HAT for the Treatment of Sepsis Associated With NASTI

Study Overview
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Brief Summary
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Evaluate the impact of HAT therapy versus placebo in the treatment of patients with an acute NSTI and sepsis.

Detailed Description
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Primary outcome: 1. Hospital survival Secondary outcomes: Duration of vasopressor therapy Requirement for renal replacement therapy in patients with Acute Kidney Injury (AKI) ICU length of stay (LOS) Change in serum procalcitonin (PCT) over first 72 hours Change in SOFA score over first 72 hours (measured as SOFA score daily for four days, with day one being admission, then 3 days after, totaling 4 days of treatment with HAT) Procalcitonin clearance (formula = initial PCT - 72 hour PCT divided by initial PCT x 100) Number of wound related surgeries Wound status at time of hospital discharge: Open Closed

Official Title
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Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Sepsis Associated With Acute Necrotizing Soft Tissue Infections, The NASTI HAT Trial

Conditions
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Necrotizing Soft Tissue Infection, Sepsis

Intervention / Treatment
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* Drug: HAT
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Necrotizing soft tissue infection by clinical diagnosis and requiring surgical treatment. Sepsis by clinical diagnosis and/or by Sepsis-3 criteria15, with source attributed to the wound. Anticipated or confirmed intensive care unit Exclusion Criteria: (Adapted from Sevransky et. al's VICTAS protocol) Age < 18 years of age Weight < 40 kg Prior enrollment in this study or current enrollment in another study of any kind Surgical findings, pathology/histology findings, or other findings determined to be inconsistent with an infectious acute NSTI such that the clinical diagnosis is no longer that of a NSTI Sepsis deemed unlikely Limitations of care during enrollment [defined as refusal of cardiovascular and respiratory support modes described in inclusion criteria, including do not intubate (DNI) status and comfort care] Known allergy or known contraindication to vitamin C, thiamine, or corticosteroids [including previous history or active diagnosis of primary hyperoxaluria and/or oxalate nephropathy, or known/suspected ethylene glycol ingestion, or known glucose-6-phosphate dehydrogenase (G6PD) deficiency] Use of vitamin C at a dose of >1g/day (IV or oral) within the 24 hours preceding first episode of qualifying organ dysfunction during a given Emergency Department or Intensive Care Unit admission Chronic disease/illness that, in the opinion of the site investigator, have an expected lifespan of < 30 days unrelated to current sepsis diagnosis (e.g., stage IV malignancy, neurodegenerative disease, etc.) Kidney Stone(s) of any kind History of Oxalate Kidney Stone(s) Pregnancy or known active breastfeeding Prisoner or Incarceration Inability or unwillingness of subject or legal surrogate/representative to give written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Patients will be enrolled within 24 hours of diagnosis of sepsis related to a necrotizing soft-tissue infections (NSTI). HAT will be initiated within 4 hours of enrollment (thus treatment with HAT can occur no later than 28 hours from diagnosis). Per Dr. Marik's original study, HAT consists of: 1.5 g vitamin C every 6 hours for 4 days or until ICU discharge 50 mg hydrocortisone every 6 hours for 7 days or until ICU discharge (followed by a taper over 3 days) 200 mg thiamine every 12 hours for 4 days or until ICU discharge In our study, due to the prolonged ICU course typical of most patients with NSTIs, it is not felt feasible to continue indefinitely until ICU discharge. Thus, treatment will be continued for 4 to 7 days plus a 3 day taper (respectively) as above, with no plan for a longer duration of treatment. | Drug: HAT<br>* hydrocortisone, ascorbic acid (vitamin C), and thiamine (vitamin B1); referred to as HAT<br>* Other names: hydrocortisone, vitamin C, vitamin B1;|
| Placebo Comparator: Control Arm<br>The control arm will receive the same standard ICU care for NSTI but will not receive HAT. They will receive a placebo consisting of normal saline, indistinguishable to the treatment team (blinded) but known to the pharmacy team (unblinded to treatment and placebo groups). This is so that if the treatment team elects to give stress dose steroids, they can be administered without breaking protocol (i.e. if the patient is getting HAT, it includes steroids, so if the treating team wanted to start hydrocortisone - because they didn't know if the patient was on HAT or placebo and felt steroids were indicated - the pharmacist could ensure the patient was on steroids one way or another without unblinding the providers). | Drug: Placebo<br>* normal saline solution<br>* Other names: NaCl 0.9%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital Survival | Hospital survival is a binary variable showing whether the patient survived their time in the hospital. Hospital survival will be assessed from date of randomization until the date of discharge or date of death from any cause, whichever comes first, assessed up to 24 months. | Outcome is measured from date of randomization to date of discharge or date of death, whichever comes first, assessed up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of vasopressor therapy | The duration of vasopressor therapy is measured after date of randomization in hours and minutes from the initiation of vasopressor therapy until the termination of vasopressor therapy. | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, assessed up to 24 months. | 
| Requirement for renal replacement therapy in patients with Acute Kidney Injury (AKI) | This is a binary variable the will record whether the patient did or did not have a requirement for renal replacement therapy in patients with Acute Kidney Injury (AKI). | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, assessed up to 24 months. | 
| ICU length of stay (LOS) | ICU LOS will be measured by the date and time the patient was admitted to the ICU and by the date and time the patient was discharged from the ICU. | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, assessed up to 24 months. | 
| Change in serum procalcitonin (PCT) over first 72 hours | This is a binary variable that will show whether there was a change in serum procalcitonin (PCT) over first 72 hours. | Over the first 72 hours from admission. | 
| Change in sequential organ failure assessment (SOFA) score over first 72 hours (measured as SOFA score daily for four days, with day one being admission, then 3 days after, totaling 4 days of treatment with HAT) | This is a group of variables that will show whether there was a change in SOFA score over the first 72 hours (measured as SOFA score daily for four days, with day one being admission, then 3 days after, totaling 4 days of treatment with HAT). | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, assessed up to 24 months. | 
| Procalcitonin Clearance | Procalcitonin clearance (formula = initial PCT - 72 hour PCT divided by initial PCT x 100) | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, assessed up to 24 months. | 
| Number of wound related surgeries | This is a variable that will show the count of wound related surgeries during the time the patient is admitted to the hospital. | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, assessed up to 24 months. | 
| Wound status at time of hospital discharge: Open or Closed | This is a binary variable that shows whether the wound status at time of hospital discharge is open or closed. | Assessed at the time of discharge for each individual patient. Patients will be discharged throughout the study so this measure will be assessed up to 24 months. |