Randomized, Double-blind, Placebo-controlled Trial of the Effect of Thiamine on Oxygen Consumption After In-hospital Cardiac Arrest.
Phase: PHASE2
Conditions: Cardiac Arrest, Shock, Lactic Acidosis, Thiamin Deficiency
Sponsor: Beth Israel Deaconess Medical Center

 
 
 
 
 
Thiamine vs. Placebo to Increase Oxygen Consumption After Cardiac Arrest: Study protocol 
and statistical analysis plan 
 
NCT02974257 
 
Finalized and submitted to Clinicaltrials.gov: August 4, 2022 
 
Principal Investigator and corresponding author: Katherine M Berg, MD 
kberg@bidmc.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 

Introduction  
The study protocol for Thiamine vs. Placebo to Increase Oxygen Consumption After Cardiac 
Arrest is summarized in the original posting for the trial on clinicaltrials.gov, NCT02974257. 
Additional details on the protocol and the statistical analysis plan are included in this 
document, which is being submitted for posting prior to unblinding or initiation of any data 
analysis.  
 
Methods 
Trial Design: 
This is a randomized, double-blind, placebo-controlled trial of high-dose intravenous 
thiamine to decrease lactate and increase global oxygen consumption (VO2) in patients who 
achieve return of spontaneous circulation (ROSC) after an in-hospital cardiac arrest (IHCA).  
Consent:  
Eligible patients will be intubated and sedated at the time of eligibility. Therefore, the legally 
authorized representative (LAR) will be approached by the research team, and written 
informed consent will be obtained prior to beginning the study protocol. If patients improve 
to the point of being consentable, they will be approached for consent for continuing 
participation. 
Intervention:  
Thiamine 500mg in 100mL 0.9% saline IV every 12 hours for 48 hours, with initial dose given 
within 12 hours of ROSC. Control arm will receive 0.9% saline of the same volume and 
frequency. 
Patient Population 
Inclusion Criteria: 
● Adult patient (age ≥ 18 years) 
● Cardiac arrest occurring while admitted to the hospital, with sustained (>20 minutes) 
return of spontaneous circulation (ROSC) 
● Mechanically ventilated at the time of enrollment 
● Within 12 hours of cardiac arrest event 
Exclusion Criteria: 
● 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 

● Comfort measures only or anticipated withdrawal of support within 24 hours 
● Severe agitation 
● Protected populations (pregnant women, prisoners) 
Randomization and blinding 
The randomization will be done in a 1:1 ratio between treatment and control arms in blocks of 
four. Random assignments will be generated by computer, and a randomization list will be 
provided to and kept in the research pharmacy. A sealed envelope with arm assignment will be 
placed in each patient’s chart for the unexpected and rare occurrence of the need to un-blind 
the study. Randomization will be stratified by screening lactate value, with stratification groups 
of lactate > 5 or ≤ 5.  
 
The research pharmacy, following the randomization list as above, will release study drug for 
each enrolled patient. Intravenous thiamine is odorless and colorless, and will be mixed in a 
100mL bag of normal saline (NS). Patients assigned to the placebo arm will receive an identical 
volume of NS. It is not possible to tell the difference between thiamine and placebo using this 
method, and all study personnel with the exception of the research pharmacist will be blinded 
to the intervention. Unblinding will take place in the unlikely event of a case of suspected 
anaphylaxis or other severe reaction to study drug 
Study Registration and Monitoring 
The trial was registered at clinicaltrials.gov (NCT02974257) on November 18, 2016, prior to 
study start. Adverse events were monitored by the PI. There were no pre-specified stopping 
rules for futility or efficacy. No statistical interim analyses were planned. This trial was 
approved by the Internal Review Board (IRB) at Beth Israel Deaconess Medical Center. 
 
Protocol:  
Intervention: Thiamine 500mg IV in 100ml 0.9% saline every 12 hours for 48 hours (5 doses) 
Placebo: 100ml 0.9% saline IV every 12 hours for 48 hours (5 doses) 
Blood collection: Blood will be drawn at enrollment/time 0 (prior to study drug 
administration), 6 hours, 12 hours, 24 hours and 48 hours. Blood for all study labs will be 
collected by the patient’s clinical nurse, using an existing intravenous or arterial line if 
present. Nursing or phlebotomy will perform a peripheral stick to obtain research blood only 
if no line is available for use. Research assistants will take all blood for immediate processing 
per the requirements of each lab test. Lactate and creatinine will be processed in the BIDMC 
clinical lab, and other clinical labs that will be obtained from the patient record include 
platelet levels and total bilirubin (for SOFA score calculation). All other research assays (see 

list of secondary outcomes) will be completed in the BIDMC Center for Resuscitation Science 
Lab.  
VO2 monitoring: All patients meeting criteria for metabolic data collection (FiO2 60% or less 
and positive end expiratory pressure (PEEP) 15cm H2O or less) will be connected to the VO2 
monitor at enrollment or as soon as the ventilator criteria are met, if still within 48 hours of 
enrollment. The monitor is made by General Electric, monitor version B650 with gas 
exchange module, and attaches in-line to the ventilator tubing, between the endotracheal 
tube and the Y-connector. All connections and disconnections of the monitor will be done by 
a trained respiratory therapist, with study staff present at the bedside. The tubing is attached 
to sensors that collect data breath-by-breath and that data is continuously recorded while 
connected to a laptop with dedicated software for this purpose. At the end of the study 
protocol all data will be downloaded and stored in a secure CSV file.  
Cerebral Performance Category (CPC) and Cerebral Performance Category-Extended (CPC-
E) score assessments: CPC and CPC-E will be assessed just prior to hospital discharge, at 30 
and 90 days. Research staff will approach patients for assessment of CPC-E prior to hospital 
discharge. The CPC-E includes several questions testing logical thinking, attention and 
memory. The outpatient portion, which will be assessed in addition to the inpatient portion 
after hospital discharge/at 30 and 90 days, also includes questions about functional status 
and return to work. The CPC score will also be assessed by research staff prior to discharge. 
Phone calls to the patient will be made at 30 and 90 days (if the patient is no longer in the 
hospital).  
 
Outcome Measures 
Primary Outcome: Lactate change 
Note: At the time of trial start, the primary outcome was change in oxygen consumption (VO2) 
over 48 hours and change in lactate was a secondary outcome. After the first year, however, 
the primary outcome was changed to lactate, and VO2 was changed to secondary. This change 
was made due to too many patients not meeting the ventilator criteria to allow collection of 
VO2 data for at least the initial several hours of the study protocol, and enrollments therefore 
lagging behind. This change in primary outcome was posted at that time on clinicaltrials.gov 
and was submitted and approved by our Internal Review Board (IRB).  
Prespecified Secondary Outcomes: 
1. Change in VO2 over 48 hours 
2. Absolute level of lactate over 48 hours 
3. absolute level and the change in oxygen consumption over 48 hours 

4. absolute level and the change in pyruvate dehydrogenase (PDH) activity, quantity 
and specific activity over 48 hours 
5. absolute level and change in creatinine over 48 hours 
6. mortality (hospital discharge, 30 and 90 days) 
7. Cerebral Performance Category (CPC) score (hospital discharge, 30 and 90 days) 
8. Cerebral Performance Category-Extended (CPC-E) (hospital discharge, 30 and 90 days) 
9. absolute level and the change in Sequential Organ Failure Assessment (SOFA) Score 
SOFA over 48 hours 
10. renal failure during first 7 days following arrest 
11. absolute level and change in cellular oxygen consumption rate over 48 hours 
Sample Size Calculations:  
Lactate: The analysis method for lactate will be linear mixed-effects modeling (LMM). This type 
of modeling is used in longitudinal or repeated-measures studies to consider the correlation of 
within-subject measurements and can optimize the power. In this case, we also want to include 
the interaction between arm (thiamine or placebo) and time, as our hypothesis is that the 
change of lactate over time will vary by arm. In this case, each subject will have lactate 
measurements at multiple time points, which are correlated. Since LMM will be used for the 
analysis, we have also used LMM for power analysis for this endpoint. We evaluated 
approximately 61 post-arrest patients in our databases, with similar characteristics to patients 
who will be included in this study, for whom we had lactate measurements over 24 hours. We 
observed that the post-CA patients have a mean lactate of 3.8±2.2 mmol/L at 6 hours, 3.5±2.2 
at 12-hours, and 2.9±2 at 24-hours. We took a conservative position to assume that the 
potential effect size (the mean difference of lactate between the two arms) will be 33%. That is, 
we assumed that the mean lactate level at the three different time points in the thiamine arm 
would be 2.55, 2.35, and 1.94. Using LMM, accounting for an interaction between arm and 
time, and assuming a within-subject correlation of 0.7 with no decay in correlation over time, 
we will need 58 subjects (29 in each arm) to obtain >80% power with type-I error of 0.05 for 
detecting a difference in the change in lactate over 24 hours between arms. We assumed an 
average baseline (time 0) lactate of 4, and a standard deviation of 2. Our inclusion criteria 
restricts the patients population to those with a lactate >/=3, which is why we made our 
standard deviation slightly smaller. We also conducted a sample size calculation using the 
ANCOVA method for one baseline and 3 follow up lactate measurements. For this method we 
used the 24 hour means of 2.9 (+/- 2) and 1.9(+/-1.5), assumed a within-subject correlation of 
0.7 between time points, and obtained target number of 54 patients (27 in each arm) to 
achieve 90% power with a type-I error of 0.05. To be conservative we will plan to enroll 60 
patients, to account for possible drop out.  

VO2: Prior to our pilot study, there was no data on the effect of thiamine on VO2 in hospitalized 
patients. We have therefore relied on our pilot data for the sample size calculation. In critically 
ill patients with preserved cardiac index (>2.4L/min/m2), the average increase in VO2 after 
thiamine administration was 35mL/min. Using the average change in VO2 of 35mL/min and the 
average standard deviation of 45mL/min, we will need to enroll 28 patients in each arm to 
achieve a power of 0.8 with a Type I error of 0.05. We have chosen to enroll 30 in each arm to 
allow some room for drop out. 
Statistical Analysis 
General Principles 
The statistical analyses and reporting will adhere to the CONSORT guidelines. 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 medication. In a double-blind 
trial, this approach is unbiased while increasing precision.  Analyses will not be adjusted for 
covariates unless there are significant arm differences in baseline characteristics. 
 
Baseline Characteristics 
A description of the baseline characteristics will be presented by treatment arm. Categorical 
variables will be summarized by frequencies and percentages. Percentages will be calculated 
according to the number of patients for whom data are available. Continuous variables will be 
summarized using mean+/-standard deviation or median (interquartile range) based on the 
distribution of the data.  
Analysis of Primary Outcome 
We will compare repeated measures of lactate levels at each time point (0h, 6h, 12h, 24h, 48h) 
between arms using a linear mixed-effects model with an independent variance–covariance 
matrix to account for the correlation of within-patient repeated measures. Covariates in the 
model include treatment arm, time (as a categorical variable with five levels, defined as 
baseline, 6 hours, 12 hours, 24 hours, and 48 hours), and the interaction between treatment 
arm and time. Linear contrasts will be used to estimate the mean difference between 
treatment arms for each time point. If a patient dies before 48 hours, levels will be imputed by 
carrying forward the last known value before the event with a 20% penalty. A sensitivity 
analysis will be performed in which patients who die before 48 hours are assigned the last 
known value before the event without a penalty. 

 
Analysis of Secondary Outcomes 
Lactate levels over 48 hours 
To test for a difference in absolute lactate level values, we will compare means or medians, as 
appropriate, between arms using either a Student’s t-test or a Wilcoxon rank-sum test, 
respectively, at 6, 12, 24 and 48 hours. 
Change in oxygen consumption (VO2) over 48 hours 
Prior to unblinding or analysis, oxygen consumption data will be cleaned using an algorithm 
designed by our research team in R version 4.1.1 (R Foundation for Statistical Computing, 
Vienna, Austria). This automated algorithm excludes VO2 data (and the corresponding value for 
carbon dioxide production, or VCO2) if one or more of the following criteria is met: all values 
recorded in the 10 min following a change in FiO2 of 10%, all values recorded while FiO2 is >61% 
(61% used in order to capture all situations when the ventilator is set for an FiO2 of 60% or less, 
as the monitor reports this number to two decimal places and a set number of 60% may be 
recorded as 60.54%), all values deviating 15% or more from the mean of the previous five 
values and the next five values (i.e, deviating 15% from the mean of the ten neighboring data 
points), and all VO2 values out of physiologic range unless these are persistent for more than 30 
minutes, as these measurements are considered artifacts. Values that will be considered out of 
physiologic range are VO2<80 mL/kg/min or VO2>800 mL/kg/min. We allow these values if they 
persist for at least 30 min and if they are not excluded per the algorithm for other reasons, as 
critically ill post-arrest patients can sometimes have values well outside of standard normal 
range, due to temperature, medication use such as sedatives and neuromuscular blockade 
and/or alterations in metabolic function. The respiratory quotient (RQ) is calculated as the ratio 
of VCO2/VO2 at each time point. After data is run through the algorithm and still prior to 
unblinding, there is a final visual review of a graphical print-out of all data points for each 
patient to provide a secondary confirmation that values were kept or dropped appropriately.  
 
To investigate the association between treatment and gas metabolism data (VO2, VCO2 and RQ) 
in the first 48 hours after ROSC, we will compare the area under the curve (AUC) for each 
oxygen consumption variable between the treatment arms. The AUCs for the oxygen 
consumption variables are influenced by the number of minutes of data available, which varies 
between patients. To account for this, AUCs for each patient will be adjusted by dividing by the 
number of minutes of oxygen consumption data available for that patient. Additionally, the 
AUCs for the VO2 and VCO2 variables are influenced by the weight of the patient, and thus will 
also be adjusted by dividing by the bodyweight of the patient, in kilograms. The median AUCs 
will be compared between treatment groups using the univariate Wilcoxon rank-sum test. To 

control for the known effect of temperature on oxygen consumption, we will use quantile 
regression to compare median AUCs between patients using the treatment assignment as the 
predictor and average temperature as a covariate. To examine the association between 
treatment and the VO2:Lactate Ratio, we will use a linear quantile mixed model (LQMM) with 
the VO2:Lactate Ratio as the outcome variable, treatment as the predictor variable and 
temperature as the covariate. To account for clustering of VO2:Lactate Ratio and temperature 
measurements within patients, we will add a random intercept for each patient to the LQMM. 
We will not control for vasopressor use or sedation in the above analyses  unless use of these 
agents is significantly imbalanced between arms. 
 
Pyruvate dehydrogenase (PDH), creatinine, SOFA score, and cellular oxygen consumption 
rate levels over 48 hours 
To test change over time, we will compare repeated measures of each outcome listed above at 
each time point (0h, 24h, 48h) between arms using a linear mixed-effects model with an 
independent variance–covariance matrix to account for the correlation of within-patient 
repeated measures. Covariates in the model include treatment arm, time, and the interaction 
between treatment arm and time. Linear contrasts will be used to estimate the mean 
difference between treatment arms for each time point. To test for a difference in absolute 
values between arms, we will compare means or medians, as appropriate, using either a 
Student’s t-test or a Wilcoxon rank-sum test, respectively, at 24 and 48 hours. 
 
Mortality, Cerebral Performance Category (CPC) Score, and Cerebral Performance Category-
Extended (CPC-E) Score at hospital discharge, 30 days, and 90 days 
Proportions of patients who do not survive to hospital discharge, 30 days, and 90 days will be 
compared between treatment arms using Fisher’s exact test. Fisher’s exact test will also be 
used to compare the proportion of patients who have a favorable CPC score at the same time 
points, with favorable CPC score defined as a score of 1-2 and unfavorable a CPC of 3-5. CPC-
E will be analyzed between treatment arms as a continuous variable in survivors to the time 
point of interest using either a Student’s t-test or a Wilcoxon rank-sum test, based on the 
distribution of the data. 
 
Acute renal failure in the first 7 days after study drug initiation 
Acute renal failure in the first 7 days after study drug initiation will be determined using the 
Kidney Disease Improving Global Outcomes (KDIGO) criteria for Stage 3 acute kidney 
injury/kidney failure. These criteria are as follows: 

1. An increase in creatinine to  ≥ 3 x  baseline (baseline defined as enrollment [post-
arrest pre-study drug] creatinine value) OR 
2. An increase in creatinine by ≥ 0.3mg/dL from baseline to ≥ 4mg/dL OR 
3. Initiation of renal replacement therapy  
Patients who die or transition to comfort measures only before 7 days and who do not meet 
the above criteria before death or transition to comfort measures only status will be 
classified as not having acute renal failure. Proportions of patients who have renal failure will 
be compared between groups using Fisher’s exact test. Patients who already have end-stage 
renal disease (defined as being on dialysis/renal replacement therapy prior to arrest) will be 
excluded from the acute renal failure analysis.  
Additional Planned Analyses 
A pre-planned subanalysis of the primary outcome will be performed stratified by arrest 
duration, dichotomized into <15 minutes and >=15 minutes. Two additional sub-analyses will 
focus only on the patients with baseline thiamine deficiency (plasma vitamin B1 level <=7 
nmol/L), one looking at the primary outcome of change in lactate and the other on the 
secondary outcome of change in VO2 (provided sufficient data are available). 
Analysis of Adverse Events 
Rates of serious expected and unexpected adverse events will be reported by arm assignment. 
Proportions of patients with adverse events will be compared between the treatment arms 
using Fisher’s exact test. 
Statistical Software 
Stata (version 17, StataCorp, College Station, Tx) & R (version 4.1.1, R Foundation for Statistical 
Computing, Vienna, Austria) will be used for all analyses and graphics.