Malaria as a Risk Factor for COVID-19 in Western Kenya and Burkina Faso

Study Overview
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Brief Summary
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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
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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.

Official Title
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Malaria as a Risk Factor for COVID-19 in Western Kenya and Burkina Faso

Conditions
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Covid-19, Malaria

Intervention / Treatment
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* Drug: Artemether-lumefantrine (AL)
* Drug: Pyronaridine-artesunate (PA)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Permuted block randomization
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Artemether-lumefantrine<br>Artemether-lumefantrine, standard 3-day antimalarial treatment regimen. | Drug: Artemether-lumefantrine (AL)<br>* 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)<br>* Other names: Coartem;|
| Experimental: Pyronaridine-artesunate<br>Pyronaridine-artesunate, standard 3-day antimalarial treatment regimen. | Drug: Pyronaridine-artesunate (PA)<br>* 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).<br>* Other names: Pyramax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of SARS-CoV-2 clearance | Defined as the proportion of participants with a negative nasal swab on Day 7 after the start of treatment | by day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median viral load of SARS-CoV-2 | Median CT value as detected from mid-nasal swabs by PCR | by day 14 | 
| Cumulative incidence of SARS-CoV-2 clearance | Defined as the proportion of participants with negative nasal swabs | by days 14, 21 and 28 | 
| Time to clearance of nasal SARS-CoV-2 | Defined as the number of days to a negative SARS-CoV-2 RNA PCR tests (swabs collected on days 1, 3, 7, 14, 21 and 28) | by days 1, 3, 7, 14 and 28 | 
| Cumulative seroconversion rates (IgG, IgM, IgA) | proportion of antibody negative patients on enrolment who seroconvert | by days 7, 14, 21 and 28 | 
| IgG, IgM, IgA antibody titres against SARS-CoV-2 | Geometric mean, maximum, and change from baseline | by days 7, 14, 21 and 28 | 
| IL-6, IL-7, IL-10, TNF-alpha and Interferon-Gamma | median, max and change from baseline | by days 3, 7, 14 and 28 | 
| CRP and angiotensin-2, angiopoietin-1 and angiopoietin-2 | median, max and change from baseline | by days 3, 7, 14 and 28 | 
| Genomic responses to SARS-CoV-2 infection | Transcriptional profiling (gene expression) of whole blood and fixed whole blood for T and B cell markers | by day 28 | 
| Cellular immune responses to SARS-CoV-2 infection | T cell responses | by day 28 | 
| The clinical and parasitological antimalarial treatment response | Expressed as the proportion with early treatment failure, late clinical failure, late parasitological failure or an adequate clinical and parasitological response. Recrudescence will be differentiated from new infection by genotyping of malaria parasites | by day 42 | 
| COVID-19 disease severity | Defined by a severity index score for COVID-19 | by day 28 | 
| COVID-19 disease duration | The proportion of days with symptoms after randomization | by day 28 | 
| COVID-19 fever duration | The proportion of days with a fever after randomization | by day 28 | 
| COVID-19 respiratory symptoms duration | The proportion of days with respiratory symptoms after randomization | by day 28 | 
| COVID-19 disease duration in days | The number of days until symptom clearance | by day 28 | 
| Treatment-related adverse events, serious adverse events, and adverse events resulting in treatment discontinuation | The cumulative proportion of patients with any of these events after the start of treatment | by day 7 |