Metabolic Disturbance, Sepsis, Septic Shock
Conditions
Keywords
Sepsis, Metabolic Resuscitation
Brief summary
In this study, we aim to determine whether the combination of Ascorbic Acid (Vitamin C), Thiamine (Vitamin B1), and Corticosteroids improves the trajectory of organ failure and reduces mortality in patients with sepsis and septic shock as compared to placebo.
Detailed description
Sepsis and Septic Shock are common and highly morbid clinical conditions without any specific therapy aside from antibiotics. A recent quasi-experimental study (Marik et. al., PMID 27940189) demonstrated a remarkable benefit when the combination of Ascorbic Acid (Vitamin C), Corticosteroids, and Thiamine (Vitamin B1) were given to patients with sepsis. In particular, patients who received this combination of medications required a shorter amount of time on vasopressors, suffered less organ failure, and had improved mortality. Vitamin C has long been suggested for treatment of patients with severe infection as it exerts significant anti-oxidant effects and reduces endothelial permeability. Corticosteroids, a mainstay of therapy for refractory shock in sepsis, have also been shown to enhance the beneficial cellular effects of vitamin C. Finally, thiamine has been shown to be an effective mitochondrial resuscitator in sepsis, especially for the \ 30% of septic shock patients who present with thiamine deficiency (Donnino et. al, PMID 26771781). In this study, we aim to reproduce the findings of Marik et. al. using a more rigorous study design (i.e. a blinded, randomized clinical trial) and focus on the important clinical outcomes of organ failure and death.
Interventions
DRUGvitamin C, vitamin B1, hydrocortisone
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.
DRUGNormal saline
Normal saline (0.9% NaCl solution) volume to match all components
Sponsors
Open Philanthropy
Beth Israel Deaconess Medical Center
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
1. Adult patient (age ≥ 18 years) 2. Suspected (cultures drawn and antibiotic given) or confirmed (via culture results) infection 3. Receiving vasopressor (norepinephrine, phenylephrine, epinephrine, dopamine, angiotensin II or vasopressin)
Exclusion criteria
1. Member of a protected population (pregnant, prisoner) 2. Known kidney stones within the past 1 year (except for asymptomatic, incidentally noted stones on imaging) 3. End stage renal disease (ESRD) requiring dialysis 4. Known Glucose-6-Phosphate Dehydrogenase deficiency 5. Known Hemachromatosis 6. Comfort Measures Only status 7. Anticipated death within 24-hours despite maximal therapy (as determined by the enrolling physician) 8. Receiving supplemental thiamine in a dose greater than that contained in a multivitamin 9. Clinical indication for steroids (e.g. chronic use) as determined by the clinical team providing this drug 10. Clinical indication for thiamine as determined by the clinical team providing this drug 11. Clinical indication for ascorbic acid as determined by the clinical team providing this drug 12. Known allergy to vitamin C, hydrocortisone, or thiamine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours | Enrollment to 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 30-day Mortality | Enrollment until 30-days after enrollment | Mortality rate |
| Renal Failure | Enrollment until 7-days or discharge from the ICU | 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
| Measure | Time frame | Description |
|---|---|---|
| Intensive Care Unit (ICU) Mortality | Enrollment until ICU discharge, death, or 30-days. Whichever comes first. | ICU mortality rate |
| Ventilator Free Days | Ventilator free days over the first 7-days after enrollment | Days not receiving invasive mechanical ventilation |
| Shock Free Days | Vasopressor free days over the first 7-days after enrollment | Days not receiving vasopressor |
| Number of Participants With Delirium | On day 3 (at approximately 72 hours) after the first study drug dose | 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: 1. Acute Onset of Changes or Fluctuations in the Course of Mental Status (AND ) 2. Inattention (AND) 3. Disorganized thinking (OR) Altered Level of Consciousness |
| Hospital Disposition: Survivors Discharged Home | Enrollment until hospital discharge, death, or 30-days, whichever comes first. | Home hospital disposition in patients who survive to discharge |
| ICU Free Days | From enrollment until 28 days after enrollment | Number of days that the patient was not in the ICU. Timeframe listed below. |
| Hospital Mortality | Enrollment until hospital discharge, death, or 30-days. Whichever comes first. | Hospital mortality rate |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 101 |
| 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 | 99 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 3 |
Baseline characteristics
| Characteristic | Vitamin C, Vitamin B1, Corticosteroids | Total | Placebo |
|---|---|---|---|
| 30 Day Predicted Survival High Likelihood | 34 Participants | 72 Participants | 38 Participants |
| 30 Day Predicted Survival Low Likelihood | 6 Participants | 13 Participants | 7 Participants |
| 30 Day Predicted Survival Uncertain | 61 Participants | 115 Participants | 54 Participants |
| Age, Continuous | 68.9 years STANDARD_DEVIATION 15 | 68.2 years STANDARD_DEVIATION 14.5 | 67.7 years STANDARD_DEVIATION 13.9 |
| Baseline Cardiovascular Component of Total SOFA Score | 4 Units on a scale | 4 Units on a scale | 4 Units on a scale |
| BMI, mean (SD) | 28.8 kg/m^2 STANDARD_DEVIATION 10.1 | 28.3 kg/m^2 STANDARD_DEVIATION 9.3 | 27.9 kg/m^2 STANDARD_DEVIATION 8.4 |
| Lactate | 1.8 mmol/L | 1.8 mmol/L | 1.8 mmol/L |
| Medical History, Liver Disease | 11 Participants | 18 Participants | 7 Participants |
| Medical History, # with Congestive Heart Failure | 14 Participants | 37 Participants | 23 Participants |
| Medical History, # with Coronary Artery Disease | 26 Participants | 52 Participants | 26 Participants |
| Medical History, # with Malignancy | 26 Participants | 58 Participants | 32 Participants |
| # on Mechanical Ventilation | 48 Participants | 92 Participants | 44 Participants |
| Primary Infectious Source Intra-abdominal | 30 Participants | 53 Participants | 23 Participants |
| Primary Infectious Source Other | 13 Participants | 33 Participants | 20 Participants |
| Primary Infectious Source Pneumonia | 31 Participants | 59 Participants | 28 Participants |
| Primary Infectious Source Urinary Tract Infection | 20 Participants | 42 Participants | 22 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 8 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 18 Participants | 34 Participants | 16 Participants |
| Race/Ethnicity, Customized More than one Race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 68 Participants | 141 Participants | 73 Participants |
| Sex: Female, Male Female | 44 Participants | 89 Participants | 45 Participants |
| Sex: Female, Male Male | 57 Participants | 111 Participants | 54 Participants |
| Time from Informed Consent to First Study Drug | 2.2 Hours | 2.1 Hours | 2.0 Hours |
| Time from Vasopressor Initiation to First Study Drug | 14.5 hours | 13.5 hours | 13.0 hours |
| Volume of Intravenous Fluids Prior to Study Drug | 2000 mL | 2000 mL | 2000 mL |
| # with Acute Respiratory Distress Syndrome | 22 Participants | 40 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 35 / 101 | 29 / 99 |
| other Total, other adverse events | 0 / 101 | 0 / 99 |
| serious Total, serious adverse events | 13 / 101 | 12 / 99 |
Outcome results
Primary
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.
Time frame: Enrollment to 72-hours
Population: For the 72 hour SOFA score, patients who expired prior to that time point are excluded from the calculation of mean (SD) of the 72 hour SOFA score.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours | Enrollment SOFA score | 9.1 Units on a scale | Standard Deviation 3.5 |
| Vitamin C, Vitamin B1, Corticosteroids | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours | 72 hour SOFA score | 4.4 Units on a scale | Standard Deviation 4.1 |
| Placebo | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours | Enrollment SOFA score | 9.2 Units on a scale | Standard Deviation 3.2 |
| Placebo | Sequential Organ Failure Assessment (SOFA) Score at Baseline and 72 Hours | 72 hour SOFA score | 5.1 Units on a scale | Standard Deviation 4.3 |
Comparison: 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.p-value: 0.1295% CI: [-1.7, 0.2]Mixed Models Analysis
Secondary
30-day Mortality
Mortality rate
Time frame: Enrollment until 30-days after enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | 30-day Mortality | 35 Participants |
| Placebo | 30-day Mortality | 29 Participants |
Comparison: Cox Regression controlling for site used to identify hazard ratio for outcome of death for treatment versus intervention group. Null hypothesis is that hazard ratio is 1.p-value: 0.0595% CI: [0.8, 2.2]Regression, Cox
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
Time frame: Enrollment until 7-days or discharge from the ICU
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | Renal Failure | 32 Participants |
| Placebo | Renal Failure | 27 Participants |
Comparison: Logistic regression analysis evaluating the key secondary outcome of kidney failure in treatment group (intervention versus placebo) controlling for treatment site.p-value: 0.5895% CI: [-10, 20]Regression, Logistic
Other Pre-specified
Hospital Disposition: Survivors Discharged Home
Home hospital disposition in patients who survive to discharge
Time frame: Enrollment until hospital discharge, death, or 30-days, whichever comes first.
Population: 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..
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | Hospital Disposition: Survivors Discharged Home | 34 Participants |
| Placebo | Hospital Disposition: Survivors Discharged Home | 35 Participants |
Comparison: Logistic regression analysis evaluating home hospital disposition in survivors to hospital discharge in intervention versus placebo group controlling for treatment site.p-value: 0.8295% CI: [-18, 14]Regression, Logistic
Other Pre-specified
Hospital Mortality
Hospital mortality rate
Time frame: Enrollment until hospital discharge, death, or 30-days. Whichever comes first.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | Hospital Mortality | 28 Participants |
| Placebo | Hospital Mortality | 23 Participants |
Comparison: Logistic regression analysis evaluating the key secondary outcome of hospital mortality in treatment group (intervention versus placebo) controlling for treatment site..p-value: 0.5595% CI: [-10, 20]Regression, Logistic
Other Pre-specified
ICU Free Days
Number of days that the patient was not in the ICU. Timeframe listed below.
Time frame: From enrollment until 28 days after enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | ICU Free Days | 22 Days |
| Placebo | ICU Free Days | 21 Days |
Comparison: Quantile regression controlling for site performed to compare treatment and control group's ICU free days.p-value: 0.6995% CI: [-3, 6]Quantile Regression
Other Pre-specified
Intensive Care Unit (ICU) Mortality
ICU mortality rate
Time frame: Enrollment until ICU discharge, death, or 30-days. Whichever comes first.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | Intensive Care Unit (ICU) Mortality | 23 Participants |
| Placebo | Intensive Care Unit (ICU) Mortality | 20 Participants |
Comparison: Logistic regression analysis evaluating the key secondary outcome of ICU mortality in treatment group (intervention versus placebo) controlling for treatment site.p-value: 0.895% CI: [-10, 10]Regression, Logistic
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: 1. Acute Onset of Changes or Fluctuations in the Course of Mental Status (AND ) 2. Inattention (AND) 3. Disorganized thinking (OR) Altered Level of Consciousness
Time frame: On day 3 (at approximately 72 hours) after the first study drug dose
Population: 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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | Number of Participants With Delirium | 31 Participants |
| Placebo | Number of Participants With Delirium | 35 Participants |
Comparison: Logistic regression analysis evaluating the key secondary outcome of occurrence of delirium in treatment group (intervention versus placebo) controlling for treatment site.p-value: 0.1695% CI: [-25, 4]Regression, Logistic
Other Pre-specified
Shock Free Days
Days not receiving vasopressor
Time frame: Vasopressor free days over the first 7-days after enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | Shock Free Days | 5 Days |
| Placebo | Shock Free Days | 4 Days |
Comparison: Quantile regression controlling for site performed to compare treatment and control group's shock free days.p-value: 0.0295% CI: [0.2, 1.8]Quantile Regression
Other Pre-specified
Ventilator Free Days
Days not receiving invasive mechanical ventilation
Time frame: Ventilator free days over the first 7-days after enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vitamin C, Vitamin B1, Corticosteroids | Ventilator Free Days | 6 Days |
| Placebo | Ventilator Free Days | 6 Days |
Comparison: Quantile regression controlling for site performed to compare treatment and control group's ventilator free days.p-value: >0.9995% CI: [-1.9, 1.9]Quantile Regression