Evaluation of Safety and Dosing of a Vitamin C Bundle for Sepsis Treatment in Africa (REVISTA-DOSE)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Septic Shock; HIV
• Intervention / Treatment: Drug: Vitamin C; Drug: Vitamin B1

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shevin T Jacob, MD MPH; Phone Number: +256.787.429365; Email: shevin.jacob@lstmed.ac.uk
• Study Contact Backup: Name: Sam Rowe, BMBS MRCP; Phone Number: +447487793696; Email: Sam.Rowe@lstmed.ac.uk

Study Locations

• Uganda
  • Kampala, Uganda
    • Recruiting
    • Infectious Diseases Institute, Makerere University
    • Contact: Christine Sekaggya-Wiltshire, MMed PhD; Phone Number: +256772479791; Email: csekaggya@idi.co.ug
  • Kampala, Uganda
    • Recruiting
    • Kiruddu National referral Hospital
    • Contact: Priscilla Haguma, MMed MS; Phone Number: +256777272582; Email: priscilla.haguma@walimu.org
    • Contact: Sharon Nyesiga, MMed; Phone Number: +256775661159; Email: sharon@walimu.org
    • Principal Investigator: Christine Sekaggya, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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
2. 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.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

1. Pregnant or known active breast feeding
2. Non-severe, localized, uncomplicated infection (e.g., cellulitis with only local symptoms) which is apparent on clinical examination
3. Severe bleeding or hemorrhagic shock
4. Hypotension likely secondary to a cause other than sepsis or sepsis-induced cardiac insufficiency
5. Detainee or prisoner
6. Admission to a surgical or obstetric/gynecological ward
7. Emergency surgery required
8. Previously recruited to the REVISTA-DOSE study
9. History of end stage renal disease requiring dialysis
10. Current symptomatic renal stones or or a previous diagnosis of primary hyperoxaluria or oxalate nephropathy
11. History of allergic reactions to vitamin C or vitamin B1
12. Use of vitamin C at a dose greater than 1 g (oral or intravenous) within 24 hours of screening
13. 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).
14. Previous or current enrolment in a trial in which co-enrolment is not allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in lactate level	A correlate for hypoperfusion (or shock)	during the intervention (hours 0, 6 and 24)
Pro-calcitonin clearance (PCT-c)	Increasing procalcitonin levels may be an indicator of increased severity of bacterial infection or sepsis. PCT-c calculated using the following formula: initial PCT minus PCT at 0 and 24 and 72 hours, divided by the initial PCT multiplied by 100.	during the intervention (hours 0, 24 and 72)
Duration of hypotension assessed by systolic and mean arterial pressures during 4-day administration of vitamin C (in combination with vitamin B1)	Lower blood pressures are associated with worsening shock and poor organ perfusion. Non invasive blood pressure readings will be recorded.	during the intervention (hours 0-96)
Change in quick sepsis related organ failure assessment (qSOFA) score	qSOFA score is a 3 point measurement of sepsis severity made up of systolic blood pressure under 100 mmHg, Glasgow Coma Scale (GCS) score <15 and respiratory rate >22. Scores increase with severity from 0-3.	during the intervention (hours 0, 6, 24, 48, 72 and 96)
Change in Universal Vital Assessment (UVA) score	The UVA score includes points for temperature, heart and respiratory rates, systolic blood pressure, oxygen saturation, GCS score and HIV serostatus. Patients are scored from zero to 13 with increasing severity	during the intervention (hours 0, 6, 24, 48, 72 and 96)
Change in Modified Early Warning Score (MEWS)	MEWS is a physiologic scoring system for bedside assessment of patients. Patients are scored from 0-14 with increasing severity according to systolic blood pressure, heart rate (HR), respiratory rate (RR), temperature and the 'alert, verbal, pain, unresponsive' (AVPU) score	during the intervention (hours 0, 6, 24, 48, 72 and 96)
Percentage of patients able to walk independently	Walking independently is defined by being able to stand independently and walk at least 10 steps without assistance	before, during and after the intervention (days 0, 1, 2, 3, 4 and 28)
Change in creatinine levels	measure of kidney function comparing baseline to measurement during and after the intervention	before, during and after the intervention (days 0, 1, 3 and 28)
mortality at 28 days	Number of participants alive 28 days after enrolment	after the intervention (day 28)
in-hospital mortality	Number of participants alive at hospital discharge (or day 7 if still an inpatient)	after the intervention (day 7 or at the time of hospital discharge)
mortality at 28 days among vitamin B1 deficient participants	Number of vitamin B1 deficient participants alive 28 days after enrolment	after the intervention (day 28)
in-hospital mortality among vitamin B1 deficient participants	Number of vitamin B1 deficient participants alive at hospital discharge (or day 7 if still an inpatient)	after the intervention (day 7 or at the time of hospital discharge)
number of oxygen-free days	number of days of hospitalization during which the participant does not require supplemental oxygen for hypoxia and/or respiratory distress	during the intervention (days 1-5)
length of hospitalization	number of days hospitalized	during the intervention (days 1-5)
number of hospital-free days	taken from 28 days; deceased patients will be assigned a score of 0 for all "free day" outcomes	during and after the intervention (days 1-28)
Frequency of re-admission to hospital	Number of re-hospitalizations after discharge from initial hospitalization for sepsis	after the intervention (day 28)
change in Vitamin C plasma concentration at day 28	Vitamin C plasma concentrations will be measured after the intervention period (at 28 days post enrolment) using HPLC with UV analysis and compared to baseline (pre-intervention) concentrations	after the intervention (day 28)

Collaborators and Investigators

• Sponsor: Liverpool School of Tropical Medicine
• Collaborators: University of Copenhagen; University of Liverpool; Infectious Diseases Institute, Uganda; Walimu
• Investigators: Principal Investigator: Shevin T Jacob, MD MPH, LSTM/IDI/Walimu

Publications and helpful links

Helpful Links

• Related Info
• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2021
• Primary Completion (Anticipated): December 29, 2021
• Study Completion (Anticipated): December 29, 2021

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: August 9, 2021
• First Posted (Actual): August 10, 2021

Study Record Updates

• Last Update Posted (Actual): September 8, 2021
• Last Update Submitted That Met QC Criteria: September 6, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: septic shock; sepsis; malnutrition; hiv; vitamin c; thiamine; ascorbate; vitamin b1
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Toxemia; Shock, Septic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Antioxidants; Vitamin B Complex; Vitamins; Ascorbic Acid; Thiamine
• Other Study ID Numbers: 19-094

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes