Adrenal Cortical Function and Vitamin A Deficiency in Sepsis

Adrenal Cortical Function and Vitamin A Deficiency in Sepsis, Severe Sepsis and Septic Shock: Prospective Randomized, Double Blind Placebo Controlled Clinical Trials

The study involves the participant to receive a 250 mcg Cortrosyn (ACTH) Stimulation Test to test the ability of the body to make Cortisol. If the body is not able to make large amount of Cortisol (Delta Cortisol < 13 mg/dl) from the stimulation test, then the participant will be given additional cortisol like medicine called Solumedrol or matching placebo.

If the body is able to make large amounts of Cortisol (> 13 mg/dl), then the participant will receive daily shots of Vitamin A for 7 days or matching placebo.

If the participant does not respond to the stimulation test, and meets the criteria for Cortisol deficiency (all 3 cortisol concentrations < 20 mg/dl), then he/she will screen failed for the study and will be offered hydrocortisone as part of routine care by the treating physician.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Solumedrol 20mg; Other: Placebo; Drug: Vitamin A 100,000 IU

Detailed Description

The eligible patients will have Sepsis, Severe Sepsis or Septic Shock. The potential subject will be approached for the study participation and if agreed will sign an Inform Consent. Patients unable to give consent, a waiver of consent was used. The participant to receive a Cortrosyn Stimulation Test to test the ability of the body to make Cortisol. The Cortrosyn Stimulation Test involves an injection into the vein in the arm. Two tablespoons of blood is collected just before the injection of Cortrosyn (250 mcg of ACTH) and again 30 minutes and 60 minutes after the injection. The results of test are available about 3 hours after the start of the test. Depending on the results of the test, subject will be either screen failed or will either receive Solumedrol or Vitamin A. Also at the beginning of the study, the amount of water in the subject's body will be measured using a machine called Impedance Monitor.

If the body is not able to make large amount of Cortisol from the stimulation test (delta increase in cortisol < 13 mg/dl), then the participant will be given additional cortisol like medicine called Solumedrol (20 mg) by injection into a vein every 8 hours for 7 days or matching placebo.

If the body is able to make large amounts of Cortisol (delta cortisol response > 13 mg/dL), then the participant will receive daily shots of Vitamin A or matching placebo for 7 days by injection into arm muscle. After 1, 3, 8 and 14 days of the study, a blood draw will performed to measure the amount of Vitamin A in the blood. Also, the urine will be collected to measure Vitamin A levels on day 1, 2, 3, 8 and 14. The ACTH stimulation test was repeated on Day 8.

The total amount of blood drawn for the study will be about 18 tablespoons.

If the participant does not respond to the stimulation test, and meets the criteria for Cortisol deficiency (All cortisol concentrations < 20 mg/dl) , then he/she will screen failed for the study and will be offered 100 mg of hydrocortisone treatment (100 mg IV every 8 hours) as part of routine care by the treating physician.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Sepsis
• Severe Sepsis
• Septic Shock

Exclusion Criteria:

• On glucocorticoids
• On Vitamin A
• On any active medical research study
• Failed ACTH stimulation test (All serum cortisol concentrations < 20 mg/dl)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Solumedrol 20mg; Solumedrol injection will be given in the vein every 8 hrs. for 7 days.	Drug: Solumedrol 20mg; Dosed Intravenous every 8 hrs.; Other Names: Methylprednisolone Sodium Succinate; Other: Placebo; Placebo dosed intravenous every 8 hrs. or Intramuscular once daily.
ACTIVE_COMPARATOR: Vitamin A 100,000 IU; Vitamin A injection will be given in the arm muscle for 7 days.	Other: Placebo; Placebo dosed intravenous every 8 hrs. or Intramuscular once daily.; Drug: Vitamin A 100,000 IU; Dosed Intramuscular once daily; Other Names: Retinol
PLACEBO_COMPARATOR: Placebo; Placebo will be given in the vein every 8 hrs. for 7 days or given in the arm muscle for 7 days.	Drug: Solumedrol 20mg; Dosed Intravenous every 8 hrs.; Other Names: Methylprednisolone Sodium Succinate; Drug: Vitamin A 100,000 IU; Dosed Intramuscular once daily; Other Names: Retinol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28 days mortality	Document the 28 days of mortality	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
14 day mortality	Mortality at day 14	14 days
Number of Secondary Infections	Document the number of secondary infections	Day 28
Days in ICU	Document the days in ICU	Day 14 and Day 28
Number of days on ventilator	Document the days on ventilator	28 days
Number of days of ventilator adjusted for mortality	Document the number of days of ventilator adjusted for mortality	28 days
Number of days on pressor agents	Document the number of days on pressor agents	28 days
Number of Days on PPI or H2 blockers	Document the days on PPI or H2 blockers	28 days
Number of days of pressor agents corrected for mortality	Document the number of days of pressor agents corrected for mortality	28 days
Change in serum albumin concentration	Document the serum albumin concentration	28 days
New Onset Renal Failure	Document any new onset renal failure	Day 14
Serum vitamin A concentration	Document levels of serum vitamin A concentration	baseline and day 14
Urine Vitamin A Concentration	Document levels of vitamin A concentration in urine	baseline and day 14
APACHE Score	Calculate and document APACHE score	Day 1 and Day 14
ACTH Stimulation Test	Efficiency of ACTH stimulation test	Day 1 and Day 8

Collaborators and Investigators

• Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Publications and helpful links

General Publications

• Cherukuri L, Gewirtz G, Osea K, Tayek JA. Vitamin A treatment for severe sepsis in humans; a prospective randomized double blind placebo-controlled clinical trial. Clin Nutr ESPEN. 2019 Feb;29:49-51. doi: 10.1016/j.clnesp.2018.10.011. Epub 2018 Nov 17.

Study record dates

Study Major Dates

• Study Start: February 1, 1993
• Primary Completion (ACTUAL): January 1, 2000
• Study Completion (ACTUAL): January 1, 2000

Study Registration Dates

• First Submitted: April 7, 2017
• First Submitted That Met QC Criteria: May 11, 2017
• First Posted (ACTUAL): May 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 16, 2017
• Last Update Submitted That Met QC Criteria: May 15, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Eye Diseases; Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Vision Disorders; Sepsis; Toxemia; Night Blindness; Vitamin A Deficiency; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Micronutrients; Vitamins; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Vitamin A
• Other Study ID Numbers: 7476-01; 7680-01 (OTHER: Los Angeles Biomedical Research Institute); 7681-01 (OTHER: Los Angeles Biomedical Research Institute); 7682-01 (OTHER: Los Angeles Biomedical Research Institute)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Only the de-identified study data will be shared with the other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No