Clinical trial NCT04999137: Evaluation of Safety and Dosing of a Vitamin C Bundle for Sepsis Treatment in Africa
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Sepsis
Septic Shock
HIV
Keywords: vitamin c
ascorbate
vitamin b1
thiamine
sepsis
septic shock
hiv
malnutrition
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Infectious Diseases Institute, Uganda
name: Walimu
name: University of Copenhagen
name: University of Liverpool
First posted: 2021-08-10
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: change in Vitamin C plasma concentration during the intervention period
timeFrame: during the intervention (days 1-5)
Secondary outcomes:
measure: Oxalate excretion in urine
timeFrame: during the intervention (hours 0-12 and 72-84)
measure: Incidence of acute hemolysis
timeFrame: during the intervention (days 0-5)
measure: Enrolment rates
timeFrame: up to 3 months
measure: Rates of adherence to protocol
timeFrame: during the intervention
Other outcomes:
measure: Change in lactate level
timeFrame: during the intervention (hours 0, 6 and 24)
measure: Pro-calcitonin clearance (PCT-c)
timeFrame: during the intervention (hours 0, 24 and 72)
measure: Duration of hypotension assessed by systolic and mean arterial pressures during 4-day administration of vitamin C (in combination with vitamin B1)
timeFrame: during the intervention (hours 0-96)
measure: Change in quick sepsis related organ failure assessment (qSOFA) score
timeFrame: during the intervention (hours 0, 6, 24, 48, 72 and 96)
measure: Change in Universal Vital Assessment (UVA) score
timeFrame: during the intervention (hours 0, 6, 24, 48, 72 and 96)
measure: Change in Modified Early Warning Score (MEWS)
timeFrame: during the intervention (hours 0, 6, 24, 48, 72 and 96)
measure: Percentage of patients able to walk independently
timeFrame: before, during and after the intervention (days 0, 1, 2, 3, 4 and 28)
measure: Change in creatinine levels
timeFrame: before, during and after the intervention (days 0, 1, 3 and 28)
measure: mortality at 28 days
timeFrame: after the intervention (day 28)
measure: in-hospital mortality
timeFrame: after the intervention (day 7 or at the time of hospital discharge)
measure: mortality at 28 days among vitamin B1 deficient participants
timeFrame: after the intervention (day 28)
measure: in-hospital mortality among vitamin B1 deficient participants
timeFrame: after the intervention (day 7 or at the time of hospital discharge)
measure: number of oxygen-free days
timeFrame: during the intervention (days 1-5)
measure: length of hospitalization
timeFrame: during the intervention (days 1-5)
measure: number of hospital-free days
timeFrame: during and after the intervention (days 1-28)
measure: Frequency of re-admission to hospital
timeFrame: after the intervention (day 28)
measure: change in Vitamin C plasma concentration at day 28
timeFrame: after the intervention (day 28)
Locations:
city: Kampala
country: Uganda
facility: Infectious Diseases Institute, Makerere University
city: Kampala
country: Uganda
facility: Kiruddu National Referral Hospital
Study officials:
affiliation: LSTM/IDI/Walimu
name: Shevin T Jacob, MD MPH
role: PRINCIPAL_INVESTIGATOR
References: