Ascorbic Ccid, Hydrocortisone, and Thiamine in Sepsis and Septic Shock - A Randomized, Double-Blind, Placebo-Controlled Trial
Phase: PHASE2
Conditions: Sepsis, Septic Shock, Metabolic Disturbance
Sponsor: Beth Israel Deaconess Medical Center

 
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Ascorbic Acid, Hydrocortisone, and Thiamine in Sepsis and Septic Shock 
– A Randomized, Double-Blind, Placebo-Controlled Trial 
 
Acronym: Ascorbic acid, Corticosteroids, and Thiamine in Sepsis (ACTS) Trial 
 
CLINICAL TRIAL PROTOCOL 
 
             Version 2.4 
December 13, 2018 
            IND: 136882 
 
 
Clinical Trials.Gov Identifier: NCT03389555 
 
Principal investigator: 
Michael W. Donnino, MD 
Director of Center for Resuscitation Science 
Associate Professor of Medicine, Harvard Medical School 
Attending Physician in Emergency and Critical Care Medicine, BIDMC 
 
Beth Israel Deaconess Medical Center 
West Clinical Campus 2nd Floor 
One Deaconess Road, Boston MA 02215 
Phone: 617-754-2295 
Fax: 617-754-2350 
Email: mdonnino@bidmc.harvard.edu 
 
Funded By: 
Open Philanthropy Project (https://www.openphilanthropy.org/) 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SYNOPSIS .........................................................................................................................................................5 
TRIAL OVERVIEW ............................................................................................................................................6 
STEERING COMMITTEE ................................................................................................................................7 
TRIAL SITES ......................................................................................................................................................8 
1. BACKGROUND AND SIGNIFICANCE ......................................................................................................9 
1.1 Scope of the Problem .............................................................................................................................9 
1.2 Existing Interventions .............................................................................................................................9 
1.3 The combination of vitamin C, hydrocortisone, and vitamin B1 may improve outcomes ............9 
1.4 Physiologic Rationale .............................................................................................................................9 
2. TRIAL DESIGN ........................................................................................................................................... 10 
2.1 Overview ................................................................................................................................................ 10 
2.2 Allocation ............................................................................................................................................... 10 
2.3 Intervention ........................................................................................................................................... 10 
2.3.1 Vitamin C, Hydrocortisone, and Vitamin B1 ............................................................................. 10 
2.3.2 Placebo........................................................................................................................................... 10 
2.4 Blinding .................................................................................................................................................. 10 
2.5 
Regulatory Issues ........................................................................................................................... 10 
3.  SETTING AND PARTICIPANT POPULATION .................................................................................... 11 
3.1 Setting .................................................................................................................................................... 11 
3.2 Inclusion criteria ................................................................................................................................... 11 
3.3 Exclusion criteria .................................................................................................................................. 11 
3.4 Pregnancy ............................................................................................................................................. 11 
4. TRIAL PROCEDURES .............................................................................................................................. 12 
4.1 Participant Identification ...................................................................................................................... 12 
4.2 Consent procedures ............................................................................................................................ 12 
4.3 Randomization ...................................................................................................................................... 12 
4.4 Drug preparation and administration ................................................................................................. 13 
4.4.1 Contingencies and Participant Withdrawal ............................................................................... 13 
4.5 Specimen collection procedures ........................................................................................................ 13 
4.5.1 Timing and volume of blood draw .............................................................................................. 13 
4.5.2 Specimen samples ....................................................................................................................... 13 
4.5.3 Biomarker tube initial processing and shipping ........................................................................ 14 
4.6 Study flow diagram .............................................................................................................................. 14 

 
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4.7 General Sepsis Management ............................................................................................................. 14 
4.8 Glucometer use during the study period .......................................................................................... 15 
5. OUTCOMES ............................................................................................................................................... 15 
5.1 Definitions .............................................................................................................................................. 15 
5.1.1 Primary Outcome .......................................................................................................................... 15 
5.1.2 Key Secondary Outcomes ........................................................................................................... 15 
5.2 Rationale for Outcomes ...................................................................................................................... 16 
5.3 Additional Secondary Outcomes ....................................................................................................... 16 
5.3.1 Additional secondary outcomes .................................................................................................. 16 
5.3.2 90-day follow-up for Quality of Life assessment ...................................................................... 17 
5.4 Safety ..................................................................................................................................................... 17 
5.4.1 Definitions ...................................................................................................................................... 17 
5.4.2 Specific adverse event data collection ...................................................................................... 17 
5.4.3 Adverse Event Reporting ............................................................................................................. 18 
5.4.5 Safety Monitoring Labs ................................................................................................................ 18 
6. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN ........................................... 18 
6.1 Sample size calculation ....................................................................................................................... 18 
6.2 Statistical analysis plan ....................................................................................................................... 19 
6.2.1 General considerations ................................................................................................................ 19 
6.2.2 SOFA score and renal failure ...................................................................................................... 19 
6.2.3 30-day mortality ............................................................................................................................. 20 
6.2.5 Subgroup analyses ....................................................................................................................... 20 
6.2.6 Statistical stopping criteria ........................................................................................................... 20 
7. DATA COLLECTION AND MANAGEMENT .......................................................................................... 20 
7.1 Data collection process ....................................................................................................................... 20 
7.2 Variables ................................................................................................................................................ 20 
7.3 Data quality and validity ...................................................................................................................... 21 
7.4 Data storage and security ................................................................................................................... 21 
8. ETHICAL CONSIDERATIONS ................................................................................................................. 21 
8.1 Risks and Benefits ............................................................................................................................... 21 
8.1.1 Potential benefits .......................................................................................................................... 21 
8.1.2 Potential harms ............................................................................................................................. 21 
9. MONITORING............................................................................................................................................. 23 
9.1 Institutional Review Board (IRB) ........................................................................................................ 23 

 
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9.2 Data Safety and Monitoring Board (DSMB) ..................................................................................... 23 
10 CLINICAL MONITORING PLAN ............................................................................................................. 24 
11. TIMELINE AND ENROLLMENT ............................................................................................................ 25 
11.1 Timeline ............................................................................................................................................... 25 
11.2 Screening & Enrollment .................................................................................................................... 25 
12. FUNDING .................................................................................................................................................. 26 
13. PUBLICATION .......................................................................................................................................... 26 
14. DATA SHARING ...................................................................................................................................... 26 
15. TASKS AND RESPONSIBILITIES ........................................................................................................ 26 
References ...................................................................................................................................................... 28 
Appendices ...................................................................................................................................................... 33 
Appendix 1: Abbreviations ......................................................................................................................... 33 
Appendix 2: CAM-ICU Form ..................................................................................................................... 34 
 

 
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SYNOPSIS 
 
The “Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis (ACTS)” trial is a multi-center, double-
blind, randomized clinical trial that aims to determine the impact of Vitamin C, Hydrocortisone, and 
Vitamin B1 vs. Placebo on organ injury and mortality on participants with sepsis and septic shock. 
The trial will be conducted in accordance with all applicable national and international laws, 
regulations, and guidelines The trial and this protocol is developed in accordance with the 
International Conference on Harmonization (ICH) guidelines1-3 and the Standard Protocol Items: 
Recommendations for Interventional Trials (SPIRIT) statement4,5. The principal investigator wrote 
the protocol with input from the steering committee. Any substantial changes or amendments to the 
protocol will be clearly documented and communicated to all relevant parties.  
 

 
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TRIAL OVERVIEW 
 
Title 
Vitamin C, Hydrocortisone, and Vitamin B1 in Sepsis and 
Septic Shock – A Randomized, Double-Blind, Placebo-
Controlled Trial (The ACTS Trial) 
Clinical Trials Number 
NCT03389555 
Sources of monetary or 
material support 
Open Philanthropy Project 
(https://www.openphilanthropy.org/)  
Study Sites 
12-sites in the United States 
Condition studied 
Sepsis and septic shock 
Interventions 
Vitamin C (1.5g every 6 hours x 4-days), hydrocortisone 
(50mg every 6 hours x 4-days), and Vitamin B1 (100mg 
every 6 hours x 4-days) 
Comparator  
Placebo  
Inclusion criteria 
• Adult participant (age ≥ 18 years) 
• Suspected (cultures drawn and antibiotic given) or 
confirmed (via culture results) infection 
• Receiving vasopressor (norepinephrine, 
phenylephrine, epinephrine, dopamine, vasopressin, or 
angiotensin II)  
Exclusion criteria 
• Member of a protected population (pregnant, prisoner) 
• Known history of kidney stones within the past 1 year 
• End stage renal disease (ESRD) requiring dialysis 
• Known history of G6PD deficiency 
• Known history of Hemochromatosis 
• Comfort Measures Only status 
• Anticipated death within 24-hours despite maximal 
therapy (as determined by the enrolling physician) 
• Receiving supplemental vitamin B1 in a dose greater 
than that contained in a multivitamin (<2mg) 
• Clinical indication for steroids (e.g. chronic use) as 
determined by the clinical team providing this drug 
• Clinical indication for ascorbic acid supplementation in 
any form  
• Clinical indication for vitamin B1 as determined by the 
clinical team providing this drug 
• Known allergy to vitamin C, hydrocortisone, or vitamin B1 
Study type 
Interventional 
Allocation: Randomized (1:1) 
Intervention model: Parallel group 
Masking: Double-blind 
Target sample size 
200 Participants (100/arm) 
Primary outcome 
Change in the Sequential Organ Failure Assessment 
(SOFA) score between enrollment and 72-hours 
Key secondary outcomes 
Incidence of renal failure during index ICU stay 
30-day mortality 

 
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STEERING COMMITTEE 
 
Michael Donnino, M.D.  
Associate Professor of Medicine 
Director, Center for Resuscitation Science  
Beth Israel Deaconess Medical Center 
Harvard Medical School  
Paul E. Marik, M.D. 
Professor of Medicine 
Chief, Division of Pulmonary and Critical 
Care Medicine 
Eastern Virginia Medical School 
Ari Moskowitz, M.D. 
Attending, Pulmonary and Critical Care Medicine 
Beth Israel Deaconess Medical Center 
Harvard Medical School  
Katherine Berg, M.D. 
Assistant Professor of Medicine 
Beth Israel Deaconess Medical Center 
Harvard Medical School  
Lars W. Andersen, M.D., MPH, Ph.D 
Associate Professor of Medicine 
Research Center for Emergency Medicine 
Department of Clinical Medicine 
Aarhus University and Aarhus University Hospital 
Anne Grossestreuer, Ph.D. 
Instructor in Emergency Medicine 
Beth Israel Deaconess Medical Center 
Harvard Medical School  
Michael N. Cocchi, MD 
Assistant Professor of Emergency Medicine 
Beth Israel Deaconess Medical Center 
Harvard Medical School  
Joseph Miller, MD 
Attending, Emergency Medicine 
Department of Emergency Medicine 
Henry Ford Hospital 
Conflicts of interest 
The members of the steering committee have no financial conflicts of interest related to the current 
trial.  

 
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TRIAL SITES 
 
Coordinating Center 
Beth Israel Deaconess Medical Center 
330 Brookline Avenue 
Boston, MA 02215 
Site Investigator: Michael W. Donnino, MD 
 
Enrolling Sites* 
 
Hospital Name 
Location 
Site Principal Investigator 
Henry Ford Hospital 
Detroit, MI 
Bruno DiGiovine, MD 
DMC-Detroit Receiving Hospital 
Detroit, MI 
Rob Sherwin, MD 
DMC-Sinai-Grace Hospital 
Detroit, MI 
Rob Sherwin, MD 
Harper Hospital 
Detroit, MI 
Rob Sherwin, MD 
UT Health, The University of Texas 
Health Science Center 
Houston, TX 
Pratik Doshi, MD 
Mayo Clinic 
Phoenix, AZ 
Ayan Sen, MD 
Beth Israel Deaconess Medical 
Center 
Boston, MA 
Ari Moskowitz, MD 
Beaumont Hospital 
Royal Oak, MI 
Ron Otero, MD 
Brigham and Women’s Hospital 
Boston, MA 
Peter Hou, MD 
Long Island Jewish Hospital Center 
- Queens 
New York, NY 
Maksim Korotun, MD; Jonathan 
Gong, MD 
Long Island Jewish Hospital Center 
– Hyde Park 
New York, NY 
Ayelet Hilewitz, MD; Jonathan 
Gong, MD 
Mount Auburn Hospital 
Cambridge, MA 
Jessica McCannon, MD 
University of Pittsburgh 
Pittsburgh, PA 
David Huang, MD 
South Shore Hospital 
Weymouth, MA 
Mark Hershey, MD 
*Depending on study progress, sites may be added or removed in the future. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. BACKGROUND AND SIGNIFICANCE 
1.1 Scope of the Problem  
The worldwide incidence of sepsis has been estimated at more than 23 million cases6 and sepsis 
contributes to more than a third of all hospital deaths in the United States.7,8 Mortality for those in 
septic shock with elevated lactate is more than 40%.9 In addition to high short-term mortality, sepsis 
is associated with significant post-discharge morbidity and mortality.10-15 The economic burden for 
participants suffering from sepsis is staggering with an estimated yearly financial burden of $17 
billion.16 Treatments are generally limited to antibiotics and intravenous fluids while providing support 
to maintain organ function.17,18  
 
1.2 Existing Interventions 
To date, numerous interventions have been tested for participants with sepsis and septic shock with 
limited, if any, success.19-22 Recently, three large studies found no benefit from early goal directed 
therapy over usual care in emergency department participants with sepsis.23-25 Other recent studies 
focusing on hemodynamics, fluid therapy, and transfusions have also failed to show a significant 
benefit in this participant population.26-28 Previous studies focusing on immunomodulary therapies or 
drotrecogin alfa have likewise shown disappointing results.29-35  
 
1.3 The combination of vitamin C, hydrocortisone, and vitamin B1 may improve outcomes  
In a before-and-after study exploring the effects of the combination of vitamin C, hydrocortisone, and 
vitamin B1 in a cohort of participants with sepsis and septic shock, Marik et. al. found a remarkable 
improvement in time to shock reversal (18.3 ± 9.8 hours vs. 54.9 ± 28.4 hours), organ injury (ΔSOFA 
4.8 ± 2.4 vs. 0.9 ± 2.7), and mortality (8.5% vs. 40.4%) following implementation of the drug ‘cocktail’ 
as compared to before implementation even after adjusting for potential confounders.36 This study 
joins other promising trials of individual elements of this drug combination. In a trial of vitamin B1 in 
septic shock, there was a substantial reduction in mortality and organ injury (particularly kidney 
injury) in those with vitamin B1 deficiency and septic shock who were given vitamin B1 as compared 
to placebo.37,38 In addition, several studies of vitamin C alone have shown promise in critically ill 
populations39-42 and a recent meta-analysis of corticosteroids in sepsis suggests potential benefit.43 
 
1.4 Physiologic Rationale 
The combination of vitamin C, hydrocortisone, and vitamin B1 is hypothesized to improve outcomes 
in sepsis through a number of mechanisms.36 Vitamin C is an important contributor to endothelial 
integrity and severe deficiency states (e.g. scurvy) can result in endothelial breakdown with resultant 
vascular leak and edema.44,45  In addition, vitamin C is a potent anti-oxidant and is integral to 
endogenous vasopressor synthesis.36 Hydrocortisone, a potential adjunctive therapy in septic 
shock46,47, may act synergistically with vitamin C.48,49 Vitamin B1, a key cofactor of pyruvate 
dehydrogenase, is a critical component of metabolic dysfunction without which a shift towards 
anaerobic energy production occurs.50 Vitamin B1 is also a necessary component of the pentose 
phosphate pathway, which plays a role in reducing oxidative stress.51,52 While the physiologic effects 
of these drugs given in combination is not entirely known, we hypothesize that there will be 
synergistic effects with respect the metabolic resuscitation of sepsis.  

 
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2. TRIAL DESIGN 
2.1 Overview 
This will be an investigator-initiated, multicenter, randomized, placebo-controlled, parallel group, 
double-blind, superiority trial of vitamin C, hydrocortisone, and vitamin B1 vs. placebo in participants 
with sepsis and septic shock. A total of 200 adult participants will be enrolled. The primary outcome 
will be the change in SOFA score between enrollment and 72-hours. Key secondary outcomes 
include the incidence of renal failure during the index ICU stay and survival at 30 days. 
 
2.2 Allocation 
Participants will be randomized in a 1:1 ratio to either the combination of vitamin C, hydrocortisone, 
and vitamin B1 or placebo in blocks with random sizes of 2 or 4. The randomization will be stratified 
according to site.53 An independent statistician will create the randomization list using a random 
number generator. The complete list will only be shared with an independent pharmacy consultant, 
who will not be involved in clinical care. The pharmacy consultant and the independent statistician 
will both store the randomization list. The research pharmacy at each enrolling site will receive a 
site-specific randomization list.   
 
2.3 Intervention 
2.3.1 Vitamin C, Hydrocortisone, and Vitamin B1 
The study drugs will consist of vitamin C (1.5g every 6 hours x 4-days), hydrocortisone (50mg every 6 
hours x 4-days), and vitamin B1 (100mg every 6 hours x 4-days). 
 
2.3.2 Placebo  
The placebo will consist of matching volumes of normal saline (0.9% NaCl). See below section 4.4 
for specifics of drug and placebo preparation.  
 
2.4 Blinding  
The trial will be double-blind; participants, investigators, and the clinical team will be blinded to the 
allocation. Only the pharmacy providing the study drug will be aware of the allocation. The 
pharmacy will not be involved with clinical care or outcome evaluation.  
 
As vitamin C possess a yellow tinge, the bags containing the vitamin C/placebo will be covered with 
light-protective bags. In testing, after dilution there is not distinguishing characteristics of the vitamin 
C vs. placebo in the IV tubing. Vitamin C, hydrocortisone, and vitamin B1 are not known to have 
distinctive rapid effects which could lead to unblinding.  
 
 
The decision to unblind will be at the complete discretion of the treating physician and clinical team. 
If a clinical team wishes to unblind a participant (e.g. if anaphylaxis occurs), they will contact the 
research pharmacy who will reveal the study group to the clinical team (but the research team will 
remain blinded). However, we do not expect many scenarios where emergency unblinding will be 
necessary. In case unblinding occurs, the reason(s) will be clearly documented in the case report 
form. The patient will no longer receive study medications, but will be followed for outcomes.  
 
2.5 Regulatory Issues 
An Investigational New Drug (IND) application was submitted to and approved by the Food and 
Drug Administration (FDA) for the study of vitamin C, hydrocortisone, and vitamin B1 in sepsis and 
septic shock (IND # 136882). 
 
The trial has been registered on ClinicalTrials.gov: NCT03389555 
 
 

 
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3.  SETTING AND PARTICIPANT POPULATION 
3.1 Setting 
The trial will be conducted at approximately 13 hospitals in the United States. Additional sites might 
be recruited if needed.  
 
3.2 Inclusion criteria 
Inclusion criteria:  
1) Adult participant (age ≥ 18 years) 
2) Suspected (cultures drawn and antibiotic given) or confirmed (via culture results) infection 
3) Receiving (continuous infusion) vasopressor (norepinephrine, phenylephrine, epinephrine, 
dopamine, angiotensin II, or vasopressin) 
a. Hypotension related primarily to sepsis as opposed to another cause of hypotension 
(e.g. bleed, cardiogenic shock) 
 
3.3 Exclusion criteria  
Exclusion criteria: 
1) Member of a protected population (pregnant, prisoner) 
2) Known history of kidney stones within the past 1 year (not including incidentally noted stones 
noted on imaging studies) 
3) End stage renal disease requiring dialysis (hemodialysis or peritoneal dialysis) 
4) Known history of G6PD deficiency 
5) Known history of Hemochromatosis 
6) Comfort Measures Only status 
7) Anticipated death within 24-hours despite maximal therapy (as determined by the enrolling 
physician)  
8) Receiving supplemental vitamin B1 in a dose greater than that contained in a multivitamin 
(<2mg) 
9) Clinical indication for steroids (e.g. chronic use) as determined by the clinical team providing this 
drug 
10) Clinical indication for ascorbic acid supplementation in any form  
11) Clinical indication for vitamin B1 as determined by the clinical team providing this drug 
12) Known allergy to vitamin C, hydrocortisone, or vitamin B1 
 
Justification of Inclusion and Exclusion Criteria: The inclusion criteria were chosen to isolate a septic 
participant population with high risk of organ injury and death. The exclusion criteria were chosen to 
minimize the risk of potential harm and to ensure that participants enrolled do not already have 
chronic end-stage renal failure with a high likelihood of early need for renal replacement therapy. By 
evaluating this high-risk population (i.e., most likely to die), we will target those most likely to benefit 
and therefore increase the probability of showing efficacy.19  
 
3.4 Pregnancy 
Hydrocortisone is considered pregnancy class C on the basis of animal studies showing an 
association between prenatal parenteral hydrocortisone use and risk of cleft-palate. In addition, 
there are concerns about effects of hydrocortisone on fetal growth and the possibility of neonatal 
adrenal insufficiency. The effects of high-dose vitamin C and thiamine in pregnancy are not entirely 
known. As such, participants who are pregnant will be excluded from the study. Prior to enrollment, 
all participants of potentially child-bearing potential (women aged <45 years54) will be required to 
have a negative serum or urine HCG test (generally performed as standard-of-care).  
 

 
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We will additionally inform all women of child-bearing potential who are randomized in this study 
that we recommend they remain abstinent or use two forms of birth control during the study period 
and for a period of 48-hours after the last dose of study drug.  
 
4. TRIAL PROCEDURES 
4.1 Participant Identification  
Screening will be performed in the emergency department and intensive care units (ICUs) with the 
assistance of electronic screening mechanisms . Detailed screening logs, with reason(s) for exclusion 
will be kept at each site and reported in the final publication.  
 
We anticipate that all patients, as part of standard-of-care for the septic patient, will have a urine or 
serum HCG test performed (if a female of child-bearing age). If this test is not sent as part of standard-
of-care, it should be sent prior to consent.   
 
4.2 Consent procedures 
Informed, written consent will be obtained for all participants prior to enrollment.  
 
After it is determined that they meet all inclusion criteria and no exclusion criteria, the participant (or 
legally authorized representative [LAR] if the participant is not able to provide consent) will be 
approached for written informed consent by a physician co-investigator from the team. The 
investigator will provide the participant/representative information regarding the background and 
significance of the study, eligibility criteria, and a description of the protocol. To ensure we are 
correctly identifying the potential participant’s LAR, we communicate with members of the clinical 
team. The consent process may need to be modified based on site-specific IRB recommendations.  
 
The name of the study investigator obtaining consent will be clearly documented, and this person will 
sign the informed consent document and provide the date and time of their signature. If a physician 
is performing remote consent, then a copy of the consent form will be signed as soon as he/she is 
physically present. Signed copies of the consent form will be given to the participant/surrogate, and 
the original consent document will be stored in the secure study file. In obtaining and documenting 
informed consent, each investigator will comply with the applicable regulatory requirements and 
adhere to the ethical and Good Clinical Practice principles that have their origin in the Declaration of 
Helsinki.  
 
4.3 Randomization 
After consent is obtained, the research team will notify the local research pharmacy. The research 
pharmacy will be in possession of the randomization list and will determine which arm (intervention 
vs. placebo) the participant will be enrolled in.  
 
Patients should be randomized, consented, and enrolled in the study as soon as possible after 
meeting inclusion criteria. Patients should not be consented if it has been >24hours since the 
patient met inclusion criteria (i.e. start of vasopressors). At the time of randomization and study drug 
administration, the patient should still be receiving a vasopressor. The patient should not be given 
study drug if the vasopressor has been stopped (e.g. patient met inclusion criteria overnight but 
could not be consented for logistical reasons and then improves to the point of no longer requiring a 
vasopressor). In this scenario, the paitent will be entered into the dabase as consented but not 
enrolled.  
 

 
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4.4 Drug preparation and administration 
The vitamin C and vitamin B1 will be mixed together in 100ml of normal saline and administered 
intravenously over 45-60 minutes. The hydrocortisone will be given intravenously as a push-dose in 
1ml of saline over 1-2 minutes. The placebo will be given using techniques and volumes matching 
those of the study medications. 
 
All study medications will be continued for 4-days or until the participant expires or leaves the 
intensive care unit.  
 
4.4.1 Contingencies and Participant Withdrawal  
• In the unlikely event that a participant is discharged alive from the hospital prior to 4 days after 
enrollment, all study medications will be stopped.The participant will remain in the study and will 
be followed for outcomes. 
• Hydrocortisone is occasionally used for refractory septic shock. If the clinical team opts to provide a 
participant hydrocortisone, the hydrocortisone will be given open-label but the vitamin C/B1 will 
remain randomized and blinded. In this case, the research team will ensure that study 
hydrocortisone/placebo is replaced by open-label hydrocortisone. The participant will remain in 
the study and will be followed for outcomes. 
• If the clinical team decides to give the participant vitamin B1 for clinical purposes, the study drug 
will be continued (including thiamine) as long as the total maximum dose of vitamin B1 is 
≤1,500mg/day. 1,500mg day is a standard dose for Wernicke’s encephalopathy at many 
institutions and has not been associated with any increased harm.  
• If the clinical team decides to give the participant vitamin C for clinical purposes, further 
administration of study meds will be stopped. The participant will remain in the study and will be 
followed for outcomes.  
• If a participant withdraws from the study, further administration of study meds will be stopped. 
Data collected prior to withdrawal will be maintained but additional data will not be collected.   
 
4.5 Specimen collection procedures 
4.5.1 Timing and volume of blood draw 
All participants will have a blood samples collected at four time-points and urine samples at two 
time-points (if not already available as part of routine clinical care). Blood will be obtained by 
venipuncture, or from an existing venous or arterial catheter. Urine will be collected via clean catch 
urine or via catheter.  
 
Specimen Collection Time Points 
1. T1=0 hrs (just before study drug administration) 
2. T2=24 hrs (+/- 2 hrs) 
3. T3=72 hrs (+/- 2 hrs) 
4. T4=120hrs (+/- 12hrs) 
 
4.5.2 Specimen samples 
At the T1, T2, T3, and T4 time points, blood will be sent for complete blood count (including 
hemoglobin, white blood cell count, platelet count), a serum chemistry (including sodium, 
potassium, chloride, bicarbonate, blood urea nitrogen, creatining, glucose, aspartate transaminase, 
alanine transaminase, and total bilirubin), and a venous blood gas to measure lactate. These tests 
will be performed by the clinical laboratory at each site. As many of these laboratory tests are 
commonly obtained for clinical purposes, these tests do not need to be repeated if a result is 
available from the clinical care of the participant within 2 hours of the time point (or within 12 hours 
of the T4 time-point).  

 
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In addition to traditional clinical markers, blood will be obtained for future biomarker analysis 
(including inflammatory biomarkers, markers of endothelial function, and markers of mitochondrial 
function), and measurement of vitamin C, vitamin B1, and cortisol levels. The total volume of blood 
that may be drawn for a participant at each time point will not exceed 60mls. Levels of vitamin C, 
vitamin B1, and cortisol will be measured at time T1 and time T3 only. 20ml of urine will be collected 
for future biomarker analysis at T1, T2, and T3. 
 
If performed as part of standard-of-care, results of urinalysis and urine sediment testing will be 
collected prior to enrollment.  
 
4.5.3 Biomarker tube initial processing and shipping 
Please see accompanying blood collection standard operating procedure for full details. In brief, 
15ml of blood will be drawn into EDTA tubes and 10ml of blood will be drawn into a corvac tube. 
From one of the EDTA tubes, 3ml of whole blood will be initially drawn and separated into 3x 1ml 
aliquots. Plasma will then be isolated from the EDTA tube(s) and aliquoted into cryovials as follows: 
4x 0.5ml aliquots and the remainder in 1ml aliquots. Serum will then be isolated from the corvac 
tube, and separated into 1ml aliquots. Cryovials will be protected from light and frozen at -80°C until 
processing. An additional 20ml of urine will also be collected, centrifuged, and separated into 1ml 
aliquots then frozen at -80°C until processing. 
 
Sites will be expected to ship frozen samples to the coordinating center after every 5 enrollments. 
The coordinating center will assist with all shipping procedures.  
 
4.6 Study flow diagram 
 
 
 
4.7 General Sepsis Management  
Investigators should follow local sepsis management guidelines. No specific sepsis bundle is 
required by this study, however the early administration of antibiotics, maintenance of a mean 
arterial pressure ≥65mmHg with a combination of volume resuscitation and vasopressors, and early 
source control are recommended—as detailed in the Suriving Sepsis Guidelines.55 Elements of 
sepsis care should be reported on the online case report form (CRF). 

 
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4.8 Glucometer use during the study period 
High dose vitamin C has been shown to falsely elevate glucose level readings when measured with 
certain point-of-care glucometers employing glucosedehydrogenase-pyrroloquinoline quinone 
amperometric methods56. Some commonly used glucometer brands using this approach include 
Accu-Chek (Roche Diagnostic) and Optium (Abbott Diabetes Care) (but not StatStrip; Nova 
Biomedical). While the effects of high-dose vitamin C on glucometer readings have been seen 
primarily at higher doses of vitamin C than are intended for use in this trial,56 we recommend that 
sites explore what glocumeters are in use in local ICUs. If locally used glucometers may be 
impacted by high serum concentrations of vitamin C (as determined by the manufacturer), we 
recommend that clinical teams caring for enrolled participants be alerted to the possibility of falsely 
elevated blood-glucose levels when measured by glucometer. If there is a clinical concern about a  
glucose reading obtained via glucometer, a serum glucose should be obtained which will not be 
impacted by vitamin C. In the event of an emergency related to suspected hypoglycemia, glucose 
should be immediately given while a serum glucose level is pending.  
 
5. OUTCOMES 
5.1 Definitions 
5.1.1 Primary Outcome 
The primary outcome will be the absolute change in the Sequential Organ Failure Assessment 
(SOFA]) score from enrollment (time=0) to 72 hours after drug administration. The SOFA score will 
be defined using a modification in which the SaO2/FiO2 ratio is substituted for the PaO2/FiO2 ratio 
as has been previously described.57,58 This modified score will be used so that participants without 
an existing arterial catheter can be spared arterial puncture.  
 
Points 
SaO2*/FiO2§ 
Blood Pressure 
GCS‖ 
Bilirubin 
(mg/dL) 
Creatinine 
(mg/dL) 
Platelets 
(x103µL) 
1 
<400 
< 70 mm/Hg 
13–
14 
1.2–1.9 
1.2 – 1.9 
<150 
2 
<326 
dopamine ≤ 5 µg/kg/min or 
dobutamine  
(any dose) 
10–
12 
2–5.9 
2.0 – 3.4 
<100 
3 
<236 (and receiving 
invasive or non-invasive 
mechanical ventilation) 
dopamine > 5µg/kg/min, 
epinephrine/norepinephrine  
≤ 0.1 µg/kg/min 
6–9 
6–11.9 
3.5 – 4.9 
Or 
UOP†<500ml/day 
<50 
4 
<151(and receiving 
invasive or non-invasive 
mechanical ventilation) 
dopamine > 15, 
epinephrine/norepinephrine 
> 0.1 µg/kg/min  
<6 
>12 
> 5.0 
UOP†<200ml/day 
Or receiving 
renal 
replacement 
therapy 
<20 
*SaO2=Oxygen saturation (%); § = Fraction of inspired oxygen (%); ‖ = Glasgow Coma Scale; † = Urine Output 
Fio2 will be determined by using either the set FiO2 (for patients receiving invasive or non-invasive 
mechanical ventilation) or by adding 3% FiO2 for each liter/minute of supplemental oxygen added 
up to 100% FiO2 (for patients not receiving mechanical ventilation). Patients with an SaO2/FiO2 
ratio <236 who are not receiving invasive or non-invasive mechanical ventilation, will be assigned a 
score of 2.  
 
5.1.2 Key Secondary Outcomes 
Incidence of Acute Renal Failure – Renal failure will be defined as the development of Kidney 
Disease Improving Global Outcomes [KDIGO] Stage 3 acute kidney injury during the index ICU stay 
after study enrollment.58 

 
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KDIGO Stage 
Serum creatinine criteria 
Urine output criteria 
1 
Increase in serum creatinine of 
more than or equal to 0.3 mg/dl (≥ 
26.4 μmol/l) or increase to more 
than or equal to 150% to 200% (1.5- 
to 2-fold) from baseline 
Less than 0.5 ml/kg per hour for 
more than 6 hours 
2 
Increase in serum creatinine to 
more than 200% to 300% (> 2- to 3-
fold) from baseline 
Less than 0.5 ml/kg per hour for 
more than 12 hours 
3 
Increase in serum creatinine to 
more than 300% (> 3-fold) from 
baseline (or serum creatinine of 
more than or equal to 4.0 mg/dl [≥ 
354 μmol/l] with an acute 
increase of at least 0.5 mg/dl [44 
μmol/l])  
Less than 0.3 ml/kg per hour for 
24 hours or anuria for 12 hours 
OR 
New renal replacement therapy 
(RRT) 
 
30-Day Mortality – Mortality at 30-days. This will be assessed by review of the medical records if the 
participant remains in the hospital or if the participant expired while in the hospital. If the participant 
was discharged, 30-day mortality will be assessed by contacting the participant by phone or by 
searching the National Center for Health Statistics (NCHS) National Death Index (NDI) consistent 
with a recent multicenter phase III trial in sepsis.23 Phone calls will be made by the research team at 
each site.  
 
5.2 Rationale for Outcomes  
Change in SOFA score: Organ failure is highly associated with mortality60 and improvement in 
organ function is a key goal for critical care physicians. In the study by Marik et al.36, participants 
who received the 3-drug regimen had substantial improvements in the trajectory of organ failure 
over the first 72-hours of their ICU stay. If the combination of vitamin C, hydrocortisone, and vitamin 
B1 can improve organ function in the first 72-hours following ICU admission, we believe that 
clinicians will likely quickly adopt this safe and inexpensive therapy. Importantly, this outcome can 
be measured early in the hospital stay and is therefore less likely to be affected by other potential 
elements of hospital care that can affect more distal outcomes (e.g., mortality).  
 
Kidney Injury: Renal failure has been estimated to occur in 23% of participants with sepsis and 
over 50% of participants with septic shock.61 In studies of participants with septic shock, there is a 
step-wise increase in mortality with worsening acute kidney injury (AKI).62 In addition, many 
participants who experience renal injury during septic shock do not recover renal function prior to 
hospital discharge and may require long term dialysis. As both data from the study by Marik et. al.36 
and a separate study of vitamin B1 in septic shock38 have shown substantial improvements in renal 
outcomes, kidney failure is a natural secondary outcome and one that could change practice 
independently from other factors – in other words, many clinicians would likely provide this therapy if 
they knew that kidney function could be protected, since this organ is vital to long-term health. 
 
Mortality: Finally, we will measure 30-day mortality. We anticipate that the combination of vitamin 
C, hydrocortisone, and vitamin B1 will reduce mortality in this high-risk population.  
 
5.3 Additional Secondary Outcomes 
5.3.1 Additional secondary outcomes 
Additional secondary outcomes will include length of ICU stay, length of hospital stay, ventilator-free 
days over the first 7-days after enrollment, shock-free days over the first 7-days after enrollment, 

 
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and the incidence of delirium on day #3 of the ICU stay (as assessed using the Confusion 
Assessment Method [CAM-ICU] system).63 Sites at which the CAM-ICU is performed daily as part of 
standard-of-care should assess whether delirium occurs on any day during the initial ICU stay. See 
Appendix #2.  
 
5.3.2 90-day follow-up for Quality of Life assessment 
Sites may choose to participate in a long-term outcomes substudy exploring the effects of ascorbic 
acid, hydrocortisone, and thiamine vs. placebo on quality of life following sepsis. If a site chooses to 
participate, a trained research assistant/investigator at the site (who is blinded to treatment arm) will 
contact all participants who were alive at 30-days, and perform the SF-36 at day 90 following 
enrollment. The SF-36 is a 36-Item Short-Form Health Survey (SF-36), a validated survey of general 
quality of life in adults, can be administered in person or over the telephone by research personnel. It 
measures eight different dimensions: physical functioning, bodily pain, role limitations due to physical 
health problems, role limitations due to personal or emotional problems, emotional well-being, social 
functioning, energy/fatigue, and general health perceptions, as well as one question asking about 
perceived changes in health. The telephone version of the 36-Item Short-Form Health Survey has 
been validated64,65 and used in sepsis.66-69  
 
5.4 Safety 
5.4.1 Definitions  
The following definitions will be used70:  
 
Adverse event: any untoward medical occurrence in a participant to whom a medicinal product is 
administered and which does not necessarily have a causal relationship with this treatment 
 
Serious adverse event: any untoward medical occurrence that at any dose requires inparticipant 
hospitalization or prolongation of existing hospitalization, results in persistent or significant disability 
or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death 
 
Unexpected serious adverse event: a serious adverse reaction, the nature, severity or outcome of 
which is not consistent with the reference safety information 
 
 
5.4.2 Specific adverse event data collection 
To assess specific amd potentially serious adverse events that may be related to the combination of 
the study medications, we will collect data on the following:  
 
Serious Adverse Event 
Definition 
Hyperglycemia 
Serum glucose >300mg/dl in the first 120-hours after 
enrollment 
Hypernatremia 
Serum sodium (> 150 mmol/L) occurring in the first 120-
hours after enrollment 
New Infection 
As determined by the site principal investigator at each 
site. Should be a new organism or site of infection and 
believed to be unrelated to the initial presenting 
infectious source. Many will have the initiation of new 
antibiotics or a change in antibiotics. 
Catheter-site 
Lung 
Gastrointestinal 
Urinary tract 
Other 
Serious allergic reaction 
Anaphylaxis or other allergic reaction requiring systemic 
corticosteroids. Allergic reaction should be related (or 
suspected to be related) to the study medicaiton  
Renal calculus 
Development of a renal calculus between enrollment 
and 30-day follow-up (based on question asked during 
follow-up phone call). 

 
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5.4.3 Adverse Event Reporting 
All unexpected serious adverse events thought to be related to the study drug, and any 
unexpected fatal or life-threatening adverse events thought to be related to the study drug 
will be recorded in the online CRF, reported directly to the coordinating center, and reported 
to the appropriate IRB shortly following the event per local protocol. In addition, unexpected 
serious adverse events related to the study drug will be undergo expedited reporting to the 
DSMB within 7 days of the coordinating center becoming aware of the event. The DSMB will 
additionally review all adverse events in aggregate after every 50 patients are enrolled. 
 
Adverse events will additionally be reported to the FDA as outlined in 21CFR312.32 and 
summarized below: 
a. All unexpected fatal or life-threatening adverse events thought to be related to the 
study drug will be reported to the FDA within 7 calendar-days of when the ACTS 
team is made aware of the event. 
b. All unexpected serious adverse events thought to be related to the study drug will be 
reported to the FDA within 15 calendar-days of when the ACTS team is made aware.  
c. All serious unexpected adverse events, and any unexpected fatal or life-threatening 
events thought to be related to the study drug, will be reported back to all site 
investigators within 15 calendar-days of the event. 
d. The ACTS team will periodically review all published information relating to the safety 
of each element of the drug combination. Any concerning safety information obtained 
from this review, or otherwise obtained (e.g. from unpublished scientific papers), will 
be reported to the FDA within 15 calendar-days. 
 
5.4.5 Safety Monitoring Labs 
As detailed above, safety monitoring labs will be obtained at 120-hours, after completion of the 
study protocol.  
 
6. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN  
6.1 Sample size calculation 
The study has been powered to have at least 80% power for the primary outcome and all key 
secondary outcomes as follows: 
 
SOFA Score: Based on preliminary data36, we conservatively anticipate a decrease in SOFA score 
of 6 (standard deviation [SD]: 4) in the treatment group and 4 (SD: 2) in the placebo group. With 
these estimates, enrollment of 200 participants (100/arm) at an alpha of 0.05 and using a t-test 
with unequal variance, the trial will provide > 99% power to detect a statistical significant difference 
between groups.  
 
Kidney Injury: Based on preliminary data from our study of vitamin B1 in septic shock,38 we 
anticipate that 30% of participants in the treatment group and 55% in the placebo group will have 
renal failure which will result in a 94% power for this outcome. This calculation and following 
calculation were performed using the Fisher’s exact test. 
  
Mortality: Based on preliminary data36,37,71, we anticipate that the control group will have a mortality 
of 40%. We estimate a treatment effect of 50% (risk ratio: 0.50) resulting in a mortality of 20% in the 
treatment group. With these estimates, 182 participants will lead to 80% power. To further increase 

 
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the trial’s power and due to potential loss-to-follow-up, we will aim to enroll 200 participants. These 
estimates are conservative compared to the Marik et al. study which found a treatment effect 
corresponding to a risk ratio of 0.21 which persisted in adjusted analysis.36  
 
Sample Size Adjustment 
 
If after 100 patients are enrolled, the overall change in SOFA score is less than anticipated in the 
above power analysis and/or the renal failure event rate or mortality rate is lower than predicted, the 
enrollment target of 200 patients may be adjusted accordingly so as to improve power for the 
primary outcome and all key secondary outcomes at the end of the trial period. Specifically, we will 
aim to maintain ≥90% power to detect a 2-point difference in ΔSOFA score (using variance seen for 
the full cohort) and ≥80% power to detect a 50% treatement effect on mortality. Whether to increase 
the study sample size, and the degree of sample size increase, will be decided on by the blinded 
Steering Committee who will not have access to data stratified by treatment group. The Steering 
Committee will take into account logistical and financial considerations when updating the 
enrollment target.  
 
6.2 Statistical analysis plan 
6.2.1 General considerations 
The statistical analyses and reporting will adhere to the CONSORT guidelines.72,73 All tests will be 
two-sided, a p-value < 0.05 will be considered significant, and all confidence intervals will have 95% 
coverage. All analyses will be conducted on a modified intention-to-treat basis only including 
participants receiving at least the first dose of the study medications. In a double-blind trial, this 
approach is unbiased while increasing precision.74 The two groups will be compared in relation to 
baseline characteristics using descriptive statistics.  
 
The persons conducting the statistical analysis will be blinded to the randomized allocation. Groups 
will be designated as “A” and “B” until all pre-specified analyses are performed and shared with all 
authors and the Data Safety Monitoring Board. 
 
6.2.2 SOFA score and renal failure 
The change in SOFA score will be calculated and compared between groups using the Wilcoxon 
Rank Sum test (if the change is not normally distributed) or by a t-test if the change is approximately 
normally distributed. Fisher’s exact tests will be used to compare the incidence of renal failure 
during the index ICU stay. 
  
If a participant expires prior to the 72-hour time point, SOFA scores will be imputed based on a pre-
defined plan as follows. If a participant expires before 24-hours has elapsed, a 20% increase from 
baseline will be imputed. If a participant expires between 24-hours and 48-hours, a 15% increase 
from the 24-hour time point will be imputed. If a participant dies between 48-hours and 72-hours, a 
20% increase from the 24-hour time point will be imputed. Sensitivity analyses will be performed using 
various other imputation techniques. Specifically, we will perform 1) a sensitivity analysis in which the 
worst possible SOFA score (score of 24) is imputed for those participants who expire, 2) a sentivity 
analysis in which the last SOFA score for participants who expire will be carried forward, and 3) a 
sensitivity analysis in which only those patients who survive to 72-hours are included. These 
sensitivity analyses were chosen to model ‘worst-possible’ and ‘best-possible’ scenarios. For the 
secondary outcome of renal failure, participants who expire during their ICU stay will be assessed to 
have developed renal failure if they demonstrated any degree of unresolved KDIGO acute kidney 
injury prior to death. If there was no evidence of acute kidney injury prior to death or if kidney injury 
had fully resolved, these participants will be assessed as not having developed renal failure.  

 
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6.2.3 30-day mortality 
Survival until 30 days will be analyzed using survival analysis. Participants lost to follow-up will be 
censored and the censoring will be assumed non-informative. Results will be presented with 
Kaplan-Meier curves and the groups compared using the log-rank test.75 Hazard ratios with 95% 
confidence intervals will be obtained using Cox’s proportional hazards models.76 The proportional 
hazards assumption will be verified by visual inspection of the Kaplan-Meier curves and statistically 
by including a product term (i.e. “interaction”) between the treatment group variable and the natural 
logarithm of time in the model.77 If the proportional hazards assumption is not met, only the Kaplan-
Meier curves and the p-value from the log-rank test will be presented. 
 
Adverse events and other binary outcomes will be presented and analyzed like renal failure. 
 
6.2.4 Additional Secondary Analyses 
Both ICU and hospital length of stay will be compared using Wilcoxon Rank Sum tests. Ventilator 
and shock free days over the first 7-days after enrollment will likewise be compared using the 
Wilcoxon Rank Sum given that the data will likely be not normally distributed. In these latter two 
analyses, patients who expire prior to 7-days will be assessed to have 0 ventilator or shock free 
days if they had died while on a ventilator or vasopressor respectively. The incidence of delirium will 
be compared using the Fisher’s exact test. For the quality-of-life outcome (i.e. 90-day SF-36), the 
primary analysis will only include patients with available data. As a secondary analysis, multiple 
imputation will be used to estimate SF-36 scores in all patients not known to be dead at 90 -days. 
 
6.2.5 Subgroup analyses  
The analysis will include three pre-defined subgroup analyses for the primary and key secondary 
outcomes according to 1) participants with initially high SOFA scores (≥9). This cut-off was chosen 
to represent a population with a ≥50% predicted likelihood of mortality78 2) baseline vitamin B1 
deficiency and 3) baseline adrenal insufficiency. We will not plan to perform a subgroup analysis 
according to vitamin C deficiency, as prior work has shown that the vast majority of participants with 
septic shock have vitamin C levels below the reference range.36 Vitamin B1 deficiency will be 
defined as a plasma vitamin B1 level ≤ 7 nmol/L as has been previously described.37 Adrenal 
insufficiency will be defined as a cortisol level <10µg/dL.43 The trial is not powered to detect 
subgroup differences and these will be considered exploratory and hypothesis generating.    
 
6.2.6 Statistical stopping criteria  
Since the primary outcome is not mortality, there will be no formal stopping criteria for efficacy. 
There will be no predefined stopping criteria for futility since enrollment of the full cohort might allow 
for detection of efficacy in subgroups or in other outcomes even if the primary outcome is negative.  
 
7. DATA COLLECTION AND MANAGEMENT  
7.1 Data collection process  
Data collection will be the responsibility of the individual site investigators with oversite from the trial 
coordinating center. Most variables (i.e. demographics, sepsis characteristics and laboratory 
results) will be obtained prospectively from the electronic medical record. 30-day follow-up 
regarding safety and mortality end-points will be obtained via telephone call post-discharge (unless 
the participant remains in the hospital at 30-days). Data will be entered directly into the online 
database software (see below).  
 
7.2 Variables 
Will be provided on the online CRF. A PDF version is available upon request. 
 

 
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7.3 Data quality and validity  
Data quality and validity will be optimized by using a detailed data dictionary which will be 
distributed to all sites. Data quality will be monitored both centrally by the coordinating site and 
locally by each site principal investigator.  
 
7.4 Data storage and security  
The database application we will use is REDCap Cloud (https://www.redcapcloud.com/). REDCap 
Cloud is a professional database that provides a user-friendly interface. The REDCap Cloud data 
management system is secure, fully compliant with all regulatory guidelines, and includes a 
complete audit-trail for data entry validation. Through these mechanisms, as well as relevant 
training for all involved parties, participant confidentiality will be safeguarded. All members of the 
research team will be required to complete standardized training in REDCap cloud, which will be 
documented within the software.  
 
The consent form and other trial documents for each participant will initially be stored in a secure, 
locked place at the individual sites. Participating sites will be responsible for maintaining their own 
trial documents and study materials (e.g. signed ICFs, site logs etc). Trial documents generated at 
the Coordinating Center will be maintained the Coordinating Center. Following completion of the 
trial, documents will be maintained for a period of at least 2-years at each site per FDA regulations 
(or longer depending on local IRB guidelines). 
 
8. ETHICAL CONSIDERATIONS  
8.1 Risks and Benefits  
8.1.1 Potential benefits 
Potential Benefits to Individual Participant: Assuming our hypothesis is correct and our results are 
comparable to those previously published36, individual participants enrolled in our study and 
randomized to the treatment arm will benefit from a better trajectory of organ failure and improved 
mortality. As many participants who survive an initial episode of sepsis will have a future admission for 
sepsis, participants participating in this study but randomized to the placebo arm may see a future 
benefit from knowledge gained. 
 
Potential Benefits to Society: Septic shock remains a highly morbid clinical condition for which there 
is no specific therapy. Our study, assuming our hypothesis is confirmed, will provide strong support for 
the widespread adoption of vitamin C, corticosteroids, and vitamin B1 for participants with septic 
shock. This, in turn, will significantly improve participant outcomes and reduce the global burden of 
death related to septic shock. Thus, even if participants are randomized to the placebo arm, their 
involvement with this study has tremendous potential benefits for society as whole. If vitamin C, 
corticosteroids, and vitamin B1 are found to be neutral or harmful (the latter being highly unlikely), 
society will benefit as the study will likely prevent the widespread dissemination of an ineffective 
medication combination.  
 
8.1.2 Potential harms  
Study Drug  
Vitamin C – Ascorbic acid is a water-soluble essential vitamin that is safe even at high doses. 
Nevertheless, adverse effects related to high-dose ascorbic acid have been described. These 
adverse effects include diarrhea/abdominal bloating, increased oxalate excretion, iron overload in 
participants with hemochromatosis, and hemolysis in participants with G6PD deficiency.79  We 
exclude participants with known renal failure,  known G6PD deficiency, or known hemochromatosis 
to limit these potential risks. We will additionally exclude participants with known allergy to ascorbic 

 
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acid. Ascorbic acid has additionally been used in at least 3 clinical trials in critically-ill populations 
without major associated adverse effect.40-42 
 
Hydrocortisone – Hydrocortisone is a well-established medication for the treatment of refractory 
shock in sepsis. Some studies (e.g. CORTICUS) have found an increased incidence of secondary 
infection in participants with septic shock who receive steroids.46 This finding has not been 
replicated in other large trials of corticosteroids for sepsis.47 Additional hypothetical risks to the 
administration of hydrocortisone to participants with septic shock (e.g. increased gastro-intestinal 
bleeding, muscle weakness, and delirium) have not been found in clinical trials of corticosteroids in 
sepsis.46,47 Finally, hydrocortisone may increase the risk of hyperglycemia and hypernatremia.  
 
Hydrocortisone will not be tapered in this study as prior studies have shown benefit with 
corticosteroids in septic shock without a taper.80 In addition, a recent large trial of corticosteroids in 
septic shock (ADRENAL, NEJM 2018) randomized patients to 7-days of corticosteroids or placebo 
and did not include a taper. In that trial there was no reported difference in rates of recurrent shock. 
 
Vitamin B1 – The only potential serious side effect that has been reported from vitamin B1 
administration is an extremely rare anaphylactic reaction (1:250,000 cases) and this might not even 
be of issue with the current manufactured version of vitamin B1 in the United States. The risk of an 
anaphylactic reaction was associated with a vitamin complex dispensed in Europe, and whether 
vitamin B1 was the actual offending agent remains unknown; however, this 0.0004% theoretical 
chance of an adverse reaction is incredibly low. In a series of 989 participants in the United States 
who received intravenous vitamin B1, none had an anaphylactic reaction and the only reported side 
effects were minor consisting of transient local irritation or in one case pruritus (0.093%).81 Further 
safety data comes from the clinical use of intravenous vitamin B1 at our coordinating site.  At Beth 
Israel Deaconess Medical Center (BIDMC, coordinating center) vitamin B1 is provided liberally for 
participants with nutritional deficiency – for example, BIDMC has administered intravenous vitamin 
B1 in over 8,000 separate participant encounters from 2002 until present. Despite this heavy usage, 
no adverse reactions were reported in any of the 8,000 participant encounters.    
 
The combination of vitamin C, hydrocortisone and vitamin B1 – To date, the only study of the 
combination of vitamin C, hydrocortisone and vitamin B1 was the above referenced study by Marik 
et. al.  
 
All procedures will take place at the study site. All research procedures and monitoring will be 
conducted by experienced personnel, and participants will be in the ICU given critical illness. This 
permits closer observation and more detailed monitoring by clinicians familiar with the care of 
participants experiencing and resuscitated from septic shock. 
 
Blood Collection 
Most participants will have existing venous or arterial catheters in place and we will be able to collect 
blood from these ports, essentially eliminating the risks associated with blood collection. In the very 
rare case that a participant does not have an indwelling line, the risk of venipuncture is extremely low, 
and will not exceed the risk of clinical blood draws the participant will already be receiving. 
 
Loss of Confidentiality 
All measures will be taken to ensure that no confidential information is released. All participant 
information will be stored in a password protected database to which only study investigators will 

 
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have access. Additionally, all hard copies of study data will be kept in a locked office accessible only 
to study investigators. Thus, the risk of loss of confidentiality is very low. 
 
9. MONITORING 
9.1 Institutional Review Board (IRB) 
The study will be reviewed and approved by the IRB at each participating site.  
 
9.2 Data Safety and Monitoring Board (DSMB) 
The DSMB will be responsible for safeguarding the interests of trial participants, assessing the 
safety and efficacy of the interventions during the trial, and for monitoring the overall conduct of the 
clinical trial. The DSMB will consist of three clinicians with critical care experience in the 
management of septic participants. An independent biostatistician/epidemiologist will prepare all 
DSMB reports. The DSMB members will be chosen such to avoid any financial or intellectual 
conflicts of interest. The DSMB will review deidentified data after every 50 participants are enrolled 
to assess for safety; unless there are group differences necessitating unblinding (as determined by 
the DSMB), the DSMB will be blinded to treatment groups. The trial will continue while the DSMB 
review data. After each review, the DSMB will create a short report to the steering committee with 
recommendations for continuation, modifications, or termination of the trial. Criteria for 
recommending termination will be at the discretion of the DSMB and there will be no formal 
statistical criteria for termination due to efficacy or safety. A detailed charter for the DSMB will be 
provided.  
 
DSMB Members 
Clifton Callaway, MD, PhD  
University of Pittsburgh 
400A Iroquois 
Pittsburgh, PA 15260 
(412) 647-8287 
callawaycw@upmc.edu 
Professor (tenured) of Emergency Medicine; Executive Vice-Chair of Emergency Medicine; UPMC 
Professor of Emergency Medicine Research 
Expertise: Cardiac Arrest/Clinical Trials  
 
Taylor Thompson, MD  
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
(617) 724-7823 
tthompson1@partners.org 
Professor of Medicine, Harvard Medical School 
Director, Critical Care Translational Research, Pulmonary/Critical Care Unit, MGH 
Medical Director, ARDS Network Clinical Coordinating Center  
Expertise:  Sepsis/Clinical Trials 
 
Shahzad Shaefi, MD MPH [DSMB Chair] 
Beth Israel Deaconess Medical Center 
One Deaconess Raod 
Boston, MA 02115 
(617) 355-6286 
sshaefi@bidmc.harvard.edu 
Attending Physician, Department of Anesthesia, Critical Care and Pain 

 
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Expertise:  Critical Care Medicine 
 
10 CLINICAL MONITORING PLAN 
The detailed clinical monitoring plan has been developed and is available from the Coordianting 
Center upon request. 

 
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11. TIMELINE AND ENROLLMENT  
11.1 Timeline  
 
Pre-trial 
Months 0-5 
Months 6-11 
Months 12-18 
Funding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol development and 
modifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FDA IND approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethical approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration with 
Clinicaltrials.gov 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation of data dictionary  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation of randomization 
list 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site start-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Education of site 
personnel  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSMB monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment and 
assessment of outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cleaning and closing of 
the database 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblinding & Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main manuscript writing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Publication and 
presentation of results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.2 Screening & Enrollment  
Enrollment at each site will be continuously monitored by the site investigator and the principal 
investigator. Each site will be expected to maintain a screening log including all participants who 
meet all eligibility criteria at that site. A standardized screening log will be provided to each site via 
RedCap Cloud—thus allowing for continuous updating of the screening log and will allow capture of 
all screening failures.    

 
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Enrollment will be competitive (i.e. without specific enrollment caps). Number of enrollments at each 
site will be shared with all sites on a monthly basis. Sites will be expected to complete all elements 
of the online CRF within 48-hours of each time point. In the case that a site continuously 
underperforms despite troubleshooting and feedback, the steering committee will evaluate whether 
enrollment will continue at that site. 
 
12. FUNDING 
Funding for the present trial is provided by the Good Ventures Foundation 
(http://www.goodventures.org/). The funding agency will have no role in the design and conduct of 
the study, collection, management, analysis, and interpretation of the data, preparation, review, or 
approval of the manuscript, or the decision to submit the manuscript for publication.  
 
13. PUBLICATION 
The manuscript will adhere to the CONSORT guidelines.72,73 The principal investigator will be 
responsible for assigning authorship position and will follow authorship guidelines from the 
International Committee of Medical Journal Editors.82 At a minimum, all members of the Steering 
Committee and all site Principal Investigators (for sites enrolling at least 10 participants) will be 
included in the primary author list. The main results will be presented at an international conference. 
The trial results will be shared with participating sites and via press releases but not directly with the 
participants. 
 
14. DATA SHARING 
Six months after the publication of the last results, all de-identified individual participant data will be 
made available for data sharing.83 Procedures, including re-coding of key variables, will be put in 
place to allow for complete de-identification of the data. All relevant trial-related documents, 
including the protocol, data dictionary, and the main statistical code, will be shared along with the 
data. There will be no predetermined end date for the data sharing. Data will be available for any 
research purpose to all interested parties who have approval from an independent ethics review 
committee and who have a methodological sound proposal as determined by the steering 
committee of the current trial. Interested parties will be able to request the data by contacting the 
principal investigator. Authorship of publications emerging from the shared data will follow standard 
authorship guidelines from the International Committee of Medical Journal Editors82 and might or 
might not include authors from the steering committee depending on the nature of their involvement.  
 
15. TASKS AND RESPONSIBILITIES  
Principal investigator and sponsor: Overall responsibility for protocol development, funding, budget 
overview, data dictionary development, ethical approval, trial registration, daily management, trial 
oversight and collection of adverse events, contact to the pharmacy, contact to Good Clinical 
Practice monitoring unit and the data and safety monitoring board, assessment of overall 
recruitments, potential recruitment of additional sites, data analysis, and dissemination and 
presentation of results.  
 
Steering committee: Protocol development, funding, budget overview, data dictionary development, 
trial oversight, dissemination of results, responsibilities as principal investigator for short time 
periods.  
 
Site investigators: Responsible for site-specific enrollment, evaluation of eligible patients not 
included, education of personnel at participating sites, reporting of site-specific issues or challenges 
to the principal investigator, participant consent for data collection, collecting and reporting data 
regarding adverse drug events. 

 
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Clinical team: Administration of the study drug, participant consent for data collection.  

 
Vitamin C, Hydrocortisone, and Vitamin B1 in Sepsis – version 2.3 
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Appendices 
 
Appendix 1: Abbreviations 
ICH………………..International Conference on Harmonization 
SPIRIT………………..Standard Protocol Items: Recommendations for Interventional Trials  
ACT………………..Ascorbic Acid, Corticosteroids, and Thiamine  
ESRD………………..End Stage Renal Disease 
SOFA………………..Sequential Organ Failure Assessment 
IND………………..Investigational New Drug 
FDA………………..Food and Drug Administration 
ICU………………..Intensive Care Unit 
SaO2………………..Oxygen Saturation 
FiO2………………..Fraction of Inspired Oxygen 
GCS………………..Glasgow Coma Scale 
UOP………………..Urine Output 
RRT………………..Renal Replacement Therapy 
CAM………………..Confusion Assessment Method 
NCHS……………….. National Center for Health Statistics 
NDI………………..National Death Index 
AKI………………..Acute Kidney Injury 
SD……………….. tandard deviation 
CRF………………..Case Report Form 
BIDMC………………..Beth Israel Deaconess Medical Center (Coordinating Center) 
IRB………………..Institutional Review Board 
DSMB………………..Data Safety and Monitoring Board 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 2: CAM-ICU Form