Clinical trial NCT03450707
Conditions: Cardiac Arrest
Keywords: cardiac arrest post-arrest
Sponsor: Michael Donnino
Start date: 2018-05-06; Completion date: 2022-02-19
Enrollment: 93 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo controlled study to investigate the effect of intravenous thiamine (vitamin B1) on lactate, cellular oxygen consumption, global oxygen consumption and biomarkers of neurologic injury after out-of-hospital cardiac arrest (OHCA). .

Detailed description:
This is a randomized, double-blind, placebo controlled study to investigate the effect of intravenous thiamine (vitamin B1) on lactate, cellular oxygen consumption, global oxygen consumption and biomarkers of neurologic injury after out-of-hospital cardiac arrest (OHCA). Patients who have sustained return of spontaneous circulation (ROSC) after OHCA and have a lactate of 3 or greater will be eligible for the study. Enrolled patients will be randomized to intravenous thiamine 500mg twice daily for 5 doses or matching placebo (100cc normal saline). Blood will be drawn at several time points and patients will be connected to a noninvasive monitor for continuous measurement of global oxygen consumption. The primary endpoint is change in lactate level. Secondary endpoints include change in pyruvate dehydrogenase activity, change in cellular and global oxygen consumption, change in NSE and S100 (biomarkers of neurologic injury) and CPC-E score (a score that assesses neurologic and functional impairment) at hospital discharge, 30 and 90 days.

Arms: arm 1: Patients randomized to the thiamine arm will receive thiamine 500mg in 100mL of normal saline intravenously every 12 hours for 5 doses. Patients will be connected to a noninvasive monitor for measurement of global oxygen consumption (VO2) for at least 48 hours or until extubated, whichever comes first. Blood will be drawn at 0,6,12,24,72 and 168 hours for measurement of lactate, thiamine level, pyruvate dehydrogenase, NSE, S100 and other markers of organ injury. CPC-E score will be assessed prior to hospital discharge and at 30 and 90 days to evaluate differences in neurologic and functional impairment. arm 2: Patients randomized to placebo will receive 100mL normal saline intravenously every 12 hours for 5 doses. All other aspects of the protocol will be the same as in the experimental arm. Patients will be connected to a noninvasive monitor for measurement of global oxygen consumption (VO2) for at least 48 hours or until extubated, whichever comes first. Blood will be drawn at 0,6,12,24,72 and 168 hours for measurement of lactate, thiamine level, pyruvate dehydrogenase, NSE, S100 and other markers of organ injury. CPC-E score will be assessed prior to hospital discharge and at 30 and 90 days to evaluate differences in neurologic and functional impairment.
Interventions: intervention 1: Thiamine 500 mg IV intervention 2: Placebo
Intervention descriptions: intervention 1: Thiamine hydrochloride (vitamin B1) 500mg IV will be given every 12 hours for 5 doses in the experimental arm. intervention 2: 100mL of intravenous normal saline will be given every 12hours for 5 doses in the placebo arm

Protocol documents:
Prot_SAP_001.pdf: 
Thiamine as a Metabolic Resuscitator After Cardiac Arrest: Study protocol and statistical 
analysis plan 
  
NCT03450707 
  
Finalized and submitted to Clinicaltrials.gov: August 18 2022 
  
Principal Investigator and corresponding author: Michael W Donnino, MD 
mdonnino@bidmc.harvard.edu 
 


 
Introduction  
The study protocol for Thiamine as a Metabolic Resuscitator After Cardiac Arrest is 
summarized in the original posting for the trial on clinicaltrials.gov, NCT03450707. Additional 
details on the protocol and the statistical analysis plan are included in this document, which 
is being submitted for posting prior to initiation of any data analysis.  
Methods 
Trial Design  
This is a randomized, double-blind, placebo controlled to investigate the effect of 
intravenous thiamine (vitamin B1) on lactate, cellular oxygen consumption, global oxygen 
consumption and biomarkers of neurologic injury in patients who achieve return of 
spontaneous circulation (ROSC) after an out-of-hospital cardiac arrest (OHCA).  
Intervention:  
Thiamine 500mg in 100mL 0.9% saline IV every 12 hours for 5 doses, with initial dose given 
within 4.5 hours of ROSC. Control arm will receive 0.9% saline of the same volume and 
frequency. 
Consent/Exception from Informed Consent (EFIC):  
This trial will be conducted under EFIC, as approved by the FDA and the Beth Israel 
Deaconess Medical Center Internal Review Board (IRB) following completion of community 
consultation and dissemination of information about the trial, including provision of the 
opportunity to opt out. EFIC will be utilized due to the need to enroll patients within 4.5 
hours of ROSC. In line with the EFIC process, if the patient’s legally authorized representative 
(LAR) is present, the research team will approach them for informed consent and the patient 
will be enrolled if the LAR consents. If the LAR is not present at the time of eligibility, the 
research team will make an attempt to contact them and provide them the opportunity to 
opt out of the trial. If the LAR is not reachable but a family member/next of kin is present or 
can be reached, that person will be provided the opportunity to opt out. If the LAR or family 
member does not opt out or if no LAR or next of kin can be reached, the patient will be 
enrolled in the trial. If a patient is enrolled under EFIC, the patient or the LAR will be 
approached for continuing consent as soon as this is possible.  
Patient Population 
Inclusion Criteria: 
● Adult patient (age ≥ 18 years) 


● Cardiac arrest occurring with sustained (> 20 minutes) return of spontaneous circulation 
(ROSC) 
● Lactate ≥3 
● Within 4.5 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 
● Traumatic etiology of arrest 
● Comfort measures only or anticipated withdrawal of support within 24 hours 
● Protected populations (pregnant women, prisoners) 
● Known allergy to thiamine 
 
Randomization and blinding 
Randomization: The randomization, completed by an independent statistician, will be generated 
using a random number generator via the use of the Statistical Analysis System (SAS) version 9.2 
software, function RANUNI. Randomization will be 1:1, in blocks of 4. This function generates a 
random number between 0 and 1 from a uniform distribution function with parameter 0 and 1. 
If the random number is less than or equal to 0.5, the assignment is to the treatment group 
(coded A). If the random number is larger than 0.5, then the assignment is to the control group 
(coded B).  
 
The research pharmacy, following the randomization list as above, will prepare and 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. Thiamine is odorless and colorless, and it is not possible to tell the 
difference between thiamine and placebo using this method. 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 (NCT03450707) on March 1, 2018, prior to study 
start. Adverse events will be monitored by the PI and reported to the IRB and FDA as 
required. A Data Safety and Monitoring Board (DSMB) has been convened for this trial as 
required for any trial conducted under EFIC. DSMB meetings will occur at pre-planned 


intervals of one year. There are no pre-specified stopping rules for futility or efficacy. No 
statistical interim analyses were planned.  
 
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, 72, and 168 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 labs for SOFA score calculation will be 
processed in the BIDMC clinical lab. 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 the 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 tube, 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 


The primary outcome is change in lactate over 24 hours following enrollment. 
Secondary Outcomes: 
1. Absolute level and change in VO2 over 48 hours 
2. Absolute level of lactate over 72 hours 
3. Absolute level and the change in pyruvate dehydrogenase (PDH) quantity, activity 
and specific activity over 72 hours 
4. Absolute level and the change in S100 levels over 72 hours 
5. Absolute level and the change in neuron-specific enolase (NSE) levels over 72 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 72 hours 
10. Acute renal failure during first 7 days following arrest 
11. Absolute level and change in cellular oxygen consumption rate over 72 hours 
12. Absolute level and the change in creatinine over 72 hours 
Sample Size Calculations:  
The analysis method for the primary endpoint will be linear mixed-effects modeling (LMM). This 
type of modeling is used in longitudinal or repeated-measures studies to take into account the 
correlation of within-subject measurements and can optimize the power. 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 for which we had lactate 
measurements over 24 hours and that matched the inclusion/exclusion criteria for the current 
proposal. 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 groups) will be 
33%. That is, we assumed that the mean lactate level at the three different time points were 
2.55, 2.35, and 1.94. We then simulated the longitudinal data with the assumption that the 
variance-covariance structure of the lactate data followed a compound-symmetry structure 
with between-subject variance of 2.07. The linear-mixed effects model was used on the 
simulated data to obtain the estimated F statistic, numerator, and denominator degrees of 
freedom. From these estimates, the non-centrality parameter was computed and used to 
obtain the power. To obtain 80% power, with type-I error of 0.05, 66 subjects (33 thiamine, 33 
placebo) will be needed to detect the stated difference over 6, 12, and 24-hours. We 


secondarily performed calculations using the difference in means approach at the time point of 
6 hours where we anticipate maximal effect of thiamine. At this time point, a reduction by 33% 
yields a power of 80% with a total sample size of 92. To be conservative we will use the larger 
sample size of 92 patients to ensure adequate power. With this sample size, the linear-mixed 
model will have 92% power to detect differences between groups with the same assumptions. 
 
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 differences in baseline characteristics between study 
arms. 
 
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) 
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 four levels, defined as 
baseline, 6 hours, 12 hours, and 24 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 24 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 24 hours are assigned the last known value before 
the event without a penalty. 


 
Analysis of Secondary Outcomes 
Lactate levels over 72 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 72 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), S100, NSE, SOFA score, creatinine, and cellular oxygen 
consumption rate levels over 72 hours 
To test change over time, we will compare repeated measures of each outcome listed above at 
each time point (0h, 24h, 72h) 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 72 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 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 
Pre-planned subanalyses of the primary outcome and of the secondary outcomes of mortality 
and VO2 will be performed stratified by arrest duration, dichotomized into <15 minutes and 
>=15 minutes and in the group of patients with baseline thiamine deficiency (plasma vitamin B1 
level <=7 nmol/L). Based on feedback from the DSMB, we will also perform subanalyses based 
on 0 hour lactate, stratified by <=5 and >5. 
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.