Evaluation of Safety and Dosing of a Vitamin C Bundle for Sepsis Treatment in Africa

Study Overview
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Brief Summary
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Open-label phase 2a Randomized Controlled Trial (RCT) assessing the pharmacokinetics of two different doses of intravenous vitamin C given alongside vitamin B1 in adult medical patients with sepsis and hypotension.

Detailed Description
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Sepsis is a life-threatening infection which, due to a dysregulated host response to infection, is responsible for more than 11 million deaths annually, a large percentage of which occur in sub-Saharan Africa (sSA). Emerging research shows promising benefits in treating sepsis patients with metabolic resuscitation using combinations of hydrocortisone, intravenous (IV) ascorbic acid (vitamin C) and IV thiamine (vitamin B1), alone or in combination. Studies are currently underway in the USA, Europe, Asia, and South America to understand whether combinations of these medicines or the medicines individually can improve outcomes for patients with sepsis. Although none of these studies are being conducted in sSA, the medicines comprising these metabolic 'bundles' are inexpensive, readily available and relatively safe to administer. It is critical that similar studies are conducted in sSA to evaluate whether or not these inexpensive medicines (or a combination of them) are efficacious for improved survival among patients with sepsis. If these studies prove that these medicines can improve survival from sepsis, there is a large potential to save many lives. Through the Preparation for Randomised Evaluation of a VItamin C bundle for Sepsis Treatment in Africa (REVISTA-Prep) studies, the investigators intend to conduct preliminary research in Uganda to help define parameters for a future RCT aimed at identifying the optimal vitamin C and vitamin B1 combination for improving survival from sepsis among adults in sSA, where resources are constrained, intensive care units are rare and issues like poverty, malnutrition and HIV are common. The study described in this protocol (i.e., REVISTA-DOSE) aims to establish the optimal vitamin C dosing strategy for the future REVISTA-RCT (assessing the efficacy of variations of a treatment bundle comprising vitamin C/B1 and/or hydrocortisone for reducing mortality among adult patients with sepsis in Africa).

Official Title
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Evaluation of Pharmacokinetics, Safety and Feasibility for Administration of Two Doses of Intravenous Vitamin C Combined With Vitamin B1 for the Management of Adult Patients Admitted With Sepsis to Kiruddu National Referral Hospital

Conditions
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HIV, Sepsis, Septic Shock

Intervention / Treatment
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* Drug: Vitamin C
* Drug: Vitamin B1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥18 years old) patients presenting to the emergency department of Kiruddu National Referral Hospital (KNRH) with: suspected infection [(any of): temperature >38 degrees Celsius or <36 degrees Celsius or (in the past seven days) fevers, rigors, night sweats or antibiotic use]; AND systolic blood pressure (SBP) <90 mmHg Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. Exclusion Criteria: Pregnant or known active breast feeding Non-severe, localized, uncomplicated infection (e.g., cellulitis with only local symptoms) which is apparent on clinical examination Severe bleeding or hemorrhagic shock Hypotension likely secondary to a cause other than sepsis or sepsis-induced cardiac insufficiency Detainee or prisoner Admission to a surgical or obstetric/gynecological ward Emergency surgery required Previously recruited to the REVISTA-DOSE study History of end stage renal disease requiring dialysis Current symptomatic renal stones or or a previous diagnosis of primary hyperoxaluria or oxalate nephropathy History of allergic reactions to vitamin C or vitamin B1 Use of vitamin C at a dose greater than 1 g (oral or intravenous) within 24 hours of screening Chronic disease/illness that, in the opinion of the site investigator, has a lifespan of less than 30 days unrelated to current sepsis diagnosis (e.g., advanced malignancy or neurodegenerative disease). Previous or current enrolment in a trial in which co-enrolment is not allowed

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous vitamin C 1.5g + intravenous vitamin B1<br>intravenous vitamin C (1.5 grams) every 6 hours for 16 doses in combination with intravenous vitamin B1 (200 mg) every 12 hours | Drug: Vitamin C<br>* Vitamin C (ascor), infused intravenously in 50 mls sodium chloride (NaCl) over 30 minutes every 6 hours for 16 doses<br>* Other names: Ascorbate;Drug: Vitamin B1<br>* Vitamin B1 (200 mg) administered intravenously every 12 hours for 8 doses<br>* Other names: Thiamin;|
| Experimental: Intravenous Vitamin C 3g + intravenous vitamin B1<br>Intravenous vitamin C (3 grams) every 6 hours for 16 doses in combination with intravenous vitamin B1 (200 mg) every 12 hours | Drug: Vitamin C<br>* Vitamin C (ascor), infused intravenously in 50 mls sodium chloride (NaCl) over 30 minutes every 6 hours for 16 doses<br>* Other names: Ascorbate;Drug: Vitamin B1<br>* Vitamin B1 (200 mg) administered intravenously every 12 hours for 8 doses<br>* Other names: Thiamin;|
| No Intervention: Usual Care<br>Usual care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in Vitamin C plasma concentration during the intervention period | Vitamin C plasma concentrations will be measured during the intervention period using high-performance liquid chromatography (HPLC) with ultraviolet (UV) analysis and compared to baseline (pre-intervention) concentrations | during the intervention (days 1-5) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxalate excretion in urine | Urine oxalate levels will be measured through two separate 12 hour urine collections. | during the intervention (hours 0-12 and 72-84) | 
| Incidence of acute hemolysis | Acute hemolysis is defined as: hemoglobin drop of at least 2.5 g/dl within 24 hours of a study drug; OR reticulocyte count >2 times upper limit of normal at clinical site lab; AND at least two of the following: i. haptoglobin < lower limit of normal; ii. indirect (unconjugated) bilirubin >2 times upper limit of normal; iii. lactate dehydrogenase (LDH) >2 times upper limit of normal | during the intervention (days 0-5) | 
| Enrolment rates | Enrolment rates of patients with sepsis and hypotension | up to 3 months | 
| Rates of adherence to protocol | Rates of adherence to protocol for treatment, clinical measurements and follow up | during the intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hiv, malnutrition, vitamin c, ascorbate, vitamin b1, thiamine, sepsis, septic shock