Thiamine as a Renal Protective Agent in Septic Shock: A Randomized, Controlled Study
Phase: PHASE2
Conditions: Sepsis, Kidney Injury, Thiamine Deficiency
Sponsor: Beth Israel Deaconess Medical Center

 
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Thiamine as a Renal Protective Agent in Septic Shock 
 
 
CLINICAL TRIAL PROTOCOL 
 
             Version 2.1 
July 2nd, 2021 
            IND: 107, 135 
 
 
Clinical Trials.Gov Identifier: NCT03550794 
 
Principal investigators: 
Ari Moskowitz, MD; Michael W. Donnino 
 
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: ari.moskow@gmail.com 
Email: mdonnino@bidmc.harvard.edu 
 
Funded By: 
National Institutes of Health 
National Institute of General Medical Sciences 
 
 
 
Revision history: 
V1.0 June 15th, 2018 
V2.0 December 1st, 2020 (change in PI, added site)  
V2.1 July 2nd, 2021 (clarification of dosing procedures) 
 
 
 
 
 
 
 
 
 

 
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Table of Contents 
 
SYNOPSIS .........................................................................................................................................................5 
TRIAL OVERVIEW ............................................................................................................................................6 
STEERING COMMITTEE ................................................................................................................................7 
1. BACKGROUND AND SIGNIFICANCE ......................................................................................................8 
1.1 Scope of the Problem .............................................................................................................................8 
1.2 Existing Interventions .............................................................................................................................8 
1.3 Renal failure is a common sequela of septic shock ...........................................................................8 
1.4 Thiamine (vitamin B1) is an essential component of mitochondrial energy production ...............8 
1.5 Thiamine may attenuate renal injury in patients with septic shock .................................................8 
2. TRIAL DESIGN ..............................................................................................................................................9 
2.1 Overview ...................................................................................................................................................9 
2.2 Allocation ..................................................................................................................................................9 
2.3 Intervention ..............................................................................................................................................9 
2.3.1 Thiamine ............................................................................................................................................9 
2.3.2 Placebo..............................................................................................................................................9 
2.4 Blinding .....................................................................................................................................................9 
2.5 
Regulatory Issues ..............................................................................................................................9 
3.  SETTING AND PARTICIPANT POPULATION .......................................................................................9 
3.1 Setting .......................................................................................................................................................9 
3.2 Inclusion criteria ................................................................................................................................... 10 
3.3 Exclusion criteria .................................................................................................................................. 10 
4. TRIAL PROCEDURES .............................................................................................................................. 10 
4.1 Participant Identification ...................................................................................................................... 10 
4.2 Consent procedures ............................................................................................................................ 10 
4.3 Randomization ...................................................................................................................................... 11 
4.4 Drug preparation and administration ................................................................................................. 11 
4.4.1 Contingencies and Participant Withdrawal ............................................................................... 11 
4.5 Specimen collection procedures ........................................................................................................ 11 
4.5.1 Timing and volume of blood draw .............................................................................................. 11 
4.5.2 Specimen samples ....................................................................................................................... 12 
4.6 General Sepsis Management ............................................................................................................. 12 
5. OUTCOMES ............................................................................................................................................... 12 

 
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5.1 Definitions .............................................................................................................................................. 12 
5.1.1 Primary Outcome .......................................................................................................................... 12 
5.1.2 Key Secondary Outcomes ........................................................................................................... 12 
5.2 Safety ..................................................................................................................................................... 12 
5.4.1 Definitions ...................................................................................................................................... 12 
5.4.2 Specific adverse event data collection ...................................................................................... 12 
5.4.3 Adverse Event Reporting ............................................................................................................. 13 
6. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN ........................................... 13 
6.1 Sample size calculation ....................................................................................................................... 13 
6.2 Statistical analysis plan ....................................................................................................................... 14 
6.2.1 General considerations ................................................................................................................ 14 
6.2.2 Creatinine at 72-hours.................................................................................................................. 14 
6.2.3 Lactate at 72-hours ....................................................................................................................... 14 
6.2.4 Receipt of Renal Replacement Therapy ................................................................................... 14 
6.2.5 In-hospital mortality ...................................................................................................................... 14 
6.2.7 Cellular Oxygen Consumption .................................................................................................... 15 
6.2.7 Other biomarkers of renal injury ................................................................................................. 15 
6.2.8 Subanalyses .................................................................................................................................. 15 
7. DATA COLLECTION AND MANAGEMENT .......................................................................................... 15 
7.1 Data collection process ....................................................................................................................... 15 
7.2 Variables ................................................................................................................................................ 15 
7.3 Data quality and validity ...................................................................................................................... 15 
7.4 Data storage and security ................................................................................................................... 16 
8. ETHICAL CONSIDERATIONS ................................................................................................................. 16 
8.1 Risks and Benefits ............................................................................................................................... 16 
8.1.1 Potential benefits .......................................................................................................................... 16 
8.1.2 Potential harms ............................................................................................................................. 16 
9. MONITORING............................................................................................................................................. 17 
9.1 Institutional Review Board (IRB) ........................................................................................................ 17 
9.2 Data Safety and Monitoring Board (DSMB) ..................................................................................... 17 
10 CLINICAL MONITORING PLAN ............................................................................................................. 17 
11. FUNDING .................................................................................................................................................. 17 
12. DATA SHARING ...................................................................................................................................... 18 
References ...................................................................................................................................................... 19 

 
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SYNOPSIS 
 
The “The “Thiamine for Renal Protection in Septic Shock (TRPSS)” study is a randomized, 
clinical trial that aims to determine the impact of Thiamine vs. Placebo on kidney injury in patients 
with 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 
Thiamine for Renal Protection in Septic Shock (TRPSS) 
Clinical Trials Number 
NCT03550794 
Sources of monetary or 
material support 
National Institute of General Medical Sciences 
Study Sites 
Beth Israel Deaconess Medical Center, Long Island 
Jewish Medical Center, North Shore Medical Center 
Condition studied 
Septic Shock 
Interventions 
Thiamine 200mg IV twice daily for 3 days  
Comparator  
Placebo  
Inclusion criteria 
1) Adult ≥18 years of age 
2) Suspected or Confirmed Infection (defined as 
collection of a blood/fluid culture and provision of an 
antimicrobial) 
3) Receipt of a vasopressor agent (e.g. norepinephrine, 
phenylephrine, vasopressin) 
4) Serum lactate ≥2mmol/L 
5) Creatinine >1.0mg/dL 
Exclusion criteria 
1) Clinical indication for thiamine administration 
(alcoholism, known or highly suspected deficiency) or 
treatment with thiamine beyond the amount found in a 
standard multivitamin within the last 10 days 
2) Renal replacement therapy within the past 30 days 
3) Comfort measures only or anticipated withdrawal of 
support within 24 hours 
4) Protected populations (pregnant women, prisoners) 
5) Known thiamine allergy 
 
Study type 
Interventional 
Allocation: Randomized (1:1) 
Intervention model: Parallel group 
Masking: Double-blind 
Target sample size 
88 Participants (44/arm) 
Primary outcome 
Change in creatinine over the first 72-hours after 
enrollment 
Key secondary outcomes 
 
Incidence of renal failure requiring renal 
replacement during index ICU stay 
 
Length of ICU stay 
 
Hospital mortality 

 
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STEERING COMMITTEE 
 
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  
Michael Donnino, M.D.  
Associate Professor of Medicine 
Director, Center for Resuscitation Science  
Beth Israel Deaconess Medical Center 
Harvard Medical School  
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  
Samir Parikh, MD 
Associate Professor of Medicine 
Beth Israel Deaconess Medical Center 
Harvard Medical School  
Conflicts of interest 
The members of the steering committee have no financial conflicts of interest related to the current 
trial.  
 
 

 
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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 Renal failure is a common sequela of septic shock and is associated with poor outcomes. 
Renal failure has been estimated to occur in 23% of patients with severe sepsis and 51% of patients 
with septic shock.36 Further, the development of renal failure during sepsis or septic shock portends 
a significantly worse outcome.36 In one study of patients with septic shock, there was a step-wise 
increase in mortality with worsening AKI.37 These data suggest that attenuating kidney injury in 
sepsis will improve outcomes.   
 
1.4 Thiamine (vitamin B1) is an essential component of mitochondrial energy production and 
may reduce oxidative stress. Thiamine is a key component in aerobic metabolism, working as a 
cofactor for pyruvate dehydrogenase. When thiamine levels are insufficient, pyruvate is unable to 
enter the Krebs Cycle, and pyruvate is converted to lactate, rather than acetyl-coenzyme A.24,25 
Relative thiamine deficiency, therefore, causes a shift in metabolism to the anaerobic pathway, 
resulting in elevated serum lactate levels. Thiamine is also a critical component of the pentose 
phosphate pathway, which may reduce oxidative stress.9,10 As the kidney maintains a high 
mitochondrial abundance relative to other organs,8 it may be especially susceptible to perturbations 
in mitochondrial function.  
 
1.5 Thiamine may attenuate renal injury in patients with septic shock. In a post-hoc analysis of 
data collected during a randomized trial of thiamine vs. placebo,3 patients who received thiamine 
were less likely to require renal replacement therapy (RRT) and had lower creatinine levels over 
time as compared to patients who received placebo.4 That study, however, was limited by its post-
hoc design, an imbalance in premorbid renal function between groups, and inconsistency with 
regards to the timing of biomarker measurement. In a non-randomized observation study of patients 
with severe sepsis or septic shock at a single center, those who received the combination of 
thiamine, vitamin C, and hydrocortisone were less likely to require RRT as compared to historical 
controls at the same site (3/31 [10%] vs. 11/30 [33%], p=0.02).26 This study likewise provides some 
support for thiamine as a renal protective agent in sepsis, but is limited by its quasi-experimental 
design and the associated potential for bias. 

 
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2. TRIAL DESIGN 
2.1 Overview 
This will be an investigator-initiated, randomized, placebo-controlled, parallel group, double-blind, 
superiority trial of thiamine vs. placebo in participants with septic shock. A total of 88 adult 
participants will be enrolled. The primary outcome will be the change serum creatinine 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 thiamine or placebo in blocks with random 
sizes of 2 or 4. The randomization will be stratified according to site.38 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.   
 
2.3 Intervention 
2.3.1 Thiamine 
The study drug will consist of thiamine 200mg in 50ml of 0.9%NACL saline solution given parenterally 
every 12 hours for 3 days. 
 
2.3.2 Placebo  
The placebo will consist of matching volumes of normal saline (0.9% NaCl).  
 
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.  
 
Vitamin B1 is not known to have distinctive rapid effects or other characteristics 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 this study (IND # 107, 135). 
 
The trial has been registered on ClinicalTrials.gov: NCT03550794 
 
3.  SETTING AND PARTICIPANT POPULATION 
3.1 Setting 
The trial will be conducted at Beth Israel Deaconess Medical Center. Additional sites might be 
recruited if needed.  
 
Enrolling Sites 
 

 
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Enrolling Site 
Site Investigator 
Beth Israel Deaconess 
Medical Center 
Ari Moskowitz MD; Michael 
Donnino MD 
North Shore Medical Center 
Jonathan Gong MD 
Long Island Jewish Medical 
Center 
Jonathan Gong MD 
 
 
3.2 Inclusion criteria 
Inclusion criteria:  
1) Adult ≥18 years of age 
2) Suspected or Confirmed Infection (defined as collection of a blood/fluid culture and provision of 
an antimicrobial) 
3) Receipt of a vasopressor agent (e.g. norepinephrine, phenylephrine, vasopressin) 
4) Serum lactate ≥2mmol/L 
5) Creatinine >1.0mg/dL 
 
3.3 Exclusion criteria  
Exclusion criteria: 
1) Clinical indication for thiamine administration (alcoholism, known or highly suspected deficiency) 
or treatment with thiamine beyond the amount found in a standard multivitamin within the last 10 days 
2) Renal replacement therapy within the past 30 days 
3) Comfort measures only or anticipated withdrawal of support within 24 hours 
4) Protected populations (pregnant women, prisoners) 
5) Known thiamine allergy 
 
Justification of Inclusion and Exclusion Criteria: The inclusion criteria reflect the definition of septic 
shock put forth by the Society of Critical Care Medicine and European Society of Intensive Care 
Medicine Task Force.16 We will include only patients with a creatinine of >1.0mg/dL to ensure we 
are evaluating a true ‘at-risk’ population for kidney injury. The trial end-points cannot be assessed in 
patients already receiving renal replacement therapy, and this population will therefore be excluded. 
We have chosen to include adult patients only due to differences in etiology and treatment of septic 
shock in children. Also, BIDMC does not have a pediatric unit. We will exclude patients who are 
presently receiving or who will likely receive supplemental thiamine for clinical purposes as we feel it 
would be unethical to randomize these patients to the placebo arm. We will also exclude patients 
with a known thiamine allergy. 
 
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.  
 
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 

 
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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 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.  
 
4.4 Drug preparation and administration 
The thiamine will be mixed in 50ml of normal saline and administered intravenously over 45-60 
minutes. The placebo will be given using techniques and volumes matching those of the study 
medication. 
 
All study medications will be continued for 3-days or until the participant expires.  
 
4.4.1 Contingencies and Participant Withdrawal  
 In the unlikely event that a participant is discharged alive from the hospital prior to 3 days after 
enrollment, all study medications will be stopped.The participant will remain in the study and will 
be followed for outcomes. 
 If a patient is tranfserred to the hospital ward from the intensive care unit, the study drug will 
continue while the patient is in the hospital until 3 days.  
 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 a participant withdraws from the study, further administration of study meds will be stopped. 
Data collected prior to withdrawal will be maintained and the patient will be followed for outcomes, 
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. Blood will be obtained by 
venipuncture, or from an existing venous or arterial catheter.  
 
Specimen Collection Time Points 
1. T1=0 hrs (just before study drug administration) 
2. T2=24 hrs (+/- 4 hrs) 
3. T3=48 hrs (+/- 4 hrs) 

 
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4. T4=72hrs (+/- 4hrs) 
 
4.5.2 Specimen samples 
At the T1, T2, T3, and T4 time points, blood will be sent for complete serum creatinine and a 
venous/arterial 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 4 hours of the time point.  
 
In addition to traditional clinical markers, 20ml of blood will be obtained for future biomarker analysis 
(including inflammatory biomarkers, markers of endothelial function, and markers of mitochondrial 
function), and thiamine levels.  
 
4.6 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.39 Elements of 
sepsis care should be reported on the online case report form (CRF). 
 
5. OUTCOMES 
5.1 Definitions 
5.1.1 Primary Outcome 
The primary outcome will be creatinine change over the first 72-hours after enrollment with a focus 
on the 72-hour creatinine measurement.  
 
5.1.2 Key Secondary Outcomes 
 
Incidence of Acute Renal Failure  
 
Length of ICU stay 
 
In-hospital Mortality  
 
Other biomarkers of renal injury (Serum cystatin C, NGAL, and KIM-1) 
 
Peripheral blood mononuclear cell mitochondrial oxygen consumption 
 
5.2 Safety 
5.4.1 Definitions  
The following definitions will be used40:  
 
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 inpatient 
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 
 
Suspected 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 and potentially serious adverse events that may be related to the study 
medication, we will collect data on the following:  

 
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Serious Adverse Event 
Definition 
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  
 
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 TRPSS 
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 TRPSS 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 TRPSS 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. 
 
6. SAMPLE SIZE CALCULATION AND STATISTICAL ANALYSIS PLAN  
6.1 Sample size calculation 
The planned sample size is based on the proposed primary outcome. In this longitudinal repeated 
measures study design, we have 4 time points, and are interested in measuring the effect of the 
intervention (thiamine) on the mean level of creatinine at the last time point (72-hours). We 
hypothesized that at 72-hours, the estimated mean difference (placebo-thiamine) would have similar 
magnitude as the pilot study’s 4 observed mean difference (about 0.51). We used a linear mixed-
effects model to estimate the parameters of the variance-covariance structure of the repeated 
measures data and used these estimates in obtaining the effect estimate of the mean difference at 
each of the 4 time points, with emphasis on 72-hours. We simulated the data using the estimated 
variance-covariance components from the pilot data which 0.19 for within-subject variance, and 1.3 
for between-subject variance, and the estimated mean differences for the 4 time points from the 
pilot data. These data were put through a linear mixed effects model where linear contrasts were 
used for estimation at each time point. We then computed the non-centrality parameter and the 
corresponding F-statistic value. Together with the numerator and denominator degrees of freedom, 
the estimate of power at each time point was derived. Through different iterations of sample size, at 
N=80 (40 patients in each arm), we obtained a power of 0.80 at 72-hours. This method of power 
analysis for linear mixed-effects model was published in 2000.41 To account for drop-out and to 

 
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ensure adequate power at the end of the trial, we will plan to enroll a total of 88 patients (44 per 
arm).  
 
6.2 Statistical analysis plan 
6.2.1 General considerations 
The statistical analyses and reporting will adhere to the CONSORT guidelines.42,43 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.44 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 Creatinine at 72-hours 
Assuming no unbalanced potentially confounding variables (as would be expected in this 
randomized trial), we will compare repeated measures of creatinine levels at each time point (0h, 
24h, 48h, 72h) between arms using repeated measures analysis. A compound symmetry 
covariance structure will be used. If a patient receives renal replacement therapy or dies before any 
time point, creatinine levels will be imputed by carrying forward the last known value before the 
event. Study site will be controlled for as a fixed-effect in the regression model.  
 
6.2.3 Lactate at 72-hours 
Assuming no unbalanced potentially confounding variables (as would be expected in this 
randomized trial), we will compare repeated measures of lactate levels at each time point (0h, 24h, 
48h, 72h) between arms using repeated measures analysis. A compound symmetry covariance 
structure will be used. If a patient receives renal replacement therapy or dies before any time point, 
lactate levels will be imputed by carrying forward the last known value before the event.  
 
6.2.4 Receipt of Renal Replacement Therapy 
Fisher’s exact tests will be used to compare the incidence of renal failure requiring renal 
replacement therapy during the index ICU stay. This outcome will be truncated at 60 days if the 
patient remains alive and in the ICU at that time.  
 
6.2.5 In-hospital mortality 
In-hospital mortality will be analyzed using survival analysis. Results will be presented with Kaplan-
Meier curves and the groups compared using the log-rank test.45 Hazard ratios with 95% confidence 
intervals will be obtained using Cox’s proportional hazards models.46 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.47 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. The patient will be considered 
to have survived their hospitalization if they remais alive and in the hospital at 60 days. 
 
6.2.6 Length of ICU stay 
Length of ICU stay will be compared between groups using Wilcoxon Rank Sum tests. As in the 
above analyses, this will be truncated at 60 days. 
 

 
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6.2.7 Cellular Oxygen Consumption 
Basal and maximum cellular oxygen consumption by peripheral blood mononuclear cells will be 
compared using a t-test   
 
6.2.7 Other biomarkers of renal injury 
Other renal injury biomarkers (cystatin C, NGAL, and KIM-1) will be measured at enrollment and 24-
hours and compared using repeated measures analysis to account for within subject correlation. 
Days alive and free of renal failure, frequency and duration of renal replacement therapy, and 
hospital mortality will be compared using t-tests and chi-square tests where appropriate. Basal and 
maximum cellular oxygen consumption will be compared using a t-test. Analyses will be conducted 
on a modified intention-to-treat basis, including only those subjects who receive a dose of study 
drug. 
 
6.2.8 Subanalyses  
A pre-planned subanalysis of the primary outcome will be performed in the group with baseline 
thiamine deficiency. Thiamine deficiency will be defined as a plasma vitamin B1 level ≤ 7 nmol/L as 
has been previously described.48 The trial is not powered to detect subgroup differences, hence this 
analysis will be considered exploratory and hypothesis-generating.    
 
7. DATA COLLECTION AND MANAGEMENT  
7.1 Data collection process  
Data collection will be the responsibility of the principal investigator. Creatinine and lactate levels 
will be obtained from blood draws at 0hr, 24hr, 48hr, and 72hr.  Most other variables (i.e. 
demographics, sepsis characteristics and laboratory results) will be obtained prospectively from the 
electronic medical record up until the time the patient dies or is discharged from the hospital. Data 
will be entered directly into the online database software (see below).  
 
7.2 Variables 
Will be provided on the online CRF.  
 
7.3 Data quality and validity  
Several measures are taken to assure data quality. They are as follows: 
1) Database access is restricted to team members specifically trained in data entry for this study. In 
addition, team members will only have access specific to their roles and only data abstractors will 
have the capacity to enter/change data entries. 
2) The REDCap Cloud database is specifically designed to maintain data integrity by preventing 
unintentional changes or lost data. Servers back up all data on a nightly basis with redundant systems. 
The REDCap data management system is fully HIPAA-compliant and includes a complete audit-trail 
for data entry validation. For additional details, see below. 
 3) Our group has a full-time database manager who will oversee the database and maintain quality. 
They will perform weekly data checks evaluating for any missing data or other concerns. Weekly reports 
will be generated on all missing data elements and feedback provided directly to the data abstractors on 
any issues that are identified. The weekly reports will allow for accounting of all data in real-time and 
allow for direct feedback to data abstractors such that future recurrences of missing data entry will be 
minimized. Of note, all missing data will be coded indicating the reason for being missing. 
 

 
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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 with capacity for easy 
statistical interface and is endorsed by the National Institutes of Health. The principal investigator 
and other members of the Center for Resuscitation Science are experienced with REDCap.  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. Following completion of the trial, documents will be maintained for a period of at least 
2-years 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 Subject: Assuming our hypothesis is correct and our results are 
comparable to those previously published, individual patients enrolled in our study and randomized to 
the treatment arm will benefit from the attenuated risk of kidney injury. All patients participating in this 
study, including those in the placebo arm, may see a future benefit from knowledge gained since 
many patients who survive an initial episode of sepsis will have a future admission for sepsis. 
 
Potential Benefits to Society: Septic shock remains a highly morbid clinical condition for which there 
is no specific therapy. Assuming our hypothesis is confirmed,  our study will provide strong support for 
the widespread adoption of Thiamine therapy for patients with septic shock. This, in turn, will 
significantly improve patient outcomes and potentially reduce the global burden of death due to septic 
shock.  
 
8.1.2 Potential harms  
Study Drug  
Vitamin B1 – Vitamin B1 (thiamine) has an excellent safety profile. The only reported potentially 
serious side effect is an extremely rare anaphylactic reaction (1:250,000 cases) and this might not 
even be of issue with the current manufactured version of thiamine in the United States. The risk of 
an anaphylactic reaction was assessed with a vitamin complex dispensed in Europe and it is not 
known if  thiamine was the actual offending agent.  However, the 0.0004% theoretical chance of an 
adverse reaction seen in the European study is incredibly low. In a series of 989 patients in the 
United States who received intravenous thiamine, 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%).50 At BIDMC (approximately 600 inpatient beds), thiamine is provided liberally for patients 
with nutritional deficiency – for example, BIDMC has administered intravenous thiamine in over 
8,000 separate patient encounters from 2002 until present. Despite this heavy usage, no adverse 
reactions have been reported. 
 
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 rare 

 
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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 
The risk of a privacy and confidentiality breach for all screened and enrolled patients will be 
minimized at multiple levels. After enrollment, trained research assistants will abstract all of the 
required data prospectively under the supervision of a research nurse, fellow, or senior investigator. 
All data will initially be recorded on a paper case report form, which will be stored in a locked file 
cabinet in a locked room while not in use. Two research assistants will independently enter the data 
into the secure online database (REDCap). In compliance with HIPPA privacy and security 
regulations, REDCap contains multiple levels of security including data safety (e.g., restricted 
access to fields), user safety (e.g. password authentication access), application security (e.g., role-
based access to features, access audit trails), and hosting service security (e.g., firewall, secure 
sockets layer). Taken together, these features ensure access control, audit control, data integrity, 
user authentication, and transmission security. Data from the present trail will be set up in REDCap 
to ensure exported datasets are de-identified as defined in the HIPAA privacy regulation [45 C.F.R. 
§164.514 (b)(2)]. A 21 CFR Part 11 compliance document is available upon request from the 
software’s creators. All study investigators have taken the CITI program exam and are well versed 
in patient confidentiality. 
 
9. MONITORING 
9.1 Institutional Review Board (IRB) 
The study is  approved by the IRB at BIDMC (#2018P000204).  
 
9.2 Data Safety and Monitoring Board (DSMB) 
A DSMB comprised of three physicianswith critical care experience in the management of septic 
pations 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. 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 30 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.  
 
10 CLINICAL MONITORING PLAN 
The detailed clinical monitoring plan has been developed and is available upon request.  Subjects 
will be monitored throughout their hospital stay and will be immediately treated if any adverse 
events occur.  All research procedures and monitoring will be conducted by experienced personnel, 
and almost all patients will be in the ICU given their potential comatose and critically ill state.  
Admittance to the ICU will permit closer observation and more detailed monitoring by clinicians 
familiar with the care and resuscitation of septic shock patients. 
 
11. FUNDING 
Funding for the present trial is provided by the National Institutes of Health, specifically the National 
Institure of General Medical Sciences.The funding agency will have no role in the design and 

 
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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.  
 
12. DATA SHARING 
Six months after the publication of the last results, all de-identified individual participant data will be 
made available for data sharing.50 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 Editors.49  

 
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