Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis (A... | NCT03389555

NCT03389555

Status Module

Sponsor/Collaborators Module

Name	Class
Open Philanthropy	OTHER

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Vitamin C, Vitamin B1, Corticosteroids	Experimental	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days	Drug: vitamin C, vitamin B1, hydrocortisone
Placebo	Placebo Comparator	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components	Drug: Normal saline

Interventions

Name	Type	Description	Arm Group Labels	Other Names
vitamin C, vitamin B1, hydrocortisone	Drug	Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9% NACL(normal saline) and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours	Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours. The SOFA score ranges from a minimum of 0 to a maximum of 24, with higher scores meaning worse outcomes.	Enrollment to 72-hours

Secondary Outcomes

Measure	Description	Time Frame
Renal Failure	Development of renal failure as defined by a Kidney Disease Improving Global Outcomes [KDIGO] stage 3 or higher. There are 3 stages in the KDIGO scale with stage 3 being the worst (corresponds to renal failure). Stage 1- serum creatinine 1.5 to 1.9 times baseline OR an increase in serum creatinine ≥ 0.3 mg/dL OR urine output < 0.5ml/kg/hour for 6-12 hours. Stage 2- serum creatinine 2.0-2.9 times baseline OR urine output <0.5mg/kg/hour for ≥ 12 hours Stage 3- serum creatinine 3.0 times baseline (or serum creatinine of more than or equal to 4.0 mg/dl with an acute increase of at least 0.5 mg/dl) (OR) Urine output less than 0.3 ml/kg/hour for 24 hours or anuria for 12 hours or new renal replacement therapy

Other Outcomes

Measure	Description	Time Frame
Ventilator Free Days	Days not receiving invasive mechanical ventilation	Ventilator free days over the first 7-days after enrollment
Shock Free Days	Days not receiving vasopressor

Eligibility Module

Contacts/Locations Module

Name	Affiliation	Role
Michael W Donnino, MD	Beth Israel Deaconess Medical Center	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic - Arizona		Phoenix	Arizona	85054	United States
Brigham and Women's Hospital

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
27940189	Background	Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036. Epub 2016 Dec 6.
28207287	Background	Moskowitz A, Andersen LW, Cocchi MN, Karlsson M, Patel PV, Donnino MW. Thiamine as a Renal Protective Agent in Septic Shock. A Secondary Analysis of a Randomized, Double-Blind, Placebo-controlled Trial. Ann Am Thorac Soc. 2017 May;14(5):737-741. doi: 10.1513/AnnalsATS.201608-656BC.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Dec 13, 2018	Oct 15, 2019

Derived Section

Miscellaneous Info Module

Submission Tracking

Condition Browse Module

Intervention Browse Module

Masking Info

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
BG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Enrollment SOFA score

- ParticipantsOG000101
- ParticipantsOG00199

Title	Measurements
	OG0009.1± 3.5

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The primary outcome was analyzed using a linear mixed-effects model where the correlation of within-patient repeated SOFA score measures was accounted for via the use of an unstructured variance-covariance matrix and linear contrasts. Covariates included age, sex, treatment group, time, and the interaction between treatment group and time. Study site was included as a random intercept. The model estimates the mean difference in SOFA score at 72 hours between treatment and control groups.	Mixed Models Analysis		0.12	A priori threshold for significance, p-value < 0.05	Mean Difference (Net)	-0.8			2-Sided	95	-1.7	0.2

Secondary

Renal Failure

Development of renal failure as defined by a Kidney Disease Improving Global Outcomes [KDIGO] stage 3 or higher. There are 3 stages in the KDIGO scale with stage 3 being the worst (corresponds to renal failure).

Stage 1- serum creatinine 1.5 to 1.9 times baseline OR an increase in serum creatinine ≥ 0.3 mg/dL OR urine output < 0.5ml/kg/hour for 6-12 hours. Stage 2- serum creatinine 2.0-2.9 times baseline OR urine output <0.5mg/kg/hour for ≥ 12 hours Stage 3- serum creatinine 3.0 times baseline (or serum creatinine of more than or equal to 4.0 mg/dl with an acute increase of at least 0.5 mg/dl) (OR) Urine output less than 0.3 ml/kg/hour for 24 hours or anuria for 12 hours or new renal replacement therapy

Posted

Count of Participants

Participants

Enrollment until 7-days or discharge from the ICU

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Secondary

30-day Mortality

Mortality rate

Posted

Count of Participants

Participants

Enrollment until 30-days after enrollment

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Units	Counts
Participants	OG000

Other Pre-specified

Ventilator Free Days

Days not receiving invasive mechanical ventilation

Posted

Median

Inter-Quartile Range

Days

Ventilator free days over the first 7-days after enrollment

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Units	Counts
Participants

Other Pre-specified

Shock Free Days

Days not receiving vasopressor

Posted

Median

Inter-Quartile Range

Days

Vasopressor free days over the first 7-days after enrollment

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Units	Counts
Participants

Other Pre-specified

ICU Free Days

Number of days that the patient was not in the ICU. Timeframe listed below.

Posted

Median

Inter-Quartile Range

Days

From enrollment until 28 days after enrollment

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Units	Counts
Participants

Other Pre-specified

Hospital Mortality

Hospital mortality rate

Posted

Count of Participants

Participants

Enrollment until hospital discharge, death, or 30-days. Whichever comes first.

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Units	Counts
Participants

Other Pre-specified

Intensive Care Unit (ICU) Mortality

ICU mortality rate

Posted

Count of Participants

Participants

Enrollment until ICU discharge, death, or 30-days. Whichever comes first.

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Units	Counts
Participants

Other Pre-specified

Number of Participants With Delirium

Describes if patient has delirium as defined by the Confusion Assessment Method (CAM)-ICU. The CAM-ICU method requires that the patient have 3 features to qualify for delirium:

Acute Onset of Changes or Fluctuations in the Course of Mental Status (AND )
Inattention (AND)
Disorganized thinking (OR) Altered Level of Consciousness

We were able to assess CAM-ICU delirium on day 3 in only 83 patients from treatment and 76 patients from the control arm (unable to assess for remaining patients due to death or discharge)

Posted

Count of Participants

Participants

On day 3 (at approximately 72 hours) after the first study drug dose

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Other Pre-specified

Hospital Disposition: Survivors Discharged Home

Home hospital disposition in patients who survive to discharge

Population of patients who survived to hospital discharge. 73 patients in the treatment group and 76 patients in the control group survived to hospital discharge..

Posted

Count of Participants

Participants

Enrollment until hospital discharge, death, or 30-days, whichever comes first.

ID	Title	Description
OG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.
OG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Vitamin C, Vitamin B1, Corticosteroids	The combination of vitamin C, vitamin B1, hydrocortisone : Vitamin C (ascorbic acid) 1.5g every 6 hours x 4-days Vitamin B1 (thiamine) 100mg every 6 hours x 4-days Hydrocortisone 50mg every 6 hours x 4-days vitamin C, vitamin B1, hydrocortisone: Vitamin C (1.5g) plus vitamin B1 (100mg) will be diluted in 100ml 0.9%NACL and administered IV every 6 hours for 4 days or until participant is discharged from the ICU. Hydrocortisone 50mg/ml will be administered via IV push over 1-2 minutes every 6hours for 4 days or until the patient is discharged from the ICU.	35	101	13	101	0	101
EG001	Placebo	Normal Saline Solution (0.9%NaCl) in a volume to match all experimental arm components Normal saline: Normal saline (0.9% NaCl solution) volume to match all components	29	99	12	99	0	99

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Hyperglycemia	Endocrine disorders	Systematic Assessment	EG000101 events12 affected101 at risk EG00199 events7 affected99 at risk
Hypernatremia	Metabolism and nutrition disorders	Systematic Assessment	EG000101 events11 affected101 at risk EG00199 events7 affected99 at risk
New Hospital Acquired Infection	Infections and infestations	Systematic Assessment	EG000101 events13 affected101 at risk EG00199 events12 affected99 at risk

Ongoing or planned corticosteroid use was the most common exclusion criterion, perhaps eliminating a subset of patients more likely to benefit from corticosteroids. Some patients were discharged alive from the ICU within 96 hours of enrollment; thus, many patients did not receive a full 4 days of study drug

Certain Agreements

First MCP Posted Date

ID	Term
D018805	Sepsis
D012772	Shock, Septic

ID	Term
D001205	Ascorbic Acid
D013831	Thiamine
D006854	Hydrocortisone
D000077330	Saline Solution

Ancestor Terms

ID	Term
D013400	Sugar Acids
D000144	Acids, Acyclic
D002264	Carboxylic Acids
D009930	Organic Chemicals
D006880	Hydroxy Acids
D002241	Carbohydrates
D013844	Thiazoles
D013457	Sulfur Compounds
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D011743	Pyrimidines
D011282	Pregnenediones
D011283	Pregnenes
D011278	Pregnanes
D013256	Steroids
D000072473	Fused-Ring Compounds
D011083	Polycyclic Compounds
D015062	11-Hydroxycorticosteroids
D006889	Hydroxycorticosteroids
D000305	Adrenal Cortex Hormones
D006728	Hormones
D006730	Hormones, Hormone Substitutes, and Hormone Antagonists
D015065	17-Hydroxycorticosteroids
D000077324	Crystalloid Solutions
D007552	Isotonic Solutions
D012996	Solutions
D004364	Pharmaceutical Preparations

ParticipantsBG002200

ID	Term
D007239	Infections
D018746	Systemic Inflammatory Response Syndrome
D007249	Inflammation
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms
D012769	Shock