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.
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.
Drug: Artemether-lumefantrine (AL)
Current first line treatment of malaria. Dose: Bodyweight (kg) Dose (mg) of artemether + lumefantrine given twice daily for 3 days (total, six doses) 5 to < 15 20 + 120 15 to < 25 40 + 240 25 to < 35 60 + 360 >=35 80 + 480; Twice daily for 3 days (total, six doses)
Other Name: Coartem
Drug: Pyronaridine-artesunate (PA)
Antimalarial; Dose: Body weight (kg) Dose (mg) of pyronaridine + aresunate given once daily for 3 days (total, three doses) 5 to < 8 60 + 20 8 to <15 120 + 40 15 to <20 180 + 60 20 to <24 kg 180 + 60 24 to <45 360 + 120 45 to <65 540 + 180 >=65 720 + 240; Once-daily for 3 days (total, three doses).
Other Name: Pyramax
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
Ouagadougou Hospitals
Ouagadougou, Burkina Faso
Kisumu County Referral Hospital
Kisumu, Kenya
Feiko ter Kuile, MD, PhD
+44 151 705 3287
Feiko.terKuile@lstmed.ac.uk
Chris Drakeley, PhD
+44 207 9272 289
Chris.Drakeley@lshtm.ac.uk