Preparation for the Randomised Evaluation of a VItamin C bundle for Sepsis Treatment in Africa (REVISTA-Prep)

Preparation for Randomised Evaluation of a VItamin C bundle for Sepsis Treatment in Africa (REVISTA-Prep)

Key points:
1) Sepsis is a life-threatening infection that can result in failure of vital organs; it is responsible for more than 7 million deaths annually, a large percentage of which occur in Africa.
2) Emerging research shows promising benefits in patients with sepsis treated with "metabolic resuscitation" using combinations of hydrocortisone (steroids), intravenous vitamin C (ascorbic acid) and intravenous vitamin B1 (thiamine).
3) Different studies are underway in the US, Europe, Asia, and South America to understand whether combinations of these medicines or the medicines individually can help improve the chances of someone with sepsis. Although none of these studies are being conducted in Africa, the different medicines that are included in this treatment are inexpensive, readily available and relatively safe to administer.
4) It is critical that similar studies are conducted in Africa to evaluate whether or not providing any of these medicine or a combination of them can help save people there from dying of sepsis.
5) If the studies prove that these medicines can improve survival from sepsis, there is a large potential to save many lives because each of the medicines are inexpensive, readily available and relatively safe to administer.

Through this Joint Global Health Trials Development Award, we intend to conduct preliminary research in Uganda (East Africa) to help us understand better what we might need to consider for conducting a future large trial that studies which of the combinations of vitamin C, vitamin B1, and steroids (or the medicines individually) will be best at improving survival from sepsis in African settings, where the resources are constrained, intensive care units are rare, and issues like poverty, malnutrition, and HIV are common.

Specifically, we will conduct a series of small studies to understand how common deficiencies of vitamin C and B1 are in sepsis patients who are HIV-infected compared to healthy individuals with and without HIV. We will also investigate or not there is a link between having low levels of these vitamins and death in sepsis patients. In addition, we will provide varying doses of vitamin C (alongside vitamin B1) to another small group of sepsis patients so we can gain a better understanding of the correct dose we should use in the future trial and whether there are any laboratory tests or clinical signs we can use to monitor the vitamin C levels specifically. Finally, because we will be conducting the future trial in a population of patients who are severely ill, we would like to interview clinicians, patients, and people living in the community about their understanding of what it means to be enrolled in a large clinical trial for which it is unclear whether the medicine being studied can help you and where you will not be able to decide which of the different medicines you will ultimately be randomised to receive.

We will use all the information we collect from this development award to apply for a full award in order to get funding for the larger trial.

Project questions: We will conduct the following studies in order to answer specific questions that will inform the future randomised controlled trial (REVISTA-RCT):

Observational Study
Q1: What are the baseline levels of ascorbic acid (vitamin C) and thiamine (vitamin B1) deficiencies in HIV-infected adult medical patients hospitalised with sepsis in Uganda compared to clinically well HIV-infected adult patients without sepsis and healthy volunteers?
Q2: Is there an association between baseline vitamin C or B1 levels and 28-day mortality?
Q3: What is the frequency of G6PD deficiency in HIV-infected adult medical patients hospitalised with sepsis in Uganda?

Pharmacokinetic (PK) and adverse event monitoring Study
Q4: What is optimal dose of intravenous vitamin C for inclusion in treatment bundle for HIV-infected adult medical patients hospitalised with sepsis in Uganda?

Qualitative Study
Q5: What is level of understanding and acceptability for participation in a randomized placebo-controlled trial evaluating efficacy of a vitamin C bundle on HIV-infected adult medical patients hospitalised with sepsis in Uganda?

Future trial question: What is the efficacy of a metabolic resuscitation bundle (comprising vitamin C, vitamin B1, and hydrocortisone) for survival among HIV-infected adults hospitalised with sepsis in Uganda when compared to the bundle's individual components or placebo?

Future trial primary outcome: 28-day mortality

Future trial intervention arms: 1) usual care (placebo); 2) intravenous vitamin C + intravenous B1; 3) hydrocortisone; 4) intravenous vitamin C + intravenous B1 + hydrocortisone

By implementing REVISTA-Prep in Uganda, our group is able to ensure value for money by leverage existing UK government investments for sepsis in Africa through the NIHR-funded ARCS programme. Part of ARCS' capacity building in sepsis research includes stakeholder engagement with key policy-makers in collaboration with African Institute for Development Policy, an African-based organization focused on translating evidence to policy. REVISTA-Prep will be embedded in work done through ARCS adding to a body of evidence generated through a number of studies related to various aspects of sepsis. Through stakeholder engagement in Uganda, we will have a forum to discuss the preliminary results that emerge from REVISTA-Prep and engage key stakeholders in the planning of REVISTA-RCT. Beyond Uganda, we will be able to leverage parallel efforts under ARCS in Malawi and Gabon as well as the multinational African Sepsis Alliance, a key partner in ARCS, for dissemination of the results of this work.