NECTAR3: Gametocytocidal and Transmission-blocking Efficacy of PQ in Combination With AL and TQ in Combination With SPAQ in Mali

Sponsor

London School of Hygiene and Tropical Medicine (Other)

Overall Status

Completed

CT.gov ID

NCT05081089

Collaborator

(none)

Enrollment

Location

Arms

3.1

Actual Duration (Months)

26.2

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 artemether-lumefantrine (AL) with and without a single dose of 0.25mg/kg primaquine (PQ) and sulfadoxine-pyrimethamine with amodiaquine (SPAQ) with and without single dose of 1.66mg/kg tafenoquine (TQ). Outcome measures will include infectivity to mosquitoes at 2, 5 and 7 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: Artemether-lumefantrine Drug: Primaquine Phosphate Drug: Sulphadoxine-pyrimethamine with amodiaquine Drug: Tafenoquine	Phase 2

Detailed Description

Full protocol available on request.

Study Design

Study Type:

Interventional

Actual Enrollment :

80 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 Four-arm Trial Comparing Artemether-lumefantrine With or Without Single-dose Primaquine and Sulphadoxine-pyrimethamine/Amodiaquine With or Without Single-dose Tafenoquine to Reduce P. Falciparum Transmission in Mali

Actual Study Start Date :

Oct 12, 2021

Actual Primary Completion Date :

Dec 16, 2021

Actual Study Completion Date :

Jan 13, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Artemether-lumefantrine (AL) Subjects will receive artemether-lumefantrine (AL) twice daily for 3 days.	Drug: Artemether-lumefantrine Tablets containing 20/80 mg artemether and 120/480 mg lumefantrine will be administered according to weight as per manufacturer guidelines. Other Names: Riamet
Experimental: AL with 0.25mg/kg primaquine (PQ) Subjects will receive artemether-lumefantrine (AL) twice daily for 3 days and a single dose of 0.25mg/kg primaquine (PQ) on the first day of AL treatment.	Drug: Artemether-lumefantrine Tablets containing 20/80 mg artemether and 120/480 mg lumefantrine will be administered according to weight as per manufacturer guidelines. Other Names: Riamet 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: Sulphadoxine-pyrimethamine with amodiaquine (SPAQ) Subjects will receive sulphadoxine-pyrimethamine with amodiaquine (SPAQ) once daily for 3 days.	Drug: Sulphadoxine-pyrimethamine with amodiaquine Sulfadoxine/pyrimethamine tablets contain 500mg sulfadoxine and 25mg pyrimethamine. Amodiaquine tablets contain 150mg amodiaquine (as hydrochloride). Tablets will be administered according to weight as per manufacturer guidelines. Other Names: Supyra
Experimental: SPAQ with 1.66mg/kg tafenoquine (TQ) Subjects will receive sulphadoxine-pyrimethamine with amodiaquine (SPAQ) once daily for 3 days and a single dose of 1.66mg/kg tafenoquine (TQ) on the first day of SPAQ treatment.	Drug: Sulphadoxine-pyrimethamine with amodiaquine Sulfadoxine/pyrimethamine tablets contain 500mg sulfadoxine and 25mg pyrimethamine. Amodiaquine tablets contain 150mg amodiaquine (as hydrochloride). Tablets will be administered according to weight as per manufacturer guidelines. Other Names: Supyra Drug: Tafenoquine 100mg tafenoquine tablets are prepared into a 1mg/mL solution in water. Solution will be given according to weight as indicated per treatment arm in 5kg bands. Other Names: Arakoda

Outcome Measures

Primary Outcome Measures

Change in mosquito infection rate assessed through membrane feeding assays (day 2 and day 7) [3 days (days 0, 2 and 7): 7 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 AL and AL-PQ arms, and day 7 post-treatment in the SPAQ and SPAQ-TQ.

Secondary Outcome Measures

Change in mosquito infection rate assessed through membrane feeding assays (all timepoints) [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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) [7 days (day 0, day 2, day 5, 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 [8 days (day 0, day 1, day 2, day 5, 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 [8 days (day 0, day 1, day 2, day 5, 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.
Methaemoglobin density [8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28)]
Methaemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.
Change in methaemoglobin density [8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span]
Within person percent change (presented as percent reduction) in methaemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms.
Incidence of adverse events [8 days (day 0, day 1, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [7 days (day 0, day 2, day 5, 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 [8 days (day 0, day 1, day 2, day 5, 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.

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
G6PD-normal defined by Carestart rapid diagnostic test or the OSMMR2000 G6PD qualitative test
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
Hemoglobin ≥ 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
Signs of severe malaria, including hyperparasitemia (defined as asexual parasitemia > 100,000 parasites / μL)
Signs of acute or chronic illness, including hepatitis
The use of other medication (except for paracetamol and/or aspirin)
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, malignancy or conditions that may affect absorption of study medication e.g., severe diarrhea 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 hematology values (laboratory guideline values for exclusion are hemoglobin < 10 g/dL, platelets < 50,000/μl, White Blood Cell count (WBC) < 2000/μl, serum creatinine >2.0mg/dL, or ALT or AST more than 3 times the upper limit of normal for age.
Blood transfusion in the last 90 days.
Consistent with the long half-life of tafenoquine, effective contraception should be continued for 5 half-lives (3 months) after the end of treatment.
History of psychiatric disorders