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

Malaria,Falciparum Clinical Trial

— NECTAR3  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05081089
• Other study ID #: 26257
• Status: Completed
• Phase: Phase 2
• Start date: October 12, 2021
• Est. completion date: January 13, 2022

Study information

• Verified date: August 2021
• Source: London School of Hygiene and Tropical Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Full protocol available on request.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: January 13, 2022
• Est. primary completion date: December 16, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 10 Years to 50 Years

Eligibility

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 (ß-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

Related Conditions & MeSH terms

• Malaria, Falciparum
• Malaria,Falciparum

Intervention

Drug:
• Artemether-lumefantrine
Tablets containing 20/80 mg artemether and 120/480 mg lumefantrine will be administered according to weight as per manufacturer guidelines.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Mali	Malaria Research and Training Centre	Bamako

Sponsors (1)

Lead Sponsor	Collaborator
London School of Hygiene and Tropical Medicine

Country where clinical trial is conducted

Mali, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	Human genomic variation analysis and association with parasite measure	Human genotype analysis at baseline (G6PD, CYP2D6, and HBB type)	day 0
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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