A Phase 2 interventional study of Thiamine 500 mg IV and Placebo in Cardiac Arrest, sponsored by Michael Donnino. Terminated at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-08-24.
Sponsored by Michael Donnino · Phase 2, Interventional, and Treatment
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). .
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.
926 studies on the registry are indexed under Heart Arrest; 226 are open to participants now.
This study's enrollment of 93 is close to the median of 100 across 518 interventional studies indexed under Heart Arrest.
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Exclusion Criteria:
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.
Drug: Thiamine 500 mg IV
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.
Other: Placebo
Thiamine hydrochloride (vitamin B1) 500mg IV will be given every 12 hours for 5 doses in the experimental arm.
Also known as: vitamin B1
100mL of intravenous normal saline will be given every 12hours for 5 doses in the placebo arm
Also known as: Normal saline
Lactate
Blood Lactate Over Time
Time frame: 24 hours
Global Oxygen Consumption
Global Oxygen Consumption over Time
Time frame: 48 hours
Lactate
Absolute Blood Level of Lactate
Time frame: 72 hours
Pyruvate Dehydrogenase (PDH) Specific Activity
Absolute PDH specific activity value
Time frame: 72 hours
Pyruvate Dehydrogenase (PDH) Activity
Absolute PDH Activity Value
Time frame: 72 hours
Pyruvate Dehydrogenase (PDH) Quantity
Absolute PDH Quantity. Please note that the measurement of Absolute PDH Quantity is done using a relative quantity assay, and that PDH is an enzyme and not a stable protein; therefore the units of measure cannot be provided in "mg" and are instead listed in "mini OD unit/min/mg protein".
Time frame: 72 hours
Mortality
Mortality in the study assessed at three timepoints.
Time frame: will be assessed at hospital discharge and up to 30 and 90 days.
Favorable Cerebral Performance Category (CPC)
Count/Proportion of Patients Scoring a Favorable CPC, defined as a score of 1 or 2. Cerebral performance category scores range from 1-5. Lower scores mean better outcomes.
Time frame: will be assessed up to 30 and 90 days
Sequential Organ Failure Assessment (SOFA) Score
SOFA score over time. SOFA score: Sequential Organ Failure Assessment Score, ranges from 0-24, higher scores mean worse outcomes.
Time frame: over 72 hours
Acute Renal Failure
Determined using the Kidney Disease Improving Global Outcomes (KDIGO) criteria for Stage 3 acute kidney injury/kidney failure.
Time frame: First 7 days following Arrest
Cellular Oxygen Consumption
Absolute Cellular Oxygen Consumption Rate: We use two measures to capture Oxygen Consumption Rate; the basal respiration and the maximal respiration.
Time frame: 0 hours and 24 hours.
Creatinine
Creatinine over Time
Time frame: 72 hours
Biomarkers of Neurologic Injury
S100 and NSE levels at various time points
Time frame: various time points over 7 days
| Milestone | Thiamine | Placebo |
|---|---|---|
| Started | 47 | 46 |
| Completed | 40 | 36 |
| Not completed | 7 | 10 |
| Withdrew: Outside enrollment window | 4 | 1 |
| Withdrew: Death | 1 | 0 |
| Withdrew: Indication for thiamine | 1 | 1 |
| Withdrew: Evidence of traumatic brain injury | 1 | 0 |
| Withdrew: Following commands | 0 | 3 |
| Withdrew: Lactate < 3.5 | 0 | 2 |
| Withdrew: Rearrest with ecmo | 0 | 1 |
| Withdrew: Indication for thiamine + head ct results | 0 | 1 |
| Withdrew: Family/patient goals of care | 0 | 1 |
Blood Lactate Over Time
| mmol/L | Thiamine | Placebo |
|---|---|---|
| Lactate | 1.8 (1.2 to 2.4) | 2.2 (1.4 to 2.5) |
Global Oxygen Consumption over Time
| Area under the Curve VO2 (mL/kg/min) | Thiamine | Placebo |
|---|---|---|
| Global Oxygen Consumption | 3.52 ± 1.50 | 3.93 ± 1.05 |
Absolute Blood Level of Lactate
| mmol/L | Thiamine | Placebo |
|---|---|---|
| Lactate | 1.3 (0.9 to 1.6) | 1.3 (0.9 to 1.5) |
Absolute PDH specific activity value
| Ratio [PDH activity/ln(PDH quantity)] | Thiamine | Placebo |
|---|---|---|
| Pyruvate Dehydrogenase (PDH) Specific Activity | 1.55 (0.88 to 2.11) | 0.97 (0.78 to 1.60) |
Absolute PDH Activity Value
| mini OD unit/min/mg protein | Thiamine | Placebo |
|---|---|---|
| Pyruvate Dehydrogenase (PDH) Activity | 8.63 (4.93 to 12.90) | 5.65 (4.77 to 9.38) |
Absolute PDH Quantity. Please note that the measurement of Absolute PDH Quantity is done using a relative quantity assay, and that PDH is an enzyme and not a stable protein; therefore the units of measure cannot be provided in "mg" and are instead listed in "mini OD unit/min/mg protein".
| mini OD unit/min/mg protein | Thiamine | Placebo |
|---|---|---|
| Pyruvate Dehydrogenase (PDH) Quantity | 588.05 (291.31 to 1080.94) | 695.55 (437.94 to 999.09) |
Mortality in the study assessed at three timepoints.
| Participants | Thiamine | Placebo |
|---|---|---|
| Discharge mortality | 30 | 23 |
| 30-day mortality | 30 | 24 |
| 90-day mortality | 30 | 24 |
Count/Proportion of Patients Scoring a Favorable CPC, defined as a score of 1 or 2. Cerebral performance category scores range from 1-5. Lower scores mean better outcomes.
| Participants | Thiamine | Placebo |
|---|---|---|
| Favorable Discharge CPC (1-2) | 8 | 10 |
| Favorable 30-day CPC (1-2) | 9 | 9 |
| Favorable 90-day CPC (1-2) | 9 | 7 |
SOFA score over time. SOFA score: Sequential Organ Failure Assessment Score, ranges from 0-24, higher scores mean worse outcomes.
| score on a scale | Thiamine | Placebo |
|---|---|---|
| Sequential Organ Failure Assessment (SOFA) Score | 9 (7 to 12) | 6 (4 to 9) |
Determined using the Kidney Disease Improving Global Outcomes (KDIGO) criteria for Stage 3 acute kidney injury/kidney failure.
| Participants | Thiamine | Placebo |
|---|---|---|
| Acute Renal Failure | 9 | 3 |
Absolute Cellular Oxygen Consumption Rate: We use two measures to capture Oxygen Consumption Rate; the basal respiration and the maximal respiration.
| pmol/min/mg protein | Thiamine | Placebo |
|---|---|---|
| Basal respiration-0 hours | 5.6 (4.3 to 7.8) | 4.8 (3.2 to 7.9) |
| Maximal respiration-0 hours | 19.3 (7.9 to 36.1) | 11.9 (6.8 to 30.3) |
| Basal respiration-24 hours | 5.5 (2.6 to 6.3) | 4.7 (3.4 to 9.3) |
| Maximal respiration-24 hours | 14.7 (10.4 to 25.1) | 16.1 (11.5 to 34.3) |
Creatinine over Time
| mg/dL | Thiamine | Placebo |
|---|---|---|
| Creatinine | 1.9 (0.9 to 2.8) | 1.1 (0.8 to 1.9) |
S100 and NSE levels at various time points
No measurements were reported for this outcome.
Collected over All-Cause Mortality was monitored upto 90 days; Serious and/or Other (Not Including Serious) Adverse Events assessed from enrollment to time of discharge, an average of one week.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Thiamine | 30/40 (75%) | 0/40 (0%) | 0/40 (0%) |
| Placebo | 24/36 (66.7%) | 0/36 (0%) | 0/36 (0%) |
| Age, Continuous(years) | Thiamine | Placebo | Total |
|---|---|---|---|
| Median | 68.5 (58.0 to 79.5) | 65.5 (58.0 to 79.0) | 66.5 (58.0 to 79.0) |
| Sex: Female, Male(Participants) | Thiamine | Placebo | Total |
|---|---|---|---|
| Female | 15 | 16 | 31 |
| Male | 25 | 20 | 45 |
| Ethnicity (NIH/OMB)(Participants) | Thiamine | Placebo | Total |
|---|---|---|---|
| Hispanic or Latino | 2 | 2 | 4 |
| Not Hispanic or Latino | 14 | 20 | 34 |
| Unknown or Not Reported | 24 | 14 | 38 |
| Race/Ethnicity, Customized(Participants) | Thiamine | Placebo | Total |
|---|---|---|---|
| Race — White | 10 | 17 | 27 |
| Race — Black | 6 | 3 | 9 |
| Race — Asian | 3 | 0 | 3 |
| Race — Other | 0 | 2 | 2 |
| Race — Unknown | 21 | 14 | 35 |
| Initial Rhythm(Participants) | Thiamine | Placebo | Total |
|---|---|---|---|
| Pulseless electrical activity | 15 | 13 | 28 |
| Asystole | 9 | 10 | 19 |
| Ventricular Fibrillation | 6 | 5 | 11 |
| Pulseless Ventricular Tachycardia | 3 | 1 | 4 |
| Unknown Shockable | 4 | 5 | 9 |
| Unknown Non-Shockable | 3 | 2 | 5 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from May 2018 to primary completion in Feb 2022, 45 months.
Results were first posted in Aug 2023, 1 year 6 months after primary completion.
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Studies of the drug tested here: Thiamine