Clinical trial NCT01372995: Vitamin D in Ventilated ICU Patients
Official title: High-Dose Vitamin D and Antimicrobial Peptide Expression in Lung Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Respiratory Failure
Keywords: critical care
nosocomial infection
antiAntimicrobial peptide expression
LL-37
hBD-2
cathelicidin
microbial peptide
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2011-06-14
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 1. 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
2. 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.
3. 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Baseline
timeFrame: Baseline
measure: Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 7
timeFrame: Day 7
measure: Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 14
timeFrame: Day 14
measure: Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 21
timeFrame: Day 21
measure: Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 28
timeFrame: Day 28
measure: Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 84
timeFrame: Day 84
Secondary outcomes:
measure: Change in Plasma LL-37 Levels
timeFrame: Baseline, Day 7, Day 14
measure: Duration of Time on Ventilator
timeFrame: 12 weeks
measure: Duration of Time in Intensive Care Unit (ICU)
timeFrame: 12 weeks
measure: Duration of Time in Hospital
timeFrame: 12 weeks
measure: Change in Sequential Organ Failure Assessment (SOFA) Score
timeFrame: Baseline, Day 7
measure: Number of Hospital Acquired Infections
timeFrame: 12 weeks
measure: Number of Hospital Mortality Cases
timeFrame: 12 weeks
measure: Day 84 Mortality
timeFrame: Day 84
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
Study officials:
affiliation: Emory University
name: Greg Martin, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Thomas Ziegler, MD
role: PRINCIPAL_INVESTIGATOR
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citation: Barlow PG, Beaumont PE, Cosseau C, Mackellar A, Wilkinson TS, Hancock RE, Haslett C, Govan JR, Simpson AJ, Davidson DJ. The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium. Am J Respir Cell Mol Biol. 2010 Dec;43(6):692-702. doi: 10.1165/rcmb.2009-0250OC. Epub 2010 Jan 22.
citation: Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, Tangpricha V. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009 Apr 23;7:28. doi: 10.1186/1479-5876-7-28.
citation: Han JE, Jones JL, Tangpricha V, Brown MA, Brown LAS, Hao L, Hebbar G, Lee MJ, Liu S, Ziegler TR, Martin GS. High Dose Vitamin D Administration in Ventilated Intensive Care Unit Patients: A Pilot Double Blind Randomized Controlled Trial. J Clin Transl Endocrinol. 2016 Jun;4:59-65. doi: 10.1016/j.jcte.2016.04.004. Epub 2016 May 5.