Kidney Injury, Sepsis, Thiamine Deficiency
Conditions
Brief summary
This is a randomized, double-blind, placebo controlled study to investigate the effect of intravenous thiamine (vitamin B1) on renal function in septic shock.
Detailed description
This is a randomized, double-blind, placebo controlled study to investigate the effect of intravenous thiamine (vitamin B1) on renal injury in septic shock. Patients admitted with septic shock who have a lactate of at least 2.0mmol/L and do not have pre-existing renal failure requiring dialysis will be eligible for the study. Enrolled patients will be randomized to intravenous thiamine 200mg twice daily for 6 doses or matching placebo. Blood will be drawn at several time points to assess biomarkers of renal injury. Secondary endpoints include need for renal replacement therapy, length of ICU stay, and hospital mortality.
Interventions
Thiamine hydrochloride is a water soluble vitamin (vitamin B1). 200mg of thiamine hydrochloride in 50ml 0.9%NACL will be administered twice daily for 3 days.
DRUGPlacebo
50ml of 0.9% NACL will serve as the placebo
Sponsors
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
A randomization list will be prepared by an independent statistician using 1:1 randomization in blocks of two and four. This list will be provided to the research pharmacy, and the research pharmacy will be the only unblinded people involved with the study, and will have no patient contact or role in the analysis or other aspects of the study. Thiamine is colorless and odorless, and the 200mg dose is mixed in 5mL of normal saline. Placebo will be 50mL of normal saline and is indistinguishable in appearance from thiamine. Study team, clinical team and patient and family will all be blind to the allocation.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kidney Injury Biomarker | Enrollment to 72-hours | Change in creatinine over time |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ICU Free Days | From date of enrollment until 28 days after enrollment | Days alive and free of the ICU through day 28 |
| In-hospital Mortality | From date of enrollment until discharge from the hospital or date of death, whichever comes first, up to 60 days after enrollment | Length of hospital stay truncated at 60 days |
| Number of Participants Experiences Acute Renal Failure | From date of enrollment until day of discharge from the index ICU admission or date of death, whichever comes first up until 60 days post-enrollment | Acute renal failure as defined by the KDIGO (Kidney Disease Improving Global Outcomes) AKI (Acute Kidney Injury) criteria. In brief, a patient can meet these criteria if their serum creatinine increases (for example, serum creatinine increases to 1.5x or higher of baseline serum creatinine, or if it crosses 4mg/dL), or if renal replacement therapy is initiated, or if urine output decreases (for example, \<0.5ml/kg/hour for 6-12 hours) or if patient becomes anuric (no urine production). |
| Number of Participants Receiving Renal Replacement Therapy | From date of enrollment until discharge from the intensive care unit (ICU) or date of death, whichever comes first, up to 60 days after enrollment | Number of participants who received renal replacement therapy in thiamine and placebo groups. |
| Number of Participants With Delirium on Day 3 | Day 3 after enrollment | Number of Participants with Delirium on Day 3 after enrollment |
| Change in the Sequential Organ Failure Assessment Score | Time of enrollment until 72 hours after enrollment | Change in Sequential Organ Failure Assessment Score (SOFA) score between enrollment and 72 hours after enrollment. SOFA scores are reported on a scale between 0-24, with 0 representing best outcome and 24 representing worst outcome. |
| Novel Biomarkers of Renal Injury | 24 hours after enrollment | KIM-1, NGAL, Cystatin-C at 24-hours after enrollment |
| Change in Lactate Level | From time of enrollment until 72 hours after enrollment | Change in lactate level between enrollment and 72 hours after enrollment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Thiamine 200mg parenterally administered thiamine hydrochloride given twice daily for a 3 days (6 doses)
Thiamine Hydrochloride: Thiamine hydrochloride is a water soluble vitamin (vitamin B1). 200mg of thiamine hydrochloride in 50ml 0.9%NACL will be administered twice daily for 3 days. | 42 |
| Placebo Matching placebo (50ml 0.9%NACL) given twice daily for 3 days (6 administrations)
Placebo: 50ml of 0.9% NACL will serve as the placebo | 46 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Goals of care changed | 1 | 0 |
| Overall Study | No longer met inclusion criteria | 1 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Thiamine | Placebo |
|---|---|---|---|
| 30-day predicted survival High likelihood | 18 Participants | 10 Participants | 8 Participants |
| 30-day predicted survival Low likelihood | 4 Participants | 3 Participants | 1 Participants |
| 30-day predicted survival Uncertain | 66 Participants | 29 Participants | 37 Participants |
| Age, Continuous | 71.5 years | 74.5 years | 70.0 years |
| Baseline cardiovascular component of the total SOFA score | 4 units on a scale | 4 units on a scale | 4 units on a scale |
| Body Mass Index | 28.9 kg/m^2 | 28.6 kg/m^2 | 30.6 kg/m^2 |
| Chronic Kidney Disease No Kidney Disease | 72 Participants | 34 Participants | 38 Participants |
| Chronic Kidney Disease Stage 2 | 2 Participants | 1 Participants | 1 Participants |
| Chronic Kidney Disease Stage 3a | 3 Participants | 2 Participants | 1 Participants |
| Chronic Kidney Disease Stage 3b | 3 Participants | 2 Participants | 1 Participants |
| Chronic Kidney Disease Stage 4 | 2 Participants | 0 Participants | 2 Participants |
| Chronic Kidney Disease Unknown/not reported | 6 Participants | 3 Participants | 3 Participants |
| Lactate | 2.9 mmol/L | 2.9 mmol/L | 3.1 mmol/L |
| Mechanically ventilated | 54 Participants | 27 Participants | 27 Participants |
| Past Medical History: Congestive Heart Failure | 22 Participants | 9 Participants | 13 Participants |
| Past Medical History: Coronary Artery Disease | 18 Participants | 10 Participants | 8 Participants |
| Past Medical History: Liver Disease | 6 Participants | 0 Participants | 6 Participants |
| Past Medical History: Malignancy | 18 Participants | 8 Participants | 10 Participants |
| Race/Ethnicity, Customized American Indian/Native Alaskan | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black/African American | 9 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown/other | 17 Participants | 8 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 58 Participants | 30 Participants | 28 Participants |
| Sex: Female, Male Female | 43 Participants | 24 Participants | 19 Participants |
| Sex: Female, Male Male | 45 Participants | 18 Participants | 27 Participants |
| Source of Sepsis Endocarditis | 2 Participants | 0 Participants | 2 Participants |
| Source of Sepsis Infection of unknown source | 6 Participants | 3 Participants | 3 Participants |
| Source of Sepsis Intra-abdominal infection | 19 Participants | 10 Participants | 9 Participants |
| Source of Sepsis Other | 11 Participants | 6 Participants | 5 Participants |
| Source of Sepsis Pneumonia | 16 Participants | 7 Participants | 9 Participants |
| Source of Sepsis Skin or soft tissue infection | 6 Participants | 4 Participants | 2 Participants |
| Source of Sepsis Urinary tract infection | 28 Participants | 12 Participants | 16 Participants |
| Time from informed consent to first study drug | 1.6 Hours | 1.6 Hours | 1.6 Hours |
| Time from vasopressor initiation to first study drug | 14.1 Hours | 12.8 Hours | 14.4 Hours |
| Volume of intravenous fluids prior to study drug | 1972.5 mL | 2000 mL | 1819.0 mL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 42 | 25 / 46 |
| other Total, other adverse events | 0 / 42 | 0 / 46 |
| serious Total, serious adverse events | 0 / 42 | 0 / 46 |
Outcome results
Primary
Kidney Injury Biomarker
Change in creatinine over time
Time frame: Enrollment to 72-hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Thiamine | Kidney Injury Biomarker | 2.24 mg/dL | Standard Deviation 1.5 |
| Placebo | Kidney Injury Biomarker | 2.79 mg/dL | Standard Deviation 1.91 |
p-value: 0.0795% CI: [-1.18, 0.04]Mixed Models Analysis
Secondary
Change in Lactate Level
Change in lactate level between enrollment and 72 hours after enrollment
Time frame: From time of enrollment until 72 hours after enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thiamine | Change in Lactate Level | 1.65 mmol/L |
| Placebo | Change in Lactate Level | 1.95 mmol/L |
p-value: 0.7995% CI: [0.71, 1.3]Mixed Models Analysis
Secondary
Change in the Sequential Organ Failure Assessment Score
Change in Sequential Organ Failure Assessment Score (SOFA) score between enrollment and 72 hours after enrollment. SOFA scores are reported on a scale between 0-24, with 0 representing best outcome and 24 representing worst outcome.
Time frame: Time of enrollment until 72 hours after enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Thiamine | Change in the Sequential Organ Failure Assessment Score | 8.09 units on a scale | Standard Deviation 5.6 |
| Placebo | Change in the Sequential Organ Failure Assessment Score | 9.61 units on a scale | Standard Deviation 5.96 |
p-value: 0.1695% CI: [-3.63, 0.58]Mixed Models Analysis
Secondary
ICU Free Days
Days alive and free of the ICU through day 28
Time frame: From date of enrollment until 28 days after enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thiamine | ICU Free Days | 22.5 days |
| Placebo | ICU Free Days | 0.0 days |
p-value: 0.00295% CI: [7.4, 36.6]Quantile regression
Secondary
In-hospital Mortality
Length of hospital stay truncated at 60 days
Time frame: From date of enrollment until discharge from the hospital or date of death, whichever comes first, up to 60 days after enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Thiamine | In-hospital Mortality | 15 Participants |
| Placebo | In-hospital Mortality | 25 Participants |
p-value: 0.1495% CI: [0.32, 1.18]Regression, Cox
Secondary
Novel Biomarkers of Renal Injury
KIM-1, NGAL, Cystatin-C at 24-hours after enrollment
Time frame: 24 hours after enrollment
Population: A total of 32 patients in thiamine and 37 patients in placebo had biomarkers available at both 0 hours and 24 hours and thus contributed to the model estimates
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Thiamine | Novel Biomarkers of Renal Injury | KIM-1 | 763.1 pg/mL |
| Thiamine | Novel Biomarkers of Renal Injury | NGAL | 1067898.2 pg/mL |
| Thiamine | Novel Biomarkers of Renal Injury | Cystatin | 1689158.2 pg/mL |
| Placebo | Novel Biomarkers of Renal Injury | KIM-1 | 793.9 pg/mL |
| Placebo | Novel Biomarkers of Renal Injury | NGAL | 1558285.0 pg/mL |
| Placebo | Novel Biomarkers of Renal Injury | Cystatin | 2183175.4 pg/mL |
Secondary
Number of Participants Experiences Acute Renal Failure
Acute renal failure as defined by the KDIGO (Kidney Disease Improving Global Outcomes) AKI (Acute Kidney Injury) criteria. In brief, a patient can meet these criteria if their serum creatinine increases (for example, serum creatinine increases to 1.5x or higher of baseline serum creatinine, or if it crosses 4mg/dL), or if renal replacement therapy is initiated, or if urine output decreases (for example, \<0.5ml/kg/hour for 6-12 hours) or if patient becomes anuric (no urine production).
Time frame: From date of enrollment until day of discharge from the index ICU admission or date of death, whichever comes first up until 60 days post-enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Thiamine | Number of Participants Experiences Acute Renal Failure | 23 Participants |
| Placebo | Number of Participants Experiences Acute Renal Failure | 34 Participants |
p-value: 0.0795% CI: [0.17, 1.06]Regression, Logistic
Secondary
Number of Participants Receiving Renal Replacement Therapy
Number of participants who received renal replacement therapy in thiamine and placebo groups.
Time frame: From date of enrollment until discharge from the intensive care unit (ICU) or date of death, whichever comes first, up to 60 days after enrollment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Thiamine | Number of Participants Receiving Renal Replacement Therapy | 6 Participants |
| Placebo | Number of Participants Receiving Renal Replacement Therapy | 10 Participants |
p-value: 0.3495% CI: [0.18, 1.74]Regression, Logistic
Secondary
Number of Participants With Delirium on Day 3
Number of Participants with Delirium on Day 3 after enrollment
Time frame: Day 3 after enrollment
Population: Excludes 8 and 4 patients in intervention and placebo groups with delirium status unable to assess
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Thiamine | Number of Participants With Delirium on Day 3 | 25 Participants |
| Placebo | Number of Participants With Delirium on Day 3 | 30 Participants |