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

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

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.

Study Overview

• Status: Completed
• Conditions: Malaria,Falciparum
• Intervention / Treatment: Drug: Primaquine Phosphate; Drug: Artemether-lumefantrine; Drug: Sulphadoxine-pyrimethamine with amodiaquine; Drug: Tafenoquine

Detailed Description

Full protocol available on request.

• Study Type: Interventional
• Enrollment (Actual): 80
• 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
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / 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: 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 20/80 mg artemether and 120/480 mg lumefantrine will be administered according to weight as per manufacturer guidelines.; Other Names: Riamet
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mosquito infection rate assessed through membrane feeding assays (day 2 and day 7)	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.	3 days (days 0, 2 and 7): 7 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, 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.	8 days (day 0, day 1, day 2, day 5, 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.	8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span
Methaemoglobin density	Methaemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.	8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28)
Change in methaemoglobin density	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.	8 days (day 0, day 1, day 2, day 5, 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.	8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Human genomic variation analysis and association with parasite measure	Human genotype analysis at baseline (G6PD, CYP2D6, and HBB type)	day 0
Parasite genomic and transcriptomic variation assessed in RNA	Parasite genotype and transcriptional analysis at baseline and at post-treatment timepoints.	7 days (day 0, day 2, day 5, 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.	7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span
ALT/AST/Creatine density	ALT/AST/Creatine density at all time-points with comparison within treatment arms compared to baseline, and between arms.	8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2021
• Primary Completion (Actual): December 16, 2021
• Study Completion (Actual): January 13, 2022

Study Registration Dates

• First Submitted: September 13, 2021
• First Submitted That Met QC Criteria: October 4, 2021
• First Posted (Actual): October 18, 2021

Study Record Updates

• Last Update Posted (Actual): January 18, 2022
• Last Update Submitted That Met QC Criteria: January 14, 2022
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Infective Agents, Urinary; Renal Agents; Lumefantrine; Artemether; Primaquine; Pyrimethamine; Artemether, Lumefantrine Drug Combination; Sulfadoxine; Fanasil, pyrimethamine drug combination; Amodiaquine; Tafenoquine
• Other Study ID Numbers: 26257

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