An observational study in Malaria Falciparum, sponsored by Strathmore University. Completed at 2 sites in Kenya. Open to participants aged 5 Years and older. Per ClinicalTrials.gov, last updated 2026-01-23.
Sponsored by Strathmore University · Observational
This implementation study evaluated the health systems feasibility, economic costs, and stakeholder acceptability of deploying multiple first-line therapies (MFTs) that were of the artemisinin-based combination therapies (ACTs) type, for uncomplicated malaria in Western Kenya. The study included a nested observational molecular surveillance of antimalarial resistance markers in Plasmodium falciparum parasites. The implementation program involved adaptive cycling of four ACTs across 28 health facilities over 28 months (June 2020 - October 2022) with and extension to January 2024 in one geographic area (Mfangano Island). Health systems outcomes (feasibility, costs, acceptability) are reported in Cole et al., Malaria Journal 2024. Molecular surveillance outcomes (resistance marker prevalence and temporal trends) are reported in a companion manuscript currently under peer-review.
BACKGROUND: Artemisinin-based combination therapies (ACTs) are first-line treatment for uncomplicated malaria in sub-Saharan Africa, but emerging artemisinin partial resistance threatens efficacy. Multiple first-line treatments (MFTs) represent a proposed strategy to delay resistance emergence by deploying several ACTs simultaneously, sequentially, or using other strategies rather than relying on a single first-line therapy.
STUDY DESIGN: This 28-month implementation program (June 2020 - October 2022) with and extension only on Mfangano Island until January 2024, deployed adaptive cycling of four artemisinin-based combinations across health facilities in Western Kenya using geographic allocation:
INTERVENTION COUNTY - HOMA BAY:
COMPARISON COUNTY - MIGORI:
- Continued artemether-lumefantrine (AL) monotherapy throughout study period (n=32,835 patients treated) PARTICIPANTS: Adults and children ≥5 years diagnosed with uncomplicated Plasmodium falciparum malaria at participating health facilities. Excluded: pregnant women and children \<5 years due to medication restrictions and lack of pediatric formulations.
OUTCOMES MEASURED:
Primary Outcomes (reported in Cole et al., Malaria Journal 2024):
Secondary Outcomes (reported in companion manuscript recently submitted for peer-review):
METHODS:
ETHICAL APPROVAL: Strathmore University Institutional Scientific and Ethics Review Committee (SU-ISERC 1730/20) and Kenya National Commission for Science, Technology and Innovation (NACOSTI).
384 studies on the registry are indexed under Malaria, Falciparum; 38 are open to participants now.
This study's enrollment of 316 is below the median of 542 across 50 observational studies indexed under Malaria, Falciparum.
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Patients diagnosed with uncomplicated Plasmodium falciparum malaria at participating government and faith-based health facilities in Homa Bay County and Migori County, Western Kenya, a malaria-endemic region with high transmission intensity.
Exclusion Criteria:
Sequential deployment of multiple first-line artemisinin-based combination therapies using 8-month adaptive cycling with crowding-out approach. Treatment sequence: Baseline artemether-lumefantrine (AL) followed by dihydroartemisinin-piperaquine (DHA-PIP) for 8 months, then artesunate-amodiaquine (AS+AQ) for 8 months, then return to AL for 8 months. Approximately 40,000 patients treated across multiple health facilities. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
Drug: Artemether + Lumefantrine · Drug: Dihydroartemisin-piperaquine · Drug: Artesunate-Amodiaquine (AS-AQ)
Extended deployment of a single alternative artemisinin-based combination therapy in a geographically isolated island setting. Treatment sequence: Baseline artemether-lumefantrine (AL) followed by pyronaridine-artesunate (AS+PYD) for extended 39-month period. Approximately 21,000 patients treated. This arm assessed health systems feasibility and molecular resistance dynamics with prolonged single MFT deployment in a relatively closed transmission environment since minimal data was available owing to AS+PYD recency of formulary inclusion. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
Drug: Artemether + Lumefantrine · Drug: Pyronaridine - artesunate
Continued artemether-lumefantrine (AL) as the only ACT throughout the entire study period as per Kenya national malaria treatment guidelines. Served as comparison group for health systems outcomes and molecular resistance surveillance. Approximately 32,835 patients treated. This arm represents standard of care without MFT intervention. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
Drug: Artemether + Lumefantrine
Fixed-dose artemisinin-based combination therapy containing artemether and lumefantrine with dosage calculated by weight-bands according to manufacturers recommendations. Administered orally twice daily for 3 days (6 doses total). Used as baseline treatment across all study arms and continued throughout study period in comparison county. First-line treatment for uncomplicated malaria in Kenya. Supplied by Kenya Medical Supplies Authority through routine government procurement.
Fixed-dose artemisinin-based combination therapy containing dihydroartemisinin and piperaquine with dosage calculated by weight-bands according to manufacturers recommendations. Administered orally once daily for 3 days (3 doses total). Deployed in Homa Bay Mainland for 8 months during adaptive cycling. Donated by Tridem Pharma Ltd through Tridem Pharma Kenya. WHO-recommended ACT for uncomplicated falciparum malaria.
Fixed-dose artemisinin-based combination therapy. Administered orally once daily for 3 days (3 doses total) with dosage calculated by weighted-bands according to manufacturers recommendations. Deployed in Homa Bay Mainland for 8 months during adaptive cycling following DHA-PIP deployment. Donated by Sanofi through Surgi Pharm Ltd Kenya. WHO-recommended ACT for uncomplicated falciparum malaria.
Fixed-dose artemisinin-based combination therapy containing pyronaridine and artesunate (granule formulation) with dosage calculated by weighted-bands according to manufacturers recommendations. Administered orally once daily for 3 days (3 doses total). Deployed in Mfangano Island for extended 39-month period. Donated by Shin Poong Pharmaceuticals Co. Ltd, Republic of South Korea. WHO-recommended ACT for uncomplicated falciparum malaria, registered in Kenya but not yet included in national treatment guidelines at time of study hence the need for an extended observational follow-up period.
Health Systems Feasibility - Commodity Management Score
Assessment of drug supply chain functionality including quantification accuracy, stock management, and distribution logistics. Measured using structured health facility assessment checklist scoring five domains: (1) drug availability, (2) stock-out frequency, (3) quantification accuracy, (4) storage conditions, (5) distribution timeliness. Score range 0-100 where higher scores indicate better commodity management. Assessed at 28 health facilities.
Time frame: June 2020 to January 2024
Health Systems Feasibility - Human Resources and Information Systems Score
Assessment of human resources adequacy and health information system functionality. Measured using structured facility assessment scoring: (1) healthcare worker availability, (2) training completion rates, (3) reporting tool adoption, (4) KHIS2 system functionality. Score range 0-100 where higher scores indicate better health systems capacity. Assessed at 28 health facilities.
Time frame: June 2020 to January 2024
Stakeholder Acceptability - Composite Acceptability Score
Composite measure of MFT deployment acceptability among three stakeholder groups: policymakers, healthcare workers, and patients. Measured through: (1) key informant interviews (n=85) using semi-structured guides rated on 5-point Likert scale, (2) patient exit interviews assessing treatment satisfaction (5-point scale), (3) healthcare worker surveys assessing implementation feasibility (5-point scale). Composite score calculated as mean across all stakeholder groups. Range 1-5 where higher scores indicate greater acceptability.
Time frame: June 2020 - January 2024
Economic Costs of Multiple First-Line Treatment Implementation
Total economic costs of MFT deployment calculated using activity-based costing approach with ingredient method. Includes start-up phase costs (training, IEC materials, reporting tool revision, KHIS2 updates, sensitization) and implementation phase costs (drug procurement, distribution, refresher training, quantification). Costs tracked prospectively from documents, receipts, and market prices. Reported as: (1) total economic vs financial costs in USD, (2) costs by category, (3) costs by funding source, (4) unit cost per facility covered in USD, (5) unit cost per patient treated in USD. Start-up costs annualized over 3-year useful life at 3% discount rate.
Time frame: June 2020 to January 2024
Prevalence of Antimalarial Resistance Markers
Frequency of known resistance-associated mutations measured as percentage allele frequency (%) for all markers. Assessed in four Plasmodium falciparum genes: (1) dhfr - dihydrofolate reductase (codons N51I, C59R, S108N, I164L), (2) dhps - dihydropteroate synthase (codons S436H, A437G, K540E, A581G), (3) mdr1 - multidrug resistance protein 1 (codons N86Y, Y184F), and (4) k13 - kelch13 propeller domain (codons A578S, A675V). Determined by targeted amplicon deep sequencing of dried blood spots (n=310) using Oxford Nanopore Technology. Allele frequencies calculated as percentage of reads supporting each allele (range 0-100%). Infections classified as wild-type, mutant, or mixed. Haplotype frequencies determined from microhaplotype analysis.
Time frame: September 2020 to January 2024
Change in Antimalarial Resistance Marker Prevalence Over Time (Cochran-Armitage Trend Test)
Change in resistance marker prevalence measured as percentage point difference between timepoints, with statistical significance assessed using Cochran-Armitage test for trend. Measured over four serial cross-sectional timepoints: T1 (September 2020, baseline when AL used at all sites), T2 (August-October 2021, during MFT deployment), T3 (May-July 2022, continued MFT deployment), T4 (November 2023-January 2024, extended follow-up Mfangano Island only). Primary measurement: percentage point change in allele frequency from T1 to T3 (all sites, n=240 balanced comparison). Secondary measurement: percentage point change T1 to T4 (Mfangano Island only, n=111 extended surveillance). Statistical significance determined using Cochran-Armitage test for trend (P\<0.05 significant). Assessed separately for each individual mutation and for combined haplotypes.
Time frame: Four time-points over 40 months: T1 (September 2020), T2 (August - October 2021), T3 (May - July 2022), T4 (November 2023 - January 2024)
Geographic Distribution of Antimalarial Resistance Markers
Comparison of resistance marker prevalence across three geographic study areas: (1) Homa Bay Mainland (intervention with 8-month adaptive cycling), (2) Mfangano Island (intervention with extended single MFT), and (3) Migori County (comparison with continued AL single ACT use). Statistical comparisons using chi-square tests for categorical variables and Fisher's exact tests for intervention vs comparison effects. Analysis accounts for unbalanced sampling design with extended follow-up only for Mfangano Island.
Time frame: September 2020 - January 2024
Complexity of Infection in Plasmodium falciparum
Mean complexity of infection (COI) defined as the number of genetically distinct parasite clones per infection. Determined using two complementary methods: (1) ama1 genotyping counting maximum number of distinct alleles at polymorphic positions (n=310 samples), and (2) direct haplotype counting from targeted amplicon deep sequencing reads (n=176 samples with sufficient coverage). Infections classified as monoclonal (COI=1) or polyclonal (COI\>1). Geographic variation assessed using Kruskal-Wallis test with post-hoc Dunn's test. Results provide context for interpretation of resistance marker data in high-transmission setting.
Time frame: September 2020 - January 2024
Plan to share: No
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