Vitamin D in Ventilated ICU Patients

Study Overview
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Brief Summary
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The increasing rate of hospital-acquired infection and antibiotic resistance are major causes of prolonged ICU stay and death in hospitalized patients. The enormous impact of ICU-related infection demands the need for cost-effective therapies that can be rapidly implemented to improve patient immune response to control infection. Unfortunately, little high-quality comparative effectiveness research has been performed on micronutrient treatment regimens as methods to decrease hospital-acquired infection in critically ill patients. Critically ill medical and surgical patients have an extremely high prevalence of vitamin D insufficiency. We will perform a rigorous, double-blind, randomized, controlled, pilot clinical trial in ventilator-dependent ICU patients to test the clinical/metabolic safety and efficacy of two doses of oral high-dose vitamin D3 therapy versus standard therapy (no supplemental vitamin D). The primary endpoint is to test whether high-dose regimens [either 50,000 or 100,000 international units (IU) of enteral vitamin D3 given daily for 5 consecutive days (total dose = 250,000 or 500,000 IU, respectively) increase plasma 25(OH)D concentrations into a desirable range (> 30 ng/mL).

Detailed Description
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We will evaluate, over 12 weeks, the safety and efficacy of two high-dose vitamin D3 regimens in severely ill ICU patients. Vitamin D or placebo ( depending on study arm) will be given sequentially in divided doses for 5 days We will explore whether these vitamin D regimens are capable of increasing the production of key antimicrobial peptides LL-37 and hBD-2 ( substances produced by our bodies to fight infections), in both the blood and in lung. We will determine whether a higher vitamin D level in the blood is associated with a decrease in hospital infection rates and other complications in high-risk ICU patients with respiratory failure. Study Design: Enrollment goal is 36 patients. Once consent is obtained subjects will be randomly assigned to one of three study groups. Each group consists of 12 patients with enteral access ; a placebo arm, an arm where subjects receive 50,000 IU of Vitamin D for 5 days, and a third arm where subjects receive 100,000 IU of Vitamin D for 5 days. Methods: Baseline blood samples (25-hydroxyvitamin D, vitamin D binding protein, ionized calcium, LL-37,and hBD-2) will be taken on study day 7,14,21,28,84 days. On study day 1 and 8, LL-37, hBD-2, cathelicidin from BAL fluid will also be analyzed. Patients will be given either placebo, Vitamin D3 50,000 IU x 5 days (total 250,000 IU) or Vitamin D3 100,000 IU x 5 days (total 500,000 IU) with an intention to treat model. Baseline data on the patients including demographic, laboratory, documented infections, severity illness score (APACHE II) and organ dysfunction score (SOFA) will be collected. ELISA assay on the serum and BAL will be performed.

Official Title
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High-Dose Vitamin D and Antimicrobial Peptide Expression in Lung Failure

Conditions
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Respiratory Failure

Intervention / Treatment
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* Drug: Enteral Vitamin D3 50,000 IU
* Drug: Enteral Vitamin D3 100,000IU
* Other: Inactive substance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Receiving care in an intensive care unit (ICU) Age greater than 18 years Expected to require mechanical ventilation for at least 72 hours after entry Expected to survive and remain in the ICU for at least 96 hours after study entry To enable delivery of study drug, the subject has enteral access in place and is deemed able to tolerate enteral drug administration Exclusion Criteria: Inability to obtain or declined informed consent from the subject and/or legally authorized representative Pregnancy Ongoing shock Current hypercalcemia (albumin-corrected serum calcium > 10.8 mg/dL or ionized calcium > 5.2 mg/dL) History of therapy with high-dose vitamin D to treat vitamin D deficiency within previous 6 months History of disorders associated with hypercalcemia; history of cancer with history of hypercalcemia within the past 1 year, hyperparathyroidism, sarcoidosis, nephrolithiasis] Chronic renal dysfunction requiring chronic dialysis Known history of cirrhosis History of AIDS The patient has received any investigational drug within 60 days prior to study entry.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enteral vitamin D3 50,000 IU<br>An arm where subjects receive 50,000 IU of Vitamin D for 5 days. | Drug: Enteral Vitamin D3 50,000 IU<br>* Enteral Vitamin D3 50,000IU x 5 days (total dose 250,000IU)<br>|
| Experimental: Enteral Vitamin D3 100,000 IU<br>Arm where subjects receive 100,000 IU of Vitamin D for 5 days | Drug: Enteral Vitamin D3 100,000IU<br>* Enteral Vitamin D3 100,000IU over 5 days (total 500,000IU)<br>|
| Placebo Comparator: Inactive Substance<br>Arm where patients receive inactive substance for 5 days. | Other: Inactive substance<br>* Inactive substance given enterally for 5 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Baseline | The number of participants with a plasma 25(OH)D concentration in the desirable range (defined as greater than 30 ng/mL) at the baseline measurement. | Baseline | 
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 7 | The number of participants with a plasma 25(OH)D concentration in the desirable range (defined as greater than 30 ng/mL) at the Day 7 measurement. | Day 7 | 
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 14 | The number of participants with a plasma 25(OH)D concentration in the desirable range (defined as greater than 30 ng/mL) at the Day 14 measurement. | Day 14 | 
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 21 | The number of participants with a plasma 25(OH)D concentration in the desirable range (defined as greater than 30 ng/mL) at the Day 21 measurement. | Day 21 | 
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 28 | The number of participants with a plasma 25(OH)D concentration in the desirable range (defined as greater than 30 ng/mL) at the Day 28 measurement. | Day 28 | 
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 84 | The number of participants with a plasma 25(OH)D concentration in the desirable range (defined as greater than 30 ng/mL) at the Day 84 measurement. | Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma LL-37 Levels | Plasma LL-37 was measured at Baseline, Day 7 and Day 14. | Baseline, Day 7, Day 14 | 
| Duration of Time on Ventilator | The number of days spent on mechanical ventilation was collected for all study participants and the average number of days for each study arm is reported. | 12 weeks | 
| Duration of Time in Intensive Care Unit (ICU) | The number of days spent in the intensive care unit (ICU) was collected for each participant and the average number of days for each study arm is reported. | 12 weeks | 
| Duration of Time in Hospital | The number of days that each participant spent in the hospital was collected and the average number of days for each study arm is reported. | 12 weeks | 
| Change in Sequential Organ Failure Assessment (SOFA) Score | Change in Sequential Organ Failure Assessment (SOFA) score between Baseline and Day 7. The Sequential Organ Failure Assessment (SOFA) score is a mortality prediction score that is based on the degree of dysfunction of 6 organ systems (respiratory, nervous, cardiovascular, liver, coagulation, and kidneys). A score ranges from 0-24. 0 (normal) to 4 (high degree of dysfunction) is given for each organ system, with a higher score indicating greater severity. A score of 0-6 is associated with a mortality rate of less than 10% while a score between 16 and 24 is associated with a greater than 90% mortality rate. Scores decreasing between the Baseline and Day 7 measurements are represented as negative values for the change in SOFA score. | Baseline, Day 7 | 
| Number of Hospital Acquired Infections | The number of study participants who had a hospital acquired infection. | 12 weeks | 
| Number of Hospital Mortality Cases | The number of study participants who died while in the hospital was collected. | 12 weeks | 
| Day 84 Mortality | The number of participants who died prior to the end of the study (Day 84) was collected. | Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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critical care, nosocomial infection, antiAntimicrobial peptide expression, LL-37, hBD-2, cathelicidin, microbial peptide