Gametocytocidal and Transmission-blocking Efficacy of ASAQ and ALAQ With or Without PQ in Mali (NECTAR4)

A Five-arm Trial Comparing Artesunate-amodiaquine and Artemether-lumefantrine-amodiaquine With or Without Single-dose Primaquine to Reduce P. Falciparum Transmission in Mali

The purpose of this study is to compare the gametocytocidal and transmission reducing activity of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine-amodiaquine (ALAQ) with and without a single dose of 0.25mg/kg primaquine (PQ). Outcome measures will include infectivity to mosquitoes at 2, 7 and 14 days after treatment, gametocyte density throughout follow-up, and safety measures including haemoglobin density and the frequency of adverse events.

Study Overview

• Status: Completed
• Conditions: Malaria,Falciparum
• Intervention / Treatment: Drug: Artesunate-amodiaquine combination; Drug: Primaquine Phosphate; Drug: Artemether-lumefantrine; Drug: Amodiaquine

Detailed Description

Full protocol available on request

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Mali
  • Bamako, Mali
    • Malaria Research and Training Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age ≥ 10 years and ≤ 50 years
• Absence of symptomatic falciparum malaria, defined by fever on enrolment
• Presence of P. falciparum gametocytes on thick blood film at a density >16 gametocytes/µL (i.e. ≥ gametocytes recorded in the thick film against 500 white blood cells)
• Absence of other non-P. falciparum species on blood film
• Haemoglobin ≥ 10 g/dL
• Individuals weighing < = 80 kg
• No evidence of acute severe or chronic disease
• Written, informed consent

Exclusion Criteria:

• Women who are pregnant or lactating (tested at baseline). Urine and/or serum pregnancy testing (β-hCG) will be used.
• Detection of a non-P. falciparum species by microscopy
• Previous reaction to study drugs / known allergy to study drugs, such as sudden high fevers, shaking or severe sore throat or ulcers in the mouth during treatment with Amodiaquine
• Current eye disease with retinal damage
• Signs of severe malaria, including hyperparasitaemia (defined as asexual parasitaemia > 100,000 parasites / µL)
• Signs of acute or chronic illness, including hepatitis
• The use of other medication (except for paracetamol and/or aspirin), including antacids, other medicines used to treat malaria, abnormal heart rhythm, depression or mental illness or HIV/AIDS, and medicines that have antibiotic/antifungal properties
• Use of antimalarial drugs over the past 7 days (as reported by the participant)
• Clinically significant illness (intercurrent illness e.g., pneumonia, pre-existing condition e.g., renal disease or HIV/AIDS, malignancy or conditions that may affect absorption of study medication e.g., severe diarrhoea or any signs of malnutrition as defined clinically)
• Signs of hepatic injury (such as nausea and/or abdominal pain associated with jaundice) or known severe liver disease (i.e., decompensated cirrhosis, Child Pugh stage B or C)
• Signs, symptoms or known renal impairment
• Clinically significant abnormal laboratory values as determined by history, physical examination, or routine blood chemistries and haematology values (laboratory guideline values for exclusion are haemoglobin < 10 g/dL, platelets < 50,000/μl, White Blood Cell count (WBC) < 2000/μl, serum creatinine >2.0mg/dL, or ALT more than 3 times the upper limit of normal for age.
• Blood transfusion in the last 90 days.
• Known Electrocardiogram (ECG) corrected QT interval of more than 450 ms
• Documented or self-reported history of cardiac conduction problems
• Documented or self-reported history of epileptic seizures

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: artesunate-amodiaquine (ASAQ); Subjects will receive artesunate-amodiaquine (ASAQ) daily for 3 days.	Drug: Artesunate-amodiaquine combination; Tablets containing 50mg/135 mg or 100mg/270 mg of artesunate/amodiaquine will be administered according to weight as per manufacturer guidelines; Other Names: Camoquin
Experimental: ASAQ with 0.25mg/kg primaquine (PQ); Subjects will receive artesunate-amodiaquine (ASAQ) daily for 3 days and a single dose of 0.25mg/kg primaquine (PQ) on the first day of ASAQ treatment.	Drug: Artesunate-amodiaquine combination; Tablets containing 50mg/135 mg or 100mg/270 mg of artesunate/amodiaquine will be administered according to weight as per manufacturer guidelines; Other Names: Camoquin; Drug: Primaquine Phosphate; The single dose of 0.25mg/kg PQ will be administered in an aqueous solution, according to a standard operating procedure (SOP) provided by the manufacturer.; Other Names: Primaquine
Active Comparator: Artemether-Lumefantrine (AL); Subjects will receive artemether-lumefantrine (AL) twice daily for 3 days.	Drug: Artemether-lumefantrine; Tablets containing 20 mg artemether and 120 mg lumefantrine will be administered according to weight as per manufacturer guidelines; Other Names: Coartem
Experimental: Artemether-Lumefantrine-Amodiaquine (ALAQ); Subjects will receive artemether-lumefantrine (AL) and amodiaquine (AQ) twice daily for 3 days.	Drug: Artemether-lumefantrine; Tablets containing 20 mg artemether and 120 mg lumefantrine will be administered according to weight as per manufacturer guidelines; Other Names: Coartem; Drug: Amodiaquine; Tablets containing 153 mg of amodiaquine will be administered according to weight, aiming for a dosage of approximately 10 mg (7.7-15.3mg)/kg/day, given once or twice daily (together with artemether-lumefantrine) for three days.
Experimental: Artemether-Lumefantrine-Amodiaquine (ALAQ) with 0.25 mg/kg primaquine (PQ); Subjects will receive artemether-lumefantrine (AL) and amodiaquine (AQ) twice daily for 3 days and a single dose of 0.25mg/kg primaquine (PQ) on the first day of ALAQ treatment.	Drug: Primaquine Phosphate; The single dose of 0.25mg/kg PQ will be administered in an aqueous solution, according to a standard operating procedure (SOP) provided by the manufacturer.; Other Names: Primaquine; Drug: Artemether-lumefantrine; Tablets containing 20 mg artemether and 120 mg lumefantrine will be administered according to weight as per manufacturer guidelines; Other Names: Coartem; Drug: Amodiaquine; Tablets containing 153 mg of amodiaquine will be administered according to weight, aiming for a dosage of approximately 10 mg (7.7-15.3mg)/kg/day, given once or twice daily (together with artemether-lumefantrine) for three days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mosquito infection rate assessed through membrane feeding assays	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 ASAQ, ASAQ-PQ, AL, ALAQ and ALAQ-PQ arms.	2 days (days 0 and 2): 3 day span

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mosquito infection rate assessed through membrane feeding assays (all timepoints)	Within person percent change (presented as percent reduction) in mosquito infection rate from baseline to all feeding time-points, with comparison within and between arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Mosquito infection rate assessed through membrane feeding assays	Mosquito infection rate at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Human infectivity to locally reared mosquitoes assessed through membrane feeding assays	Infectivity to mosquitoes at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Mosquito infection density assessed through membrane feeding assays	Oocyst intensity (in all/all infected mosquitoes) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Gametocyte infectivity	Infectiousness to mosquitoes for a given gametocyte density (measured as mosquito infection rate/gametocyte) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Asexual/sexual stage parasite prevalence	Male and female gametocyte prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. Asexual and total parasite prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Asexual/sexual stage parasite density	Male and female gametocyte density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. Asexual and total parasite density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Sexual stage parasite sex ratio	Male and female gametocyte sex ratio (proportion male) at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Sexual stage parasite circulation time	Gametocyte circulation time (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Sexual stage parasite area under the curve (AUC)	Gametocyte area under the curve (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Haemoglobin density	Haemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.	7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span
Change in haemoglobin density	Within person percent change (presented as percent reduction) in haemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms.	7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span
Incidence of adverse events	The frequency and prevalence of adverse events (all AE's, treatment related AE's, and haematological AE's) observed up to and including day 2, 7, and 14 post-treatment, and at all timepoints.	7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasite genomic and transcriptomic variation assessed in RNA	Parasite genotype and transcriptional analysis at baseline and at post-treatment timepoints.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
The impact of plasma biomarkers on malaria transmission efficiency	Plasma biomarkers (antibodies and parasite protein) at baseline and at post-treatment timepoints.	6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span
Human genomic variation analysis and association with parasite measure	Human genotype analysis at baseline (G6PD, CYP2D6, and HBB type)	day 0
ALT/AST/Creatine density	ALT/AST/Creatine density at all time-points with comparison within treatment arms compared to baseline, and between arms.	7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span
Impact of magnetic-activated cell sorting (MACS) enrichment of gametocytes on malaria transmission efficiency	• Gametocyte density, mosquito infection rate and mean oocyst intensity before and after MACS, for within treatment arm comparison to baseline and comparison between treatment arms.	2 days (day 0, day 2): 3 day span

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Investigators: Principal Investigator: Alassane Dicko, Malaria Research and Training Centre, Mali

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2022
• Primary Completion (Actual): December 30, 2022
• Study Completion (Actual): January 26, 2023

Study Registration Dates

• First Submitted: September 15, 2022
• First Submitted That Met QC Criteria: September 21, 2022
• First Posted (Actual): September 22, 2022

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 26, 2024
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Mosquito-Borne Diseases; Malaria, Falciparum; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Lumefantrine; Artemether; Primaquine; Artesunate; Artemether, Lumefantrine Drug Combination; Amodiaquine; Amodiaquine, artesunate drug combination
• Other Study ID Numbers: 28041

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Anonymised individual participant data may be shared on a digital repository or upon reasonable request.

Drug and device information, study documents

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