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| Name | Class |
|---|---|
| London School of Hygiene and Tropical Medicine | OTHER |
| Radboud University Medical Center | OTHER |
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A prospective study will be carried out in an area where parasites with reduced sensitivity to malaria drugs (artemisinins) have recently emerged. The study will recruit participants from patients who attend the clinic with uncomplicated malaria and asymptomatically infected individuals. Participants are treated with conventional artemisinin-combination therapies (ACT) as part of standard clinical care. From this population, we will select P. falciparum gametocyte carriers.
Before, during and after ACT treatment, the transmission potential of artemisinin resistant and wild type infections will be assessed by microscopy, molecular methods, parasite culture and mosquito feeding assays. Parasite clearance will be determined in the first days (d0-3) after treatment.
The study population will consist of passively recruited patients with uncomplicated P. falciparum malaria and asymptomatically infected individuals who are microscopy positive for gametocytes. Participants will be treated with conventional therapies for uncomplicated malaria without randomization: artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHA-PPQ). All doses are supervised. Parasite clearance is assessed ex vivo by ring-stage survival assays and by daily slides during the first days of treatment.
Gametocyte carriage and gametocyte commitment/production will be determined for resistant and wild type infections before, during and after treatment. In addition, venous blood will be collected at three timepoints to assess transmission to mosquitoes before (d0), during (d2) and after treatment (d7). The total duration of participation will be 7 days, the primary endpoint will be the reduction in mosquito infection rates at d2 (artemether-lumefantrine) or d7 (dihydroartemisinin-piperaquine) compared to pre-treatment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| artemether-lumefantrine | Active Comparator | artemether-lumefantrine according to manufacturer instructions |
|
| dihydroartemisinin-piperaquine | Experimental | dihydroartemisinin-piperaquine according to manufacturer instructions |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Artemether-lumefantrine | Drug | Participants in the Artemether-Lumefantrine arm will be treated with standard doses of AL (Coartem, Novartis). Tablets containing 20/80 mg artemether and 120/480 mg lumefantrine will be administered per manufacturer guidelines. All doses will be given under direct supervision with fatty food. |
| Measure | Description | Time Frame |
|---|---|---|
| Mean within person percent change (presented as percent reduction) in mosquito infection rate in infectious individuals from baseline. | Mean within person percent change (presented as percent reduction) in mosquito infection rate in infectious individuals from baseline (day 0, pre-treatment) to day 2 post treatment in the AL and day 7 post-treatment in the DHA-PPQ arm. Infectivity is assessed by mosquito membrane feeding assays; percent reduction is calculated separately for ΔPfK13 vs wild type infections. | day 2 vs day 0 (AL arm) and day 7 vs day 0 (DP arm) |
| Measure | Description | Time Frame |
|---|---|---|
| Mean within person percent change (presented as percent reduction) in mosquito infection rate from baseline | Mean within person percent change (presented as percent reduction) in mosquito infection rate from baseline to all feeding time-points. Infectivity is assessed by mosquito membrane feeding assays; comparisons are performed within treatment arms for ΔPfK13 vs wild type infections. | days 0, 2, 7 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Teun Bousema, PhD | London School of Hygiene and Tropical Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dr. Ambrosoli Memorial Hospital | Kalongo | Agago District | Uganda | |||
| Patongo Health Facility IV |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37611122 | Result | Conrad MD, Asua V, Garg S, Giesbrecht D, Niare K, Smith S, Namuganga JF, Katairo T, Legac J, Crudale RM, Tumwebaze PK, Nsobya SL, Cooper RA, Kamya MR, Dorsey G, Bailey JA, Rosenthal PJ. Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda. N Engl J Med. 2023 Aug 24;389(8):722-732. doi: 10.1056/NEJMoa2211803. | |
| 36289202 |
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Anonymized data will be shared through an online repository
Upon publication
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|
| Dihydroartemisinin-Piperaquine | Drug | Participants in the DHA-PPQ arm will be treated with standard doses of DHA-PPQ. Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine tablets (Eurartesim, Sigma Tau or Duocotecxin, Beijing Holley-Cotect Pharmaceutical Co) will be administered per manufacturer guidelines. All doses will be given under direct supervision on an empty stomach, as per manufacturer instructions. |
|
|
| Mean oocyst intensity (in all/all infected mosquitoes) | Mean oocyst intensity (in all/all infected mosquitoes) will be assessed at all feeding time-points; comparisons are performed within treatment arms for ΔPfK13 vs wild type infections | days 0, 2, 7 |
| Male and female gametocyte sex ratio (proportion male) | Male and female gametocyte sex ratio (proportion male) at all time-points, determined by molecular assays; comparisons are performed within treatment arms for ΔPfK13 vs wild type infections. | days 0, 1, 2, 3, 7, 14 |
| Gametocyte circulation time | Gametocyte circulation time (cumulative), determined by microscopy or molecular assays, compared between treatment arms and between ΔPfK13 vs wild type infections | days 0, 1, 2, 3, 7, 14 |
| Gametocyte area under the curve | Gametocyte area under the curve (cumulative), determined by microscopy or molecular assays, compared between treatment arms, and between ΔPfK13 vs wild type infections | days 0, 1, 2, 3, 7, 14 |
| Asexual parasite prevalence | Asexual parasite prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms, between arms, and between ΔPfK13 vs wild type infections | Hours 0, 8, 16, Days 1, 2, 3, 7, 14 |
| Asexual parasite density | Asexual parasite density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms, between arms, and between ΔPfK13 vs wild type infections | Hours 0, 8, 16, Days 1, 2, 3, 7, 14 |
| Total parasite prevalence | Total parasite prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms, between arms, and between ΔPfK13 vs wild type infections | Hours 0, 8, 16, Days 1, 2, 3, 7, 14 |
| Total parasite density | Total parasite density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms, between arms, and between ΔPfK13 vs wild type infections | Hours 0, 8, 16, Days 1, 2, 3, 7, 14 |
| The density of ΔPfK13 vs wild type genotypes | The density of ΔPfK13 vs wild type genotypes in peripheral blood, the asexual parasite fraction and gametocyte fraction before and after initiation of treatment. The relative abundance of ΔPfK13 genotypes will be compared between pre- and post-treatment timepoints | days 0, 1, 2, 3, 7, 14 |
| The density of ΔPfK13 vs wild type genotypes in oocysts and sporozoites in mosquitoes that become infected before and after initiation of treatment | The density of ΔPfK13 vs wild type genotypes in oocysts and sporozoites in mosquitoes that become infected before and after initiation of treatment. The relative abundance of ΔPfK13 genotypes will be compared between pre- and post-treatment timepoints | days 0, 2, 7 |
| Mean within person percent change (presented as percent reduction) in mosquito infection rate from baseline after gametocyte enrichment | Mean within person percent change (presented as percent reduction) in mosquito infection rate from baseline to all feeding time-points. Infectivity is assessed by mosquito membrane feeding assays after gametocyte enrichment; comparisons are performed within treatment arms for ΔPfK13 vs wild type infections. | days 0, 2, 7 |
| Patongo |
| Agago District |
| Uganda |
| Tumwebaze PK, Conrad MD, Okitwi M, Orena S, Byaruhanga O, Katairo T, Legac J, Garg S, Giesbrecht D, Smith SR, Ceja FG, Nsobya SL, Bailey JA, Cooper RA, Rosenthal PJ. Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda. Nat Commun. 2022 Oct 26;13(1):6353. doi: 10.1038/s41467-022-33873-x. |
| ID | Term |
|---|---|
| D016778 | Malaria, Falciparum |
| ID | Term |
|---|---|
| D008288 | Malaria |
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
| D000079426 | Vector Borne Diseases |
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| ID | Term |
|---|---|
| D000077611 | Artemether, Lumefantrine Drug Combination |
| ID | Term |
|---|---|
| D000077549 | Artemether |
| D037621 | Artemisinins |
| D017382 | Reactive Oxygen Species |
| D005609 | Free Radicals |
| D007287 | Inorganic Chemicals |
| D009930 | Organic Chemicals |
| D000078102 | Lumefantrine |
| D005449 | Fluorenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D012717 | Sesquiterpenes |
| D013729 | Terpenes |
| D011083 | Polycyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
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