Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in Sepsis.

NCT03422159 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 17-004
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 2

Brief Summary

This study has been created to compare the addition of intravenous (IV) vitamin C, thiamine, and hydrocortisone to the usual standard of care of sepsis and septic shock. Sepsis is a possibly life-threatening condition in which a patient may have organ dysfunction due to an infection. Septic shock is defined as low blood pressure and organ dysfunction that do not improve after administering IV fluids. Standard of care for sepsis and septic shock include early administration of IV antibiotics, IV fluids, and vasopressors if need be to provide oxygen to vital organs. A large amount of experimental data has shown that vitamin C and corticosteroids decrease the release of inflammatory substances which may lead to organ failure seen in sepsis. Vitamin C and corticosteroids also improve blood flow to vital organs and increase the body's ability to respond well to vasopressor medications used in septic shock. Low blood levels of both thiamine and vitamin C are common in sepsis. The study will be placebo controlled, meaning one group will receive vitamin C, thiamine, and hydrocortisone, and the other will receive an inactive substance ("placebo"). The goal of the study is to compare the effects of receiving vitamin C, thiamine, and hydrocortisone (along with the standard sepsis care) versus placebo and standard sepsis care.

Conditions

Sepsis, Severe; Septic Shock

Outcome Measures

Primary Outcomes (2)

• Time to Vasopressor Independence (Hours)

  Defined as the time from starting the active treatment/placebo to discontinuation of all pressors.

  From start of vasopressor medication to final discontinuation of vasopressor medication, up to 7 days.

• Change in Sequential Organ Failure Assessment (SOFA) Score

  Defined as the day 4 post-randomization SOFA score minus the initial SOFA score. The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. The score is calculated on admission and every 24 hours until discharge using the worst parameters measured during the prior 24 hours SOFA score ranges from 0 (no organ dysfunction) to 24 (highest possible score / organ dysfunction).

  4 days post-randomization

Secondary Outcomes (6)

• Procalcitonin (PCT) Clearance

  4 days post-randomization

• ICU Mortality

  From admission to hospital until final discharge from the ICU, up to 28 days.

• ICU Length of Stay

  From admission to the ICU until final discharge from the ICU, up to an average of 7 days.

• Ventilator Free Days

  28 Days post-randomization

• Hospital Length of Stay

  From admission to the hospital until final discharge, up to 28 days.

Study Arms (2)

Treatment Arm

EXPERIMENTAL

Based on published clinical data, vitamin C pharmacokinetic modeling, the package insert as well as the preliminary study by Marik et al, Vitamin C will be administered as an intravenous dose of 6gm per day divided in 4 equal doses. This dosage is reported to be devoid of any complications or side effects. Hydrocortisone will be dosed according to the consensus guidelines of the American College of Critical Care Medicine. Thiamine will be administered according to current recommendations in a dose of 200mg q 12 hourly. This will be continued for 4 days, or less if discharged from the ICU prior.

Drug: Ascorbic Acid; Drug: Thiamine; Drug: Hydrocortisone

Placebo Arm

PLACEBO COMPARATOR

Vitamin C placebo will consist of an identical bag of 100mL normal saline (but with no vitamin C) and will be labeled "Vitamin C or Placebo". Placebo will be infused over 30 minutes as per the infusion instructions of the active vitamin and protected from light with a brown bag. Hydrocortisone placebo will be provided as an identical 3mL syringe as 1mL of normal saline.The thiamine placebo will be placed in a 50mL bag of Normal Saline labeled "Thiamine 200mg or Placebo" and run over 30 minutes (100mL/hr) Placebo patients will receive a matching 50mL bag of Normal Saline. All of these will be given for up to 4 days, or less if discharged from the ICU prior.

Drug: Sodium Chloride 0.9%

Interventions

Ascorbic Acid DRUG

Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days).

Also known as: Vitamin C

Treatment Arm

Thiamine DRUG

Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days).

Treatment Arm

Hydrocortisone DRUG

Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days).

Also known as: Solucortef

Treatment Arm

Sodium Chloride 0.9% DRUG

Placebo "Ascorbic Acid" 100mL IV piggyback every 6 hours, Placebo "Thiamine" 50mL IV piggyback every 12 hours, and Placebo "Hydrocortisone" IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days).

Also known as: Placebo

Placebo Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• i. Diagnosis of sepsis or septic shock within 12 hours of admission to the ICU ii. Informed consent as dictated by IRB and local practice. iii. Compliance with the 3 hour sepsis bundle
• ml/kg of intravenous crystalloid fluid (e.g.: sodium chloride 0.9%) for lactic acid \>4 and/or systolic blood pressure \<90mmHg / mean arterial pressure \<65mmHg
• Lactic acid level drawn
• Broad spectrum antibiotics given after obtaining blood cultures

You may not qualify if:

• i. Age \< 18 years ii. Pregnant iii. DNR/DNI with limitations of care on admission iv. Patients with terminal end stage disease (i.e. stage IV cancer, end stage heart failure) that are unlikely to survive to hospital discharge v. Patients with a primary admitting diagnosis of an acute cerebral vascular event, acute coronary syndrome, active gastrointestinal bleeding, burn or trauma \[64-66\] vi. Requirement for immediate surgery \[64-66\] vii. Patients with HIV and a CD4 \< 50 mm2 \[64-66\] viii. Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency.\[39\] ix. Patients with sepsis/septic shock transferred from another hospital x. Patients with features of sepsis/septic shock \> 24 hours after admission

Sponsors & Collaborators

• Community Medical Center, Toms River, NJ: lead

Study Sites (2)

Monmouth Medical Center, Southern Campus

Lakewood, New Jersey, 08701, United States

Location

Community Medical Center

Toms River, New Jersey, 08755, United States

Location

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• Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10. doi: 10.1007/BF01709751. No abstract available.

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• Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest. 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049. Epub 2020 Mar 17.

  PMID: 32194058 DERIVED

MeSH Terms

Conditions

Sepsis; Shock, Septic

Interventions

Ascorbic Acid; Thiamine; Hydrocortisone; Sodium Chloride

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

The relative weakness was its small, homogenous (primarily caucasian) cohort size, limiting the ability to detect differences in hospital mortality and length of stay.

Results Point of Contact

• Title: Jose Iglesias, DO
• Organization: Community Medical Center Department of Critical Care, Department of Nephrology

jiglesias23@gmail.com

732-557-8070

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Patients will be randomized to receive either vitamin C/hydrocortisone/thiamine or triple placebo using a random number table provided to the dispensing pharmacists. Each patient will be allocated a unique subject ID which will be linked to the randomization sequence. Only the dispensing pharmacists will have a record of the subject ID and randomization sequence.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a double-blind placebo controlled study. Only the dispensing pharmacist will be aware of the treatment allocation. Patients will be randomized to receive either vitamin C/hydrocortisone/thiamine or triple placebo using a random number table provided to the dispensing pharmacists. Each patient will be allocated a unique subject ID which will be linked to the randomization sequence. Only the dispensing pharmacists will have a record of the subject ID and randomization sequence.

Study Record Dates

• First Submitted: January 25, 2018
• First Posted: February 5, 2018
• Study Start: February 5, 2018
• Primary Completion: June 5, 2019
• Study Completion: August 27, 2019
• Last Updated: September 21, 2021
• Results First Posted: September 21, 2021

Record last verified: 2020-11

Locations

US (2)