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

Sponsor

London School of Hygiene and Tropical Medicine (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT05550909

Collaborator

(none)

100

Enrollment

Location

Arms

3.3

Anticipated Duration (Months)

30.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria,Falciparum	Drug: Artesunate-amodiaquine combination Drug: Primaquine Phosphate Drug: Artemether-lumefantrine Drug: Amodiaquine	Phase 2

Detailed Description

Full protocol available on request

Study Design

Study Type:

Interventional

Actual Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

This is a single blind randomised controlled trial. The treating physician and staff involved with assessing all laboratory outcomes of the study are blinded, but no placebo will be used. The study pharmacist will be unblinded and responsible for randomisation and treatment administration.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 17, 2022

Actual Primary Completion Date :

Dec 30, 2022

Anticipated Study Completion Date :

Jan 25, 2023

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

Change in mosquito infection rate assessed through membrane feeding assays [2 days (days 0 and 2): 3 day span]
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.

Secondary Outcome Measures

Change in mosquito infection rate assessed through membrane feeding assays (all timepoints) [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
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.
Mosquito infection rate assessed through membrane feeding assays [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
Mosquito infection rate at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.
Human infectivity to locally reared mosquitoes assessed through membrane feeding assays [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
Infectivity to mosquitoes at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.
Mosquito infection density assessed through membrane feeding assays [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
Oocyst intensity (in all/all infected mosquitoes) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.
Gametocyte infectivity [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
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.
Asexual/sexual stage parasite prevalence [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
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.
Asexual/sexual stage parasite density [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
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.
Sexual stage parasite sex ratio [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
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.
Sexual stage parasite circulation time [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
Gametocyte circulation time (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.
Sexual stage parasite area under the curve (AUC) [6 days (day 0, day 2, day 7, day 14, day 21, day 28): 28 day span]
Gametocyte area under the curve (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.
Haemoglobin density [7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span]
Haemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.
Change in haemoglobin density [7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span]
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.
Incidence of adverse events [7 days (day 0, day 1, day 2, day 7, day 14, day 21, day 28): 28 day span]
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.

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

10 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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