Vitamin D in Ventilated ICU Patients

Respiratory Failure Clinical Trial

— R21 HL-110044  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01372995
• Other study ID #: IRB00049610
• Status: Completed
• Phase: Phase 2
• First received: June 13, 2011
• Last updated: May 28, 2015
• Start date: July 2011
• Est. completion date: April 2014

Study information

• Verified date: May 2015
• Source: Emory University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Emory University IRBUnited States: National Heart Lung and Blood Institute
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Respiratory Failure
• Respiratory Insufficiency

Intervention

Dietary Supplement:
• Enteral Vitamin D3 50,000 IU
Enteral Vitamin D3 50,000IU x 5 days (total dose 250,000IU)
• Enteral Vitamin D3 100,000IU
Enteral Vitamin D3 100,000IU over 5 days (total 500,000IU)
• Inactive substance
Inactive substance given enterally for 5 days.

Locations

Country	Name	City	State
United States	Emory University Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Emory University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (8)

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. — View Citation

De Smet K, Contreras R. Human antimicrobial peptides: defensins, cathelicidins and histatins. Biotechnol Lett. 2005 Sep;27(18):1337-47. Review. — View 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. — View Citation

Manaseki-Holland S, Qader G, Isaq Masher M, Bruce J, Zulf Mughal M, Chandramohan D, Walraven G. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health. 2010 Oct;15(10):1148-55. doi: 10.1111/j.1365-3156.2010.02578.x. Epub 2010 Aug 17. — View Citation

Tejada Artigas A, Bello Dronda S, Chacón Vallés E, Muñoz Marco J, Villuendas Usón MC, Figueras P, Suarez FJ, Hernández A. Risk factors for nosocomial pneumonia in critically ill trauma patients. Crit Care Med. 2001 Feb;29(2):304-9. — View Citation

Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010 May;91(5):1255-60. doi: 10.3945/ajcn.2009.29094. Epub 2010 Mar 10. — View Citation

Winther B, Greve JM, Gwaltney JM Jr, Innes DJ, Eastham JR, McClelland A, Hendley JO. Surface expression of intercellular adhesion molecule 1 on epithelial cells in the human adenoid. J Infect Dis. 1997 Aug;176(2):523-5. — View Citation

Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G. Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3). J Cyst Fibros. 2007 Nov 30;6(6):403-10. Epub 2007 Apr 27. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To test whether two high-dose Vitamin D3 regimens given daily for 5 consecutive days increase plasma 25(OH)D concentrations into a desirable range (> 30 ng/mL).	To 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);	12 weeks	Yes
Secondary	To determine whether high-dose vitamin D treatment regimens increase antimicrobial peptide expression.	To determine, whether high-dose vitamin D treatment regimens increase LL-37 and hBD-2 concentrations in plasma and BAL fluid (by ELISA), cathelicidin and hBD-2 mRNA expression in PBMCs (by quantitative PCR), LL-37 and hBD-2 protein expression in alveolar macrophages (AM) (by immunohistochemistry), and ex vivo AM phagocytosis function.	12 wks	No
Secondary	To determine if high-dose vitamin D3 regimens decrease the overall incidence of ICU- and hospital-acquired infection	To determine if high-dose vitamin D3 regimens decrease the overall incidence of ICU- and hospital-acquired infection (as a composite sum of all nosocomial infectious complications), reduce the occurrence of organ dysfunction (measured as SOFA score), and decrease the duration of mechanical ventilation and length of ICU and hospital stay.	12 weeks	Yes