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

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ClinicalTrials.gov Identifier: NCT03422159
Recruitment Status : Recruiting
First Posted : February 5, 2018
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
Community Medical Center, Toms River, NJ

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.


Condition or disease Intervention/treatment Phase
Sepsis, Severe Septic Shock Drug: Ascorbic Acid Drug: Thiamine Drug: Hydrocortisone Drug: Sodium Chloride 0.9% Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis.
Actual Study Start Date : February 5, 2018
Estimated Primary Completion Date : February 5, 2019
Estimated Study Completion Date : June 1, 2019


Arm Intervention/treatment
Experimental: Treatment Arm
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
Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
Other Name: Vitamin C

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

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

Placebo Comparator: Placebo Arm
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%
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).
Other Name: Placebo




Primary Outcome Measures :
  1. Hospital Mortality [ Time Frame: Through study completion ]
    In-hospital mortality rate.


Secondary Outcome Measures :
  1. 28-day mortality [ Time Frame: 28 days post-randomization ]
    28 day mortality rate

  2. Time to vasopressor independence (hours) [ Time Frame: Through study completion ]
    Defined as the time from starting the active treatment/placebo to discontinuation of all pressors.

  3. Procalcitonin (PCT) clearance [ Time Frame: 4 days post-randomization ]
    PCT at 96 hours minus initial PCT, divided by the initial PCT multiplied by 100.

  4. Change in Sequential Organ Failure Assessment (SOFA) score [ Time Frame: 4 days post-randomization ]
    Defined as the day 4 post-randomization SOFA score minus the initial SOFA score. SOFA score ranges from 0 (no organ dysfunction) to 24 (highest possible score / organ dysfunction).

  5. ICU Mortality [ Time Frame: Through study completion ]
    ICU mortality rate

  6. ICU Length of Stay [ Time Frame: Through study completion ]
    Time from admitting to ICU to discharge.

  7. ICU-Free Days [ Time Frame: 28 Days post-randomization ]
    Number of days alive and out of the ICU at day 28.

  8. Hospital Length of Stay [ Time Frame: Through study completion ]
    Time from admitting to discharge of hospital stay.



Information from the National Library of Medicine

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

Inclusion Criteria:

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

  • 30ml/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

Exclusion Criteria:

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03422159


Contacts
Contact: Andrew V Vassallo, PharmD 732-557-8000 ext 12929 Andrew.Vassallo@rwjbh.org

Locations
United States, New Jersey
Monmouth Medical Center, Southern Campus Not yet recruiting
Lakewood, New Jersey, United States, 08701
Contact: Yasmine Elbaga, PharmD         
Community Medical Center Recruiting
Toms River, New Jersey, United States, 08755
Contact: Andrew V Vassallo, PharmD    732-557-8000 ext 11992    Andrew.Vassallo@rwjbh.org   
Contact: Jose Iglesias, DO         
Sponsors and Collaborators
Community Medical Center, Toms River, NJ
  Study Documents (Full-Text)

Documents provided by Community Medical Center, Toms River, NJ:
Informed Consent Form  [PDF] June 6, 2017
Study Protocol  [PDF] October 31, 2017


Publications:
The 10 leading causes of death by country income group 2012. WHO factsheets. http://www.who.int/mediacentre/factsheets/fs310/en/index1.html . 2015. World Health Organization. 5-24-2016.
de Grooth HJ, Choo WP, Spoelstra-de Man AM et al. Pharmacokinetics of four high- dose regimens of intravenous Vitamin C in critically ill patients [Abstract]. Intensive Care Med 2016.
Ascorbic Acid Injection. http://www.drugs.com/pro/ascorbic-acid-injection.html . 2015. The Torrance Company. 6-12-2016.
Nooraei N, Fathi M, Edalat L et al. Effect of Vitamin C on serum cortisol after etomidate induction of anesthesia. J Cell Mol Anesth 2016; 1:28-33.
Marik PE. The physiology of volume resuscitation. Curr Anesthesiol Rep 2014; 4:353-59.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.

Responsible Party: Community Medical Center, Toms River, NJ
ClinicalTrials.gov Identifier: NCT03422159     History of Changes
Other Study ID Numbers: 17-004
First Posted: February 5, 2018    Key Record Dates
Last Update Posted: June 14, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Glucocorticoids
Sepsis
Toxemia
Shock, Septic
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock
Vitamins
Ascorbic Acid
Thiamine
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Cortisol succinate
Hydrocortisone
Micronutrients
Growth Substances
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Vitamin B Complex