Clinical trial NCT06347471: The Transmission of Artemisinin Resistant Parasites Before and After Conventional Artemisinin-combination Therapy
Official title: The Transmission of Artemisinin Resistant Parasites Before and After Conventional Artemisinin-combination Therapy: a Longitudinal Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Falciparum; Malaria
Keywords: Malaria Transmission
Artemisinin resistance
Gametocytes
Spread of resistance
Lead sponsor: Infectious Diseases Research Collaboration, Uganda
Sponsor class: OTHER
Collaborators: name: London School of Hygiene and Tropical Medicine
name: Radboud University Medical Center
First posted: 2024-04-04
Enrollment: 120
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* age ≥2 years
* blood smear positive for P. falciparum gametocytes
* mono-infection with P. falciparum confirmed by positive blood smear;
* parasitaemia of \>100 P. falciparum asexual forms/µL;
* ability to swallow oral medication;
* ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule;
* informed consent from parent or guardian;
* haemoglobin ≥ 7.0 g/dl for children below 10 years of age or ≥8.0g/dL for older individuals

Exclusion Criteria:

* presence of general danger signs;
* mixed or mono-infection with another Plasmodium species detected by microscopy;
* presence of severe malnutrition defined as a very low weight for height (below -3z scores of the median WHO growth standards), by visible severe wasting, or by the presence of nutritional oedema.
* presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS);
* history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested

Primary outcomes:
measure: Mean within person percent change (presented as percent reduction) in mosquito infection rate in infectious individuals from baseline.
timeFrame: day 2 vs day 0 (AL arm) and day 7 vs day 0 (DP arm)
Secondary outcomes:
measure: Mean within person percent change (presented as percent reduction) in mosquito infection rate from baseline
timeFrame: days 0, 2, 7
measure: Mean oocyst intensity (in all/all infected mosquitoes)
timeFrame: days 0, 2, 7
measure: Male and female gametocyte sex ratio (proportion male)
timeFrame: days 0, 1, 2, 3, 7
measure: Gametocyte circulation time
timeFrame: days 0, 1, 2, 3, 7
measure: Gametocyte area under the curve
timeFrame: days 0, 1, 2, 3, 7
measure: Asexual parasite prevalence
timeFrame: days 0, 1, 2, 3, 7
measure: Asexual parasite density
timeFrame: days 0, 1, 2, 3, 7
measure: Total parasite prevalence
timeFrame: days 0, 1, 2, 3, 7
measure: Total parasite density
timeFrame: days 0, 1, 2, 3, 7
measure: The density of ΔPfK13 vs wild type genotypes
timeFrame: days 0, 1, 2, 3, 7
measure: The density of ΔPfK13 vs wild type genotypes in oocysts and sporozoites in mosquitoes that become infected before and after initiation of treatment
timeFrame: days 0, 2, 7
measure: Mean within person percent change (presented as percent reduction) in mosquito infection rate from baseline after gametocyte enrichment
timeFrame: days 0, 2, 7
Other outcomes:
Locations:
city: Kalongo
country: Uganda
facility: Dr. Ambrosoli Memorial Hospital
state: Agago district
city: Patongo
country: Uganda
facility: Patongo Health Facility IV
state: Agago district
Study officials:
affiliation: London School of Hygiene and Tropical Medicine
name: Teun Bousema, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.