Vitamin D in Ventilated ICU Patients (R21 HL-110044)

• ClinicalTrials.gov Identifier: NCT01372995
• Recruitment Status: Completed
• First Posted: June 14, 2011
• Results First Posted: January 9, 2017
• Last Update Posted: January 9, 2017
• Sponsor: Emory University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Greg S. Martin, M.D., M.Sc., Emory University

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Respiratory Failure	Drug: Enteral Vitamin D3 50,000 IU; Drug: Enteral Vitamin D3 100,000IU; Other: Inactive substance	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: High-Dose Vitamin D and Antimicrobial Peptide Expression in Lung Failure
• Study Start Date: July 2011
• Actual Primary Completion Date: April 2014
• Actual Study Completion Date: April 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Baseline [ Time Frame: 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.
2. Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 7 [ Time Frame: 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.
3. Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 14 [ Time Frame: 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.
4. Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 21 [ Time Frame: 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.
5. Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 28 [ Time Frame: 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.
6. Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 84 [ Time Frame: 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.

Secondary Outcome Measures :

1. Change in Plasma LL-37 Levels [ Time Frame: Baseline, Day 7, Day 14 ]
   Plasma LL-37 was measured at Baseline, Day 7 and Day 14.
2. Duration of Time on Ventilator [ Time Frame: 12 weeks ]
   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.
3. Duration of Time in Intensive Care Unit (ICU) [ Time Frame: 12 weeks ]
   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.
4. Duration of Time in Hospital [ Time Frame: 12 weeks ]
   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.
5. Change in Sequential Organ Failure Assessment (SOFA) Score [ Time Frame: Baseline, Day 7 ]
   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.
6. Number of Hospital Acquired Infections [ Time Frame: 12 weeks ]
   The number of study participants who had a hospital acquired infection.
7. Number of Hospital Mortality Cases [ Time Frame: 12 weeks ]
   The number of study participants who died while in the hospital was collected.
8. Day 84 Mortality [ Time Frame: Day 84 ]
   The number of participants who died prior to the end of the study (Day 84) was collected.

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, Georgia

Emory University Hospital Midtown

Atlanta, Georgia, United States, 30308

Emory University Hospital

Atlanta, Georgia, United States, 30322

Sponsors and Collaborators

Emory University

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Greg Martin, MD, MSc; Emory University
• Principal Investigator: Thomas Ziegler, MD; Emory University

More Information

Publications:

Tejada Artigas A, Bello Dronda S, Chacon Valles E, Munoz Marco J, Villuendas Uson MC, Figueras P, Suarez FJ, Hernandez A. Risk factors for nosocomial pneumonia in critically ill trauma patients. Crit Care Med. 2001 Feb;29(2):304-9. doi: 10.1097/00003246-200102000-00015.

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. doi: 10.1086/517280.

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.

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.

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. doi: 10.1016/j.jcf.2007.03.003. Epub 2007 Apr 27.

De Smet K, Contreras R. Human antimicrobial peptides: defensins, cathelicidins and histatins. Biotechnol Lett. 2005 Sep;27(18):1337-47. doi: 10.1007/s10529-005-0936-5.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Greg S. Martin, M.D., M.Sc., Associate Professor, Emory University
• ClinicalTrials.gov Identifier: NCT01372995
• Other Study ID Numbers: IRB00049610
• First Posted: June 14, 2011
• Results First Posted: January 9, 2017
• Last Update Posted: January 9, 2017
• Last Verified: November 2016

Keywords provided by Greg S. Martin, M.D., M.Sc., Emory University:

critical care; nosocomial infection; antiAntimicrobial peptide expression; LL-37; hBD-2; cathelicidin; microbial peptide

Additional relevant MeSH terms:

Respiratory Insufficiency; Respiration Disorders; Respiratory Tract Diseases; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents