Respiratory Failure
Conditions
Keywords
critical care, nosocomial infection, antiAntimicrobial peptide expression, LL-37, hBD-2, cathelicidin, microbial peptide
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.
Interventions
DRUGEnteral Vitamin D3 50,000 IU
Enteral Vitamin D3 50,000IU x 5 days (total dose 250,000IU)
DRUGEnteral Vitamin D3 100,000IU
Enteral Vitamin D3 100,000IU over 5 days (total 500,000IU)
OTHERInactive substance
Inactive substance given enterally for 5 days.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Baseline | 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. |
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 7 | 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. |
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 14 | 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. |
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 21 | 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. |
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 28 | 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. |
| Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 84 | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Hospital Mortality Cases | 12 weeks | The number of study participants who died while in the hospital was collected. |
| Change in Plasma LL-37 Levels | Baseline, Day 7, Day 14 | Plasma LL-37 was measured at Baseline, Day 7 and Day 14. |
| Day 84 Mortality | Day 84 | The number of participants who died prior to the end of the study (Day 84) was collected. |
| Duration of Time on Ventilator | 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. |
| Duration of Time in Intensive Care Unit (ICU) | 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. |
| Duration of Time in Hospital | 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. |
| Change in Sequential Organ Failure Assessment (SOFA) Score | 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. |
| Number of Hospital Acquired Infections | 12 weeks | The number of study participants who had a hospital acquired infection. |
Countries
United States
Participant flow
Recruitment details
Study participants were recruited from critical care units at three hospitals in Atlanta, Georgia. 658 patients were assessed for eligibility, of these 562 did not meet inclusion and exclusion criteria. 65 eligible patients declined to participate while 31 gave informed consent and were randomized to one of the three study arms.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to receive an inactive substance administered enterally for 5 days | 10 |
| 250,000 IU of Vitamin D3 Participants randomized to receive 50,000 IU of Vitamin D3 per day for 5 days, for a total dose of 250,000 IU administered enterally | 9 |
| 500,000 IU of Vitamin D3 Participants randomized to receive 100,000 IU per day of Vitamin D3 for 5 days, for a total dose of 500,000 administered enterally | 11 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Spouse withdrew participant from study | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | 250,000 IU of Vitamin D3 | 500,000 IU of Vitamin D3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 4 Participants | 7 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 4 Participants | 14 Participants |
| Asthma Asthma Present | 1 participants | 1 participants | 0 participants | 2 participants |
| Asthma No Asthma | 9 participants | 8 participants | 11 participants | 28 participants |
| Chronic Obstructive Pulmonary Disease (COPD) COPD Present | 2 participants | 1 participants | 4 participants | 7 participants |
| Chronic Obstructive Pulmonary Disease (COPD) No COPD | 8 participants | 8 participants | 7 participants | 23 participants |
| Congestive Heart Failure Congestive Heart Failure Present | 1 participants | 2 participants | 5 participants | 8 participants |
| Congestive Heart Failure No Congestive Heart Failure | 9 participants | 7 participants | 6 participants | 22 participants |
| Coronary Artery Disease Coronary Artery Disease Present | 1 participants | 2 participants | 7 participants | 10 participants |
| Coronary Artery Disease No Coronary Artery Disease | 9 participants | 7 participants | 4 participants | 20 participants |
| Diabetes Diabetes Present | 4 participants | 1 participants | 2 participants | 7 participants |
| Diabetes No Diabetes | 6 participants | 8 participants | 9 participants | 23 participants |
| Gender Female | 4 Participants | 4 Participants | 3 Participants | 11 Participants |
| Gender Male | 6 Participants | 5 Participants | 8 Participants | 19 Participants |
| Race/Ethnicity, Customized African American | 4 participants | 7 participants | 3 participants | 14 participants |
| Race/Ethnicity, Customized American Indian/Alaskan | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 5 participants | 2 participants | 8 participants | 15 participants |
| Region of Enrollment United States | 10 participants | 9 participants | 11 participants | 30 participants |
| Vitamin D at baseline Deficient (<20 ng/mL) | 5 participants | 3 participants | 5 participants | 13 participants |
| Vitamin D at baseline Insufficient (20-30 ng/mL) | 3 participants | 4 participants | 5 participants | 12 participants |
| Vitamin D at baseline Sufficient (>30 ng/mL) | 2 participants | 2 participants | 1 participants | 5 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 9 | 0 / 11 |
| serious Total, serious adverse events | 1 / 10 | 1 / 9 | 2 / 11 |
Outcome results
Primary
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.
Time frame: Baseline
Population: Blood samples were obtained every 7 days while participants remained hospitalized. Follow up discontinued once the participant was discharged from the hospital. At the baseline time point, 10 patients were randomized to the placebo arm, 9 to the arm receiving 250,000 IU of Vitamin D3, and 11 to the arm receiving 500,000 of Vitamin D3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Baseline | 2 participants |
| 250,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Baseline | 2 participants |
| 500,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Baseline | 1 participants |
Primary
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.
Time frame: Day 14
Population: Blood samples were obtained every 7 days while participants remained hospitalized. Follow up discontinued once the participant was discharged from the hospital. The number of participants analyzed for each time point decreased over the course of the study as participants were discharged from the hospital.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 14 | 2 participants |
| 250,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 14 | 5 participants |
| 500,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 14 | 5 participants |
Primary
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.
Time frame: Day 21
Population: Blood samples were obtained every 7 days while participants remained hospitalized. Follow up discontinued once the participant was discharged from the hospital. The number of participants analyzed at each time point decreased over the course of the study as participants were discharged from the hospital.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 21 | 1 participants |
| 250,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 21 | 3 participants |
| 500,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 21 | 2 participants |
Primary
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.
Time frame: Day 28
Population: Blood samples were obtained every 7 days while participants remained hospitalized. Follow up discontinued once the participant was discharged from the hospital. The number of participants analyzed at each time point decreased over the course of the study as participants were discharged from the hospital.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 28 | 0 participants |
| 250,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 28 | 2 participants |
| 500,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 28 | 1 participants |
Primary
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.
Time frame: Day 7
Population: Blood samples were obtained every 7 days while participants remained hospitalized. Follow up discontinued once the participant was discharged from the hospital. The number of participants analyzed at each time point decreased over the course of the study as participants were discharged from the hospital.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 7 | 2 participants |
| 250,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 7 | 4 participants |
| 500,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 7 | 9 participants |
Primary
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.
Time frame: Day 84
Population: Blood samples were obtained every 7 days while participants remained hospitalized. Follow up discontinued once the participant was discharged from the hospital. The number of participants analyzed at each time point decreased over the course of the study as participants were discharged from the hospital.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 84 | 1 participants |
| 250,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 84 | 0 participants |
| 500,000 IU of Vitamin D3 | Number of Participants With Plasma 25(OH)D Concentration >30ng/mL at Day 84 | 0 participants |
Secondary
Change in Plasma LL-37 Levels
Plasma LL-37 was measured at Baseline, Day 7 and Day 14.
Time frame: Baseline, Day 7, Day 14
Population: For the Day 14 analysis there were 8 participants in the Placebo arm, 6 participants in the 250,000 of Vitamin D arm, and 5 participants in the 500,000 of Vitamin D arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Change in Plasma LL-37 Levels | Day 7 Compared to Baseline | -3.8 ng/mL |
| Placebo | Change in Plasma LL-37 Levels | Day 14 Compared to Baseline | 1.1 ng/mL |
| 250,000 IU of Vitamin D3 | Change in Plasma LL-37 Levels | Day 7 Compared to Baseline | 6.0 ng/mL |
| 250,000 IU of Vitamin D3 | Change in Plasma LL-37 Levels | Day 14 Compared to Baseline | -12.3 ng/mL |
| 500,000 IU of Vitamin D3 | Change in Plasma LL-37 Levels | Day 7 Compared to Baseline | -13.5 ng/mL |
| 500,000 IU of Vitamin D3 | Change in Plasma LL-37 Levels | Day 14 Compared to Baseline | -6.0 ng/mL |
Secondary
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.
Time frame: Baseline, Day 7
Population: SOFA score obtained daily while in the ICU. The portion of the study participants included in the analysis of the change in SOFA score between Baseline and Day 7 is limited to participants having values for both time points..
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Sequential Organ Failure Assessment (SOFA) Score | -2 units on a scale | Standard Deviation 3 |
| 250,000 IU of Vitamin D3 | Change in Sequential Organ Failure Assessment (SOFA) Score | -3 units on a scale | Standard Deviation 3 |
| 500,000 IU of Vitamin D3 | Change in Sequential Organ Failure Assessment (SOFA) Score | -2 units on a scale | Standard Deviation 3 |
Secondary
Day 84 Mortality
The number of participants who died prior to the end of the study (Day 84) was collected.
Time frame: Day 84
Population: The number of participants in the hospital mortality analysis for the arm receiving 500,000 IU of Vitamin D3 was 10, rather than 11, as one participant withdrew.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Day 84 Mortality | 2 participants |
| 250,000 IU of Vitamin D3 | Day 84 Mortality | 1 participants |
| 500,000 IU of Vitamin D3 | Day 84 Mortality | 4 participants |
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Duration of Time in Hospital | 36 days | Standard Deviation 19 |
| 250,000 IU of Vitamin D3 | Duration of Time in Hospital | 25 days | Standard Deviation 14 |
| 500,000 IU of Vitamin D3 | Duration of Time in Hospital | 18 days | Standard Deviation 11 |
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Duration of Time in Intensive Care Unit (ICU) | 23 days | Standard Deviation 14 |
| 250,000 IU of Vitamin D3 | Duration of Time in Intensive Care Unit (ICU) | 17 days | Standard Deviation 14 |
| 500,000 IU of Vitamin D3 | Duration of Time in Intensive Care Unit (ICU) | 15 days | Standard Deviation 10 |
Secondary
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Duration of Time on Ventilator | 20 days | Standard Deviation 15 |
| 250,000 IU of Vitamin D3 | Duration of Time on Ventilator | 12 days | Standard Deviation 10 |
| 500,000 IU of Vitamin D3 | Duration of Time on Ventilator | 14 days | Standard Deviation 10 |
Secondary
Number of Hospital Acquired Infections
The number of study participants who had a hospital acquired infection.
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Hospital Acquired Infections | 3 participants |
| 250,000 IU of Vitamin D3 | Number of Hospital Acquired Infections | 3 participants |
| 500,000 IU of Vitamin D3 | Number of Hospital Acquired Infections | 2 participants |
Secondary
Number of Hospital Mortality Cases
The number of study participants who died while in the hospital was collected.
Time frame: 12 weeks
Population: The number of participants in the hospital mortality analysis for the arm receiving 500,000 IU of Vitamin D3 was 10, rather than 11.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Hospital Mortality Cases | 1 participants |
| 250,000 IU of Vitamin D3 | Number of Hospital Mortality Cases | 0 participants |
| 500,000 IU of Vitamin D3 | Number of Hospital Mortality Cases | 1 participants |