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This is a randomized, double-blind, placebo controlled study to investigate the effect of intravenous thiamine (vitamin B1) on renal function in septic shock.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Thiamine | Experimental | 200mg parenterally administered thiamine hydrochloride given twice daily for a 3 days (6 doses) |
|
| Placebo | Placebo Comparator | Matching placebo (50ml 0.9%NACL) given twice daily for 3 days (6 administrations) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Thiamine Hydrochloride | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Kidney Injury Biomarker | Change in creatinine over time | Enrollment to 72-hours |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Receiving Renal Replacement Therapy | Number of participants who received renal replacement therapy in thiamine and placebo groups. | 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 |
| ICU Free Days |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ari Moskowitz, MD | Beth Israel Deaconess Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States | ||
| Northshore University Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28207287 | Background | Moskowitz A, Andersen LW, Cocchi MN, Karlsson M, Patel PV, Donnino MW. Thiamine as a Renal Protective Agent in Septic Shock. A Secondary Analysis of a Randomized, Double-Blind, Placebo-controlled Trial. Ann Am Thorac Soc. 2017 May;14(5):737-741. doi: 10.1513/AnnalsATS.201608-656BC. | |
| 26771781 | Background | Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, Wolfe R, Moskowitz A, Smithline H, Ngo L, Cocchi MN; Center for Resuscitation Science Research Group. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016 Feb;44(2):360-7. doi: 10.1097/CCM.0000000000001572. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Kidney Injury Biomarker | Change in creatinine over time | Posted | Mean | Standard Deviation | mg/dL | Enrollment to 72-hours |
|
From enrollment to time of discharge, an average of 2 weeks.
As detailed in the clinical trial protocol.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Ari Moskowitz | Montefiore Medical Center | 7189202956 | amoskowitz@montefiore.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 2, 2021 | Apr 28, 2023 | Prot_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 15, 2022 | Jun 15, 2022 | SAP_000.pdf |
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| ID | Term |
|---|---|
| D018805 | Sepsis |
| D013832 | Thiamine Deficiency |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| C000712172 | thiamine hydrochloride |
| D013831 | Thiamine |
| D000077330 | Saline Solution |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
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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.
|
| Placebo | Drug | 50ml of 0.9% NACL will serve as the placebo |
|
|
Days alive and free of the ICU through day 28 |
| From date of enrollment until 28 days after enrollment |
| In-hospital Mortality | Length of hospital stay truncated at 60 days | From date of enrollment until discharge from the hospital or date of death, whichever comes first, up to 60 days after enrollment |
| 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). | 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 |
| Change in Lactate Level | Change in lactate level between enrollment and 72 hours after enrollment | From time of enrollment until 72 hours after enrollment |
| Number of Participants With Delirium on Day 3 | Number of Participants with Delirium on Day 3 after enrollment | Day 3 after enrollment |
| 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 of enrollment until 72 hours after enrollment |
| Novel Biomarkers of Renal Injury | KIM-1, NGAL, Cystatin-C at 24-hours after enrollment | 24 hours after enrollment |
| Manhasset |
| New York |
| 11030 |
| United States |
| Montefiore Medical Center | New York | New York | 10467 | United States |
| Long Island Jewish Hospital | Queens | New York | 11040 | United States |
| 38321529 | Derived | Vine J, Lee JH, Kravitz MS, Grossestreuer AV, Balaji L, Leland SB, Berlin N, Moskowitz A, Donnino MW. Thiamine administration in septic shock: a post hoc analysis of two randomized trials. Crit Care. 2024 Feb 6;28(1):41. doi: 10.1186/s13054-024-04818-1. |
| 37364280 | Derived | Moskowitz A, Berg KM, Grossestreuer AV, Balaji L, Liu X, Cocchi MN, Chase M, Gong MN, Gong J, Parikh SM, Ngo L, Berlin N, Donnino MW. Thiamine for Renal Protection in Septic Shock (TRPSS): A Randomized, Placebo-controlled, Clinical Trial. Am J Respir Crit Care Med. 2023 Sep 1;208(5):570-578. doi: 10.1164/rccm.202301-0034OC. |
| Withdrawal by Subject |
|
| Death |
|
| 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 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Body Mass Index | Median | Inter-Quartile Range | kg/m^2 |
|
| Past Medical History: Malignancy | Count of Participants | Participants |
|
| Past Medical History: Coronary Artery Disease | Count of Participants | Participants |
|
| Past Medical History: Congestive Heart Failure | Count of Participants | Participants |
|
| Past Medical History: Liver Disease | Count of Participants | Participants |
|
| Chronic Kidney Disease | Participants were staged using the KDIGO (Kidney disease - improving global outcomes) classification of the stages of chronic kidney disease, which uses the clinically observed glomerular filtration rate (GFR) to classify patients. A decreased GFR indicates a higher "stage" of KDIGO and thus corresponds to a worse outcome [A patient with stage 4 is sicker than a patient with stage 2]. | Count of Participants | Participants |
|
| Source of Sepsis | Count of Participants | Participants |
|
| Volume of intravenous fluids prior to study drug | Median | Inter-Quartile Range | mL |
|
| Baseline cardiovascular component of the total SOFA score | Score on a scale that ranges from 0-24, with 24 being the worst outcome. | Median | Inter-Quartile Range | units on a scale |
|
| Time from vasopressor initiation to first study drug | Median | Inter-Quartile Range | Hours |
|
| Time from informed consent to first study drug | Median | Inter-Quartile Range | Hours |
|
| Mechanically ventilated | Count of Participants | Participants |
|
| Lactate | Median | Inter-Quartile Range | mmol/L |
|
| 30-day predicted survival | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Secondary | Number of Participants Receiving Renal Replacement Therapy | Number of participants who received renal replacement therapy in thiamine and placebo groups. | Posted | Count of Participants | Participants | 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 |
|
|
|
|
| Secondary | ICU Free Days | Days alive and free of the ICU through day 28 | Posted | Median | Inter-Quartile Range | days | From date of enrollment until 28 days after enrollment |
|
|
|
|
| Secondary | In-hospital Mortality | Length of hospital stay truncated at 60 days | Posted | Count of Participants | Participants | From date of enrollment until discharge from the hospital or date of death, whichever comes first, up to 60 days after enrollment |
|
|
|
|
| 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). | Posted | Count of Participants | Participants | 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 |
|
|
|
|
| Secondary | Change in Lactate Level | Change in lactate level between enrollment and 72 hours after enrollment | Posted | Median | Inter-Quartile Range | mmol/L | From time of enrollment until 72 hours after enrollment |
|
|
|
|
| Secondary | Number of Participants With Delirium on Day 3 | Number of Participants with Delirium on Day 3 after enrollment | Excludes 8 and 4 patients in intervention and placebo groups with delirium status "unable to assess" | Posted | Count of Participants | Participants | Day 3 after enrollment |
|
|
|
| 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. | Posted | Mean | Standard Deviation | units on a scale | Time of enrollment until 72 hours after enrollment |
|
|
|
|
| Secondary | Novel Biomarkers of Renal Injury | KIM-1, NGAL, Cystatin-C at 24-hours after enrollment | 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 | Posted | Median | Inter-Quartile Range | pg/mL | 24 hours after enrollment |
|
|
|
| 15 |
| 42 |
| 0 |
| 42 |
| 0 |
| 42 |
| EG001 | 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 | 25 | 46 | 0 | 46 | 0 | 46 |
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| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D014804 | Vitamin B Deficiency |
| D001361 | Avitaminosis |
| D003677 | Deficiency Diseases |
| D044342 | Malnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011743 | Pyrimidines |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| Cystatin |
|