Clinical trial NCT04695197: Malaria as a Risk Factor for COVID-19 in Western Kenya and Burkina Faso
Official title: Malaria as a Risk Factor for COVID-19 in Western Kenya and Burkina Faso
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid-19
Malaria
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: London School of Hygiene and Tropical Medicine
name: Kenya Medical Research Institute
name: Groupe de Recherche Action en Sante
name: Centres for Disease Control and Prevention, Kenya.
name: Bill and Melinda Gates Foundation
name: Centers for Disease Control and Prevention
First posted: 2021-01-05
Enrollment: 143
Sex: ALL
Minimum age (years): 6
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Permuted block randomization
Primary purpose: TREATMENT

Brief summary: It is unknown whether malaria or malaria treatment affects COVID-19 severity, immune responses to SARS-CoV-2 virus, or viral loads and/or duration of shedding and therewith the onwards spread of SARS-COV-2. An observational cohort study will be conducted in 708 newly diagnosed COVID-19 patient of all ages in western Kenya and Burkina-Faso. They will be enrolled in hospitals with COVID-19 testing facilities from a source population screened for SARS-CoV-2 (N\~4,720). Approximately 142 of the 708 COVID-19 patients are expected to be co-infected with malaria. They will be enrolled in the nested malaria treatment trial and randomized to receive 3-days of artemether-lumefantrine (the current standard of care) or pyronaridine-artesunate, a highly effective antimalarial with known antiviral properties against SARS-CoV-2 in-vitro, that is newly registered and being rolled out in Africa. Disease progression will be assessed and nasal swabs and blood samples will be taken during home/clinic visits on days 1, 3, 7, 14, 21, 28, and 42. Patients self-isolating will be phoned daily in between scheduled visits for the first 14 days to assess signs and symptoms. Hospitalisation, self-isolation and home-based care will follow national guidelines. The WHO clinical progression scale and FLU-PRO plus scales will be used to compare disease progression between COVID-19 patients with and without malaria, and by malaria. Other endpoints include seroconversion/reversion rates, chemokine/cytokine responses, T and B cell responses, viral load and duration of viral carriage. Infection prevention and control (IPC), including the use of personal protection equipment (PPE), and measures for patient transport will follow national guidelines in each country. Written informed consent/assent will be sought. The study is anticipated to start in January 2021 and last for approximately 18 months.

Detailed description: Background: In Africa, COVID-19 has the potential to cripple the continent's fragile healthcare systems and be devastating economically. It is unknown whether malaria infection worsens COVID-19, affects the acquisition of protective antibodies against the SARS-CoV-2 virus, or contributes to its onwards spread by resulting in higher viral loads and/or longer duration of viral shedding. It is also unknown if the effective clearance of malaria parasites and/or the choice of antimalarials affects any of these potential associations. His study will determine if the antimalarial pyronaridine, in the fixed-dose combination of pyronaridine-artesunate, has a positive, negative or negligible effect on COVID-19 disease progression or duration of viral carriage and the seroconversion rate to SARS-CoV-2.

Methods: A malaria treatment trial will be conducted nested within a larger observational COVID-19 cohort study in highly malaria-endemic areas in western Kenya and Burkina-Faso. The COVID-19 cohort study consists of approximately 708 newly diagnosed COVID-19 patient of all ages. They will be enrolled from a source population of approximately 4,720 individuals of all ages screened for SARS-CoV-2. It is anticipated that approximately 142 of the 708 cohort participants will be co-infected with malaria. These co-infected participants will be enrolled in the nested malaria treatment trial if they have uncomplicated malaria and are able to take oral medication. They will be randomized to receive either a standard 3-day treatment course of artemether-lumefantrine (the current first-line treatment) or pyronaridine-artesunate, a new highly effective antimalarial combination that is being rolled out as first or second-line treatment in western Kenya and Burkina Faso. All 142 patients will be followed for 42 days and nasal swabs and blood samples taken on days 1, 3, 7, 14, and 28. Malaria smears will be taken on days 3, 7, 14, 21, 28 and 42. The primary endpoint is the rate of SARS-CoV-2 clearance by day-7.

To limit the transmission of SARS-CoV-2, strict adherence to infection prevention and control (IPC) guidelines, including use of personal protection equipment (PPE), and measures for patient transport will be followed as per national guidelines in each country. Written informed consent/assent will be sought.

Partners: This 18-months study is funded by the Bill and Melinda Gates Foundation and is part of a collaboration between the Kenyan Medical Research Institute (KEMRI) in Kenya; the US Centers for Disease Control and Prevention (CDC); the Liverpool School of Tropical Medicine (LSTM); the Ministry of Health, Kenya; the Groupe de Recherche Action en Santé (GRAS), Ouagadougou, Burkina Faso; the Ministry of Health in Burkina Faso, and the London School of Hygiene and Tropical Medicine (LSHTM). LSTM and LSHTM will act as sponsors for the studies in Kenya and Burkina Faso, respectively.

Eligibility criteria: Inclusion Criteria:

* Laboratory confirmed SARS-CoV-2 infection, with positive molecular test results within the past 72 hours\*
* Aged \>=6 months \*\*
* Resident in the study area
* The participant or caretaker is willing and able to give informed consent or assent with parent/guardian informed consent for participation in the study
* Agrees not to self-medicate with chloroquine, hydroxychloroquine or other antimalarials with potential anti-SARS-CoV-2 properties
* Not previously diagnosed with COVID-19
* Contactable by phone for follow-up permitting real-time, reliable information
* Uncomplicated malaria, defined as able to take oral medication
* Bodyweight ≥5kg
* Confirmed malaria infection by RDT (pLDH) or microscopy

Exclusion Criteria:

* Unwilling or unable to provide informed consent/assent
* The participant is judged by the Investigator to be at significant risk of failing to comply with the provisions of the protocol as to cause harm to self or seriously interfere with the validity of the study results
* Inability/unlikely to be in the study area for the duration of the 28-day follow-up period
* Pregnant or lactating women
* Severe disease requiring parenteral treatment
* Currently receiving, or recently received (within the last 28 days) pyronaridine-artesunate or artemether-lumefantrine
* Received chloroquine in the last three days
* Inability/unlikely to be in the study area for the duration of the 42-day follow-up period
* Known hypersensitivity or specific contraindication to the use of any of the study drugs in the treatment arms
* Known chronic kidney disease (signs or symptoms of stage IV renal impairment or receiving dialysis)
* Known liver cirrhosis (Child-Pugh Class B or greater) or signs or symptoms of severe hepatotoxicity

Primary outcomes:
measure: Incidence of SARS-CoV-2 clearance
timeFrame: by day 7
Secondary outcomes:
measure: Median viral load of SARS-CoV-2
timeFrame: by day 14
measure: Cumulative incidence of SARS-CoV-2 clearance
timeFrame: by days 14, 21 and 28
measure: Time to clearance of nasal SARS-CoV-2
timeFrame: by days 1, 3, 7, 14 and 28
measure: Cumulative seroconversion rates (IgG, IgM, IgA)
timeFrame: by days 7, 14, 21 and 28
measure: IgG, IgM, IgA antibody titres against SARS-CoV-2
timeFrame: by days 7, 14, 21 and 28
measure: IL-6, IL-7, IL-10, TNF-alpha and Interferon-Gamma
timeFrame: by days 3, 7, 14 and 28
measure: CRP and angiotensin-2, angiopoietin-1 and angiopoietin-2
timeFrame: by days 3, 7, 14 and 28
measure: Genomic responses to SARS-CoV-2 infection
timeFrame: by day 28
measure: Cellular immune responses to SARS-CoV-2 infection
timeFrame: by day 28
measure: The clinical and parasitological antimalarial treatment response
timeFrame: by day 42
measure: COVID-19 disease severity
timeFrame: by day 28
measure: COVID-19 disease duration
timeFrame: by day 28
measure: COVID-19 fever duration
timeFrame: by day 28
measure: COVID-19 respiratory symptoms duration
timeFrame: by day 28
measure: COVID-19 disease duration in days
timeFrame: by day 28
measure: Treatment-related adverse events, serious adverse events, and adverse events resulting in treatment discontinuation
timeFrame: by day 7
Other outcomes:
Locations:
city: Ouagadougou
country: Burkina Faso
facility: Ouagadougou Hospitals
city: Kisumu
country: Kenya
facility: Kisumu County Referral Hospital
Study officials:
affiliation: Kenya Medical Research Institute
name: Kariuki Simon, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Groupe de Recherche Action en Sante
name: Sirima Sodiomon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: