Trial Outcomes & Findings for Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in Sepsis. (NCT NCT03422159)
NCT ID: NCT03422159
Last Updated: 2021-09-21
Results Overview
Defined as the time from starting the active treatment/placebo to discontinuation of all pressors.
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
140 participants
Primary outcome timeframe
From start of vasopressor medication to final discontinuation of vasopressor medication, up to 7 days.
Results posted on
2021-09-21
Participant Flow
Between February 14th, 2018 and April 29th, 2019, 256 patients were evaluated within two community hospital intensive care units.
Patients excluded from enrollment based on their diagnosis upon admission (ineligible unless they were admitted to the ICU for sepsis, 33 patients), end stage disease (20), had a DNR/DNI (17), or required immediate surgery (11).
Participant milestones
| Measure |
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.
Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days).
Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
|
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.
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).
|
|---|---|---|
|
Overall Study
STARTED
|
70
|
70
|
|
Overall Study
COMPLETED
|
68
|
69
|
|
Overall Study
NOT COMPLETED
|
2
|
1
|
Reasons for withdrawal
| Measure |
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.
Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days).
Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
|
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.
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).
|
|---|---|---|
|
Overall Study
Exclusion due to terminal disease
|
2
|
1
|
Baseline Characteristics
Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in Sepsis.
Baseline characteristics by cohort
| Measure |
Treatment
n=68 Participants
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.
Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days).
Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
|
Comparator
n=69 Participants
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.
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).
|
Total
n=137 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
70 years
STANDARD_DEVIATION 12 • n=5 Participants
|
67 years
STANDARD_DEVIATION 14 • n=7 Participants
|
68 years
STANDARD_DEVIATION 13 • n=5 Participants
|
|
Sex: Female, Male
Female
|
36 Participants
n=5 Participants
|
42 Participants
n=7 Participants
|
78 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
32 Participants
n=5 Participants
|
27 Participants
n=7 Participants
|
59 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Caucasian
|
66 Participants
n=5 Participants
|
65 Participants
n=7 Participants
|
131 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Non-Caucasian
|
2 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Comorbidities
Coronary Artery Disease (CAD)
|
25 Participants
n=5 Participants
|
21 Participants
n=7 Participants
|
46 Participants
n=5 Participants
|
|
Comorbidities
Diabetes
|
24 Participants
n=5 Participants
|
33 Participants
n=7 Participants
|
57 Participants
n=5 Participants
|
|
Comorbidities
Dementia
|
7 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
|
Comorbidities
Heart failure
|
18 Participants
n=5 Participants
|
13 Participants
n=7 Participants
|
31 Participants
n=5 Participants
|
|
Comorbidities
Malignancy
|
15 Participants
n=5 Participants
|
11 Participants
n=7 Participants
|
26 Participants
n=5 Participants
|
|
Comorbidities
Chronic Obstructive Pulmonary Disease (COPD)
|
23 Participants
n=5 Participants
|
17 Participants
n=7 Participants
|
40 Participants
n=5 Participants
|
|
Comorbidities
Cirrhosis
|
0 Participants
n=5 Participants
|
3 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
|
Comorbidities
End Stage Renal Disease (ESRD)
|
3 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
|
Comorbidities
Chronic Kidney Disease (CKD)
|
10 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
14 Participants
n=5 Participants
|
|
Comorbidities
Morbid Obesity (BMI >40)
|
16 Participants
n=5 Participants
|
13 Participants
n=7 Participants
|
29 Participants
n=5 Participants
|
|
Comorbidities
Immunocompromised
|
6 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
|
Primary diagnosis
Pneumonia
|
29 Participants
n=5 Participants
|
30 Participants
n=7 Participants
|
59 Participants
n=5 Participants
|
|
Primary diagnosis
Urinary tract infection
|
18 Participants
n=5 Participants
|
25 Participants
n=7 Participants
|
43 Participants
n=5 Participants
|
|
Primary diagnosis
Primary bacteremia
|
9 Participants
n=5 Participants
|
11 Participants
n=7 Participants
|
20 Participants
n=5 Participants
|
|
Primary diagnosis
Gastrointestinal/biliary
|
9 Participants
n=5 Participants
|
8 Participants
n=7 Participants
|
17 Participants
n=5 Participants
|
|
Primary diagnosis
Other
|
13 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
22 Participants
n=5 Participants
|
|
Other Baseline Characteristics
Need for mechanical ventilation
|
34 Participants
n=5 Participants
|
35 Participants
n=7 Participants
|
69 Participants
n=5 Participants
|
|
Other Baseline Characteristics
Vasopressor usage during hospital admission
|
56 Participants
n=5 Participants
|
47 Participants
n=7 Participants
|
103 Participants
n=5 Participants
|
|
Other Baseline Characteristics
Acute Kidney Injury (Stage 1 or higher based on KDIGO definitions)
|
54 Participants
n=5 Participants
|
52 Participants
n=7 Participants
|
106 Participants
n=5 Participants
|
|
Other Baseline Characteristics
Positive blood cultures
|
22 Participants
n=5 Participants
|
23 Participants
n=7 Participants
|
45 Participants
n=5 Participants
|
|
Baseline Labs
Creatinine (mg/dL)
|
2.1 mg/dL
STANDARD_DEVIATION 1.5 • n=5 Participants
|
2 mg/dL
STANDARD_DEVIATION 1.51 • n=7 Participants
|
2 mg/dL
STANDARD_DEVIATION 0 • n=5 Participants
|
|
Baseline Labs
Ascorbic acid level (mg/dL)
|
0.52 mg/dL
STANDARD_DEVIATION 1 • n=5 Participants
|
0.48 mg/dL
STANDARD_DEVIATION 0.4 • n=7 Participants
|
0.5 mg/dL
STANDARD_DEVIATION 0 • n=5 Participants
|
|
Baseline Labs
Thiamine (mg/dL)
|
193 mg/dL
STANDARD_DEVIATION 144 • n=5 Participants
|
148 mg/dL
STANDARD_DEVIATION 53 • n=7 Participants
|
170 mg/dL
STANDARD_DEVIATION 0 • n=5 Participants
|
|
Baseline White Blood Cell Count (WBC) x10^9/L
|
16 x10^9 cells/L
STANDARD_DEVIATION 10 • n=5 Participants
|
19 x10^9 cells/L
STANDARD_DEVIATION 9.7 • n=7 Participants
|
17.5 x10^9 cells/L
STANDARD_DEVIATION 0 • n=5 Participants
|
|
Baseline Lactate (mM/L)
|
4.45 mM/L
STANDARD_DEVIATION 3.5 • n=5 Participants
|
4.8 mM/L
STANDARD_DEVIATION 4.2 • n=7 Participants
|
4.6 mM/L
STANDARD_DEVIATION 0 • n=5 Participants
|
|
Baseline Procalcitonin (ng/mL)
|
44 ng/mL
STANDARD_DEVIATION 72 • n=5 Participants
|
23 ng/mL
STANDARD_DEVIATION 38 • n=7 Participants
|
33.5 ng/mL
STANDARD_DEVIATION 0 • n=5 Participants
|
|
Baseline Sequential Organ Failure Assessment (SOFA) Score
|
8.3 scores on a scale
STANDARD_DEVIATION 3 • n=5 Participants
|
7.9 scores on a scale
STANDARD_DEVIATION 3.5 • n=7 Participants
|
8.1 scores on a scale
STANDARD_DEVIATION 0 • n=5 Participants
|
|
Acute Physiology And Chronic Health Evaluation (APACHE) II
|
24 scores on a scale
STANDARD_DEVIATION 7.6 • n=5 Participants
|
24.9 scores on a scale
STANDARD_DEVIATION 8.7 • n=7 Participants
|
24.5 scores on a scale
STANDARD_DEVIATION 0 • n=5 Participants
|
|
Acute Physiology And Chronic Health Evaluation (APACHE) IV
|
88 scores on a scale
STANDARD_DEVIATION 28.3 • n=5 Participants
|
87.5 scores on a scale
STANDARD_DEVIATION 29.7 • n=7 Participants
|
87.8 scores on a scale
STANDARD_DEVIATION 0 • n=5 Participants
|
|
APACHE IV predicted mortality (%)
|
34 percentage of predicted mortality
STANDARD_DEVIATION 3 • n=5 Participants
|
33.6 percentage of predicted mortality
STANDARD_DEVIATION 2.6 • n=7 Participants
|
33.8 percentage of predicted mortality
STANDARD_DEVIATION 0 • n=5 Participants
|
PRIMARY outcome
Timeframe: From start of vasopressor medication to final discontinuation of vasopressor medication, up to 7 days.Population: Patients on vasopressor therapy in each group.
Defined as the time from starting the active treatment/placebo to discontinuation of all pressors.
Outcome measures
| Measure |
HAT Treatment
n=60 Participants
Receiving Hydrocortisone, Ascorbic Acid, and Thiamine
|
Comparator
n=57 Participants
Receiving placebo
|
|---|---|---|
|
Time to Vasopressor Independence (Hours)
|
27 hours
Standard Deviation 22
|
53 hours
Standard Deviation 38
|
PRIMARY outcome
Timeframe: 4 days post-randomizationDefined 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).
Outcome measures
| Measure |
HAT Treatment
n=68 Participants
Receiving Hydrocortisone, Ascorbic Acid, and Thiamine
|
Comparator
n=69 Participants
Receiving placebo
|
|---|---|---|
|
Change in Sequential Organ Failure Assessment (SOFA) Score
|
2.9 score on a scale
Standard Deviation 3.3
|
1.93 score on a scale
Standard Deviation 3.5
|
SECONDARY outcome
Timeframe: 4 days post-randomizationPCT at 96 hours minus initial PCT, divided by the initial PCT multiplied by 100.
Outcome measures
| Measure |
HAT Treatment
n=68 Participants
Receiving Hydrocortisone, Ascorbic Acid, and Thiamine
|
Comparator
n=69 Participants
Receiving placebo
|
|---|---|---|
|
Procalcitonin (PCT) Clearance
|
63 Percent
Standard Deviation 170
|
58 Percent
Standard Deviation 66
|
SECONDARY outcome
Timeframe: From admission to hospital until final discharge from the ICU, up to 28 days.ICU mortality rate
Outcome measures
| Measure |
HAT Treatment
n=68 Participants
Receiving Hydrocortisone, Ascorbic Acid, and Thiamine
|
Comparator
n=69 Participants
Receiving placebo
|
|---|---|---|
|
ICU Mortality
|
6 Participants
|
10 Participants
|
SECONDARY outcome
Timeframe: From admission to the ICU until final discharge from the ICU, up to an average of 7 days.Time from admitting to ICU to discharge.
Outcome measures
| Measure |
HAT Treatment
n=68 Participants
Receiving Hydrocortisone, Ascorbic Acid, and Thiamine
|
Comparator
n=69 Participants
Receiving placebo
|
|---|---|---|
|
ICU Length of Stay
|
4.76 days
Standard Deviation 4.3
|
4.66 days
Standard Deviation 3.45
|
SECONDARY outcome
Timeframe: 28 Days post-randomizationNumber of days alive and off of the ventilator at day 28.
Outcome measures
| Measure |
HAT Treatment
n=68 Participants
Receiving Hydrocortisone, Ascorbic Acid, and Thiamine
|
Comparator
n=69 Participants
Receiving placebo
|
|---|---|---|
|
Ventilator Free Days
|
22 Days
Standard Deviation 6.2
|
22.4 Days
Standard Deviation 4.3
|
SECONDARY outcome
Timeframe: From admission to the hospital until final discharge, up to 28 days.Time from admitting to discharge of hospital stay.
Outcome measures
| Measure |
HAT Treatment
n=68 Participants
Receiving Hydrocortisone, Ascorbic Acid, and Thiamine
|
Comparator
n=69 Participants
Receiving placebo
|
|---|---|---|
|
Hospital Length of Stay
|
11.5 Days
Standard Deviation 6.8
|
11 Days
Standard Deviation 6.2
|
SECONDARY outcome
Timeframe: Survival until hospital discharge, up to 28 days.In-hospital mortality rate.
Outcome measures
| Measure |
HAT Treatment
n=68 Participants
Receiving Hydrocortisone, Ascorbic Acid, and Thiamine
|
Comparator
n=69 Participants
Receiving placebo
|
|---|---|---|
|
Hospital Mortality
|
11 Participants
|
13 Participants
|
Adverse Events
Treatment Arm
Serious events: 0 serious events
Other events: 0 other events
Deaths: 11 deaths
Placebo Arm
Serious events: 0 serious events
Other events: 0 other events
Deaths: 13 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Jose Iglesias, DO
Community Medical Center Department of Critical Care, Department of Nephrology
Phone: 732-557-8070
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place