vit. D level below 12ng/ml) so both interventional and placebo group patients will receive our routine treatment for vit.D deficiency which is 50,000 IU of cholecalciferol through enteral route per week.

Intervention: Patients randomized to vitamin D group will receive 400,000 IU of cholecalciferol dissolved in 45 ml of fresh milk through orogastric tube/nasogastric tube/Oral within 1st 24 hours of ICU admission. This high dose is in addition to our routine treatment for vitamin D deficiency.

Post-recruitment retention strategies: the study will follow our patients for 30 days or as long as they stay in ICU after supplementation of a single high dose of vitamin D or placebo. As the investigators are working with critically ill patients, expecting at least a few weeks of hospital stay. However, the patient having early and quick recovery will be discharged home and will be followed up by one of the assigned research team members who will be contacting them by phone and inquire about any complications related to the research study.

Method: the investigator will complete a randomized controlled trial by supplementing cholecalciferol 400,000 IU versus placebo within 24 hours of ICU admission that would be added to our routine treatment for vit.D deficiency. Safety of this high dose of vit D has been validated in previous studies. This trial will employ block randomization and intention to treat protocol. This single-center study would be completed over a period of 2 complete years here in KAMC Intensive care Unit.

Laboratory Measurements: Blood samples will be obtained at baseline (day 0) and days 1, 3, 7, and 28 to assess serum parathyroid hormone, total and bioavailable 25-hydroxyvitamin D levels, phosphate, procalcitonin, leukocytic count, hemoglobin, creatinine, bilirubin, beta natriuretic peptide (BNP), blood glucose and albumin levels. In addition, the investigator will also measure urinary calcium and urinary creatinine levels

Data Collection: Patients will be followed up (1 month) closely for the development of study-drug related complications if any, for example, hypercalcemia, hypercalciuria, fractures, etc. Data elements to be collected will include, but not limited to:

1. - Date and time of admission to hospital
2. - Mode of admission (Emergency Room or in-patients)
3. - Date and time of ICU admission
4. - 25 - hydroxyl vitamin D level on admission to ICU.
5. - Sequential Organ Failure Assessment (SOFA) score
6. - Acute Physiology And Chronic Health Index (APACHI) Score 7-Patient's co-morbidities (Diabetes, Hypertension, Chronic kidney disease, Chronic obstructive pulmonary disease, Ischemic Heart Disease, Coronary Artery Bypass Grafting, Cerebrovascular accident, Arrhythmias, Anemias, smoking, obesity, cancer)

8 - Mode of Oxygen delivery to the patient 9 - Previous positive cultures and antibiotic therapy within the last 3 months 10 - Empirical antibiotic therapy on admission to hospital and ICU 11 - Baseline clinically relevant investigation, for example, Echo, Electrocardiography, Ultrasound Doppler for Deep venous thrombosis, CT brain/chest/abdomen, 12 - Endo/bronchoscopic findings if any 13 - Vasopressors and ionotropic support duration 14 - Central venous catheter, arterial line, pigtail, chest tube (site, date and time of insertion) 15 - Evidence of acute or acute on chronic kidney injury on admission to ICU. 16 - Surgeries - previous and recent surgeries and any post-op complications 17 - Previous immunosuppressive therapies for example chemo/radio/glucocorticoid therapy.

Sample size calculation: A recent RCT demonstrated almost 50% reduction in hospital mortality (46.1% in placebo versus 28.6% in Vit D group) by supplementing 540,000 IU of Vit D3 to critically ill patients having severe vitamin D deficiency (25-hydroxyvitamin D level ≤ 12 ng/ml). With an alpha = 5% (two tailed test), power = 95%, baseline mortality control group 30% and test group mortality 15%, the sample size required would be 195 patients per group. To account for losses to follow up of around 10%, the study aims to recruit 215 patients in each group. So the total number of patients required for both the groups would be 430 in 2 full years.

Statistical Analysis: the investigator will use an intention to treat approach to avoid the effects of crossover and dropout. Standard statistical analysis will include normally or near normally distributed variables reported as means and non-normally distributed variables as medians. Means will be compared by using student's t-test and medians by using Mann-Whitney U test. Differences in proportions among categorical data will be assessed using Fisher's exact test. A p-value of less than 0.05 will be considered to represent statistical significance for all comparisons.

Eligibility criteria: Inclusion Criteria:

1. 18 years or older.
2. Both male and female
3. Within 24 hours from admission.
4. Having 25 -Hydroxyvitamin D level of 12 ng/ml or lower.

Exclusion Criteria

1. Pregnant or lactating females.
2. Do not resuscitate (DNR) status or comfort measures only
3. No consent
4. Severely impaired gastrointestinal functions (e.g, paralytic ileus, continuous nasogastric tube drainage, strict nil per oral- no medication, malabsorption syndrome, chronic diarrhea etc)
5. History of renal stones within past year
6. Past history of hypercalcemia, tuberculosis or sarcoidosis.
7. Baseline serum total calcium ≥10.6 mg/dl or ionized serum calcium ≥ 5.4 mg/dl.

Primary outcomes:
measure: Reduction in hospital mortality
timeFrame: 28 days
Secondary outcomes:
measure: Emergence of Multidrug resistant (MDR) organisms
timeFrame: 28 days
measure: Vasopressor requirement
timeFrame: 28 days
measure: Ventilator free days
timeFrame: 28 days
measure: ICU length of stay
timeFrame: 28 days
measure: Hospital length of stay
timeFrame: 28 days
measure: New onset of Acute kindney injury
timeFrame: 28 days
measure: Development of acute CVA
timeFrame: 28 days
measure: Upper and lower GI bleeding
timeFrame: 28 days
measure: Acute co-morbidities
timeFrame: 28 days
Other outcomes:
Locations:
city: Mecca
country: Saudi Arabia
facility: King Abdullah Medical City, Holy Capital
state: Makkah Western
Study officials:
affiliation: King Abdullah Medical City Makkah
name: Asiah S Rugaan, MD, MRCP
role: STUDY_CHAIR
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