The Transmission of Artemisinin Resistant Parasites Before and After Conventional Artemisinin-combination Therapy (SPARTAN)

The Transmission of Artemisinin Resistant Parasites Before and After Conventional Artemisinin-combination Therapy: a Longitudinal Study

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 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 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Falciparum; Malaria
• Intervention / Treatment: Drug: Artemether-lumefantrine; Drug: Dihydroartemisinin-Piperaquine

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Emmanuel Arinaitwe, PhD; Phone Number: +256 752900078; Email: earinaitwe@idrc-uganda.org
• Study Contact Backup: Name: Teun Bousema, PhD; Phone Number: +31612198451; Email: teun.bousema@radboudumc.nl

Study Locations

• Uganda
  • Agago District
    • Kalongo, Agago District, Uganda
      • Dr. Ambrosoli Memorial Hospital
      • Contact: Maurice Akao, MBChB
    • Patongo, Agago District, Uganda
      • Patongo Health Facility IV
      • Contact: MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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;
• presence of axillary temperature ≥ 37.5 °C or history of fever during the past 48 h;
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: artemether-lumefantrine; artemether-lumefantrine according to manufacturer instructions	Drug: Artemether-lumefantrine; 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.; Other Names: Coartem
Experimental: dihydroartemisinin-piperaquine; dihydroartemisinin-piperaquine according to manufacturer instructions	Drug: Dihydroartemisinin-Piperaquine; 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.; Other Names: Eurartesim; Duocotecxin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Secondary Outcome Measures

Outcome Measure	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
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
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
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
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	days 0, 1, 2, 3, 7
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	days 0, 1, 2, 3, 7
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	days 0, 1, 2, 3, 7
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	days 0, 1, 2, 3, 7
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
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

Collaborators and Investigators

• Sponsor: Infectious Diseases Research Collaboration, Uganda
• Collaborators: London School of Hygiene and Tropical Medicine; Radboud University Medical Center
• Investigators: Principal Investigator: Teun Bousema, PhD, London School of Hygiene and Tropical Medicine

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: March 29, 2024
• First Submitted That Met QC Criteria: March 29, 2024
• First Posted (Actual): April 4, 2024

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Artemisinin resistance; Gametocytes; Malaria Transmission; Spread of resistance
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination; Piperaquine; Artenimol
• Other Study ID Numbers: SBS-2023-477

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized data will be shared through an online repository
• IPD Sharing Time Frame: Upon publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No