Single Low Dose Tafenoquine to Reduce P. Falciparum Transmission in Mali (NECTAR2) (NECTAR2)

The purpose of this study is to assess the gametocytocidal and transmission reducing activity of dihydroartemisinin-piperaquine (DP) with and without various low doses of tafenoquine (TQ; 1.66mg/kg, 0.83mg/kg, or 0.415mg/kg). Outcome measures will include infectivity to mosquitoes at 2 and 7 days after treatment, gametocyte density throughout follow-up, and safety measures including haemoglobin density.

Study Overview

• Status: Completed
• Conditions: Malaria, Falciparum
• Intervention / Treatment: Drug: Dihydroartemisinin/Piperaquine; Drug: Tafenoquine 100mg [Arakoda]

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: 12 years to 50 years (ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 12 years and ≤ 50 years
• Glucose 6 phosphate dehydrogenase (G6PD) normal status defined by Carestart rapid diagnostic test or the G6PD qualitative test (OSMMR2000)
• 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
• No allergies to study drugs
• No use of antimalarial drugs over the past 7 days (as reported by the participant)
• Hemoglobin ≥ 10 g/dL
• Individuals weighing < = 80 kg
• No evidence of acute severe or chronic disease
• Written, informed consent

Exclusion Criteria:

• Age < 12 years or > 50 years
• Women who are pregnant or lactating
• Blood thick film negative for sexual stages of malaria
• 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 (with the exception of paracetamol and/or aspirin)
• Consent not given
• G6PD-deficiency by Carestart rapid diagnostic test or the OSMMR2000 G6PD qualitative test
• Use of antimalarial drugs over the past 7 days (as reported by the participant)
• The use of other medication (with the exception of paracetamol and/or aspirin)
• 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.
• Family history of diseases leading to QT prolongation or recent treatment with drugs linked to QT prolongation
• 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
• Masking: SINGLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Dihydroartemisinin-Piperaquine (DP); Subjects will receive Dihydroartemisinin-Piperaquine (DP) once daily for 3 days, and a low dose of 1.66mg/kg, 0.83mg/kg, or 0.415mg/kg. Tafenoquine (TQ) on the first date of DP treatment.	Drug: Dihydroartemisinin/Piperaquine; Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine (Eurartesim, Sigma Tau), administered according to weight as per the manufacturer instructions.; Other Names: Euartesim
EXPERIMENTAL: DP with 0.415mg/kg Tafenoquine (TQ); Subjects will receive Dihydroartemisinin-Piperaquine (DP) once daily for 3 days, and a single dose of 0.415mg/kg Tafenoquine (TQ) on the first date of DP treatment.	Drug: Dihydroartemisinin/Piperaquine; Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine (Eurartesim, Sigma Tau), administered according to weight as per the manufacturer instructions.; Other Names: Euartesim; Drug: Tafenoquine 100mg [Arakoda]; Extemporaneous preparation of 1mg/mL Tafenoquine solution, from tablets containing 100mg primaquine (Arakoda, 60degrees pharmaceuticals, DC) dissolved in 100mL water with a non-interacting fruit-flavoured syrup. Solution will be given according to weight as indicated per treatment arm in 5kg bands.; Other Names: Arakoda
EXPERIMENTAL: DP with 0.83 mg/kg TQ; Subjects will receive Dihydroartemisinin-Piperaquine (DP) once daily for 3 days, and a single dose of 0.83mg/kg Tafenoquine (TQ) on the first date of DP treatment.	Drug: Dihydroartemisinin/Piperaquine; Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine (Eurartesim, Sigma Tau), administered according to weight as per the manufacturer instructions.; Other Names: Euartesim; Drug: Tafenoquine 100mg [Arakoda]; Extemporaneous preparation of 1mg/mL Tafenoquine solution, from tablets containing 100mg primaquine (Arakoda, 60degrees pharmaceuticals, DC) dissolved in 100mL water with a non-interacting fruit-flavoured syrup. Solution will be given according to weight as indicated per treatment arm in 5kg bands.; Other Names: Arakoda
EXPERIMENTAL: DP with 1.66mg/kg TQ; Subjects will receive Dihydroartemisinin-Piperaquine (DP) once daily for 3 days, and single dose of 1.66mg/kg Tafenoquine (TQ) on the first date of DP treatment.	Drug: Dihydroartemisinin/Piperaquine; Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine (Eurartesim, Sigma Tau), administered according to weight as per the manufacturer instructions.; Other Names: Euartesim; Drug: Tafenoquine 100mg [Arakoda]; Extemporaneous preparation of 1mg/mL Tafenoquine solution, from tablets containing 100mg primaquine (Arakoda, 60degrees pharmaceuticals, DC) dissolved in 100mL water with a non-interacting fruit-flavoured syrup. 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 infectivity assessed through membrane feeding assays (day 7)	The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 7 post feed, compared to baseline	2 days (Days 0 & 7): 7 day span

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mosquito infectivity assessed through membrane feeding assays (days 2 and 14)	The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 2 and 14 post feed, compared to baseline	3 days (Days 0, 2, & 14): 14 day span
Mosquito infection density assessed through membrane feeding assays	Mosquito infection density, assessed through membrane feeding and measured as oocyst density in mosquitoes dissected on day 2, 7 and 14 post feed, compared within and between study arms	4 days (Days 0, 2, 7 & 14): 14 day span
Mosquito infection prevalence assessed through membrane feeding assays	Mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 2, 7 and 14 post feed, compared within and between study arms	4 days (Days 0, 2, 7 & 14): 14 day span
Human infectivity assessed through membrane feeding assays	The proportion of individuals that infect any number of mosquitoes, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 2, 7 and 14 post feed, compared within and between study arms	4 days (Days 0, 2, 7 & 14): 14 day span
Haemoglobin density	Haemolysis will be monitored by measuring haemoglobin levels (g/dL) on days 0, 1, 2, 7, 14, 21, and 28 post treatment as part of the clinical assessment.	7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span
Methmoglobin density	Methmoglobin density (g/dL) will be monitored on days 0, 1, 2, 7, 14, 21, and 28 post treatment as part of the clinical assessment.	7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span
Aspartate transaminase (AST)/alanine transaminase (ALT) ratio	Aspartate transaminase (AST)/alanine transaminase (ALT) ratio will be recorded on days 0, 1, 2, 7, 14, 21, and 28 post treatment as part of the clinical assessment.	7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span
Blood creatinine level	Blood creatine level will be recorded on days 0, 1, 2, 7, 14, 21, and 28 post treatment as part of the clinical assessment.	7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span
Asexual/sexual stage parasite density	Asexual/sexual stage parasite density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 14, 21, and 28 post treatment.	7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span
Asexual/sexual stage parasite prevalence	Asexual/sexual stage parasite prevalence will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 14, 21, and 28 post treatment.	7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span
Asexual/sexual stage parasite circulation time	Asexual/sexual stage parasite circulation time (days) will be determined from measures of density.	28 days
Asexual/sexual stage parasite area under the curve (AUC)	Asexual/sexual stage parasite area under the curve (AUC: Gametocytes per microlitre per day) will be determined from measures of density.	28 days
Sexual stage parasite sex ratio	Gametocyte density will be determined by molecular methods for males and females separately, allowing analysis of sex ratio (proportion of total that is male) on days 0, 1, 2, 7, 14, 21 and 28 post treatment.	7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span
Incidence of adverse events	Incidence of adverse events will be monitored at each active (day 0,1,2,7,14,21,28) follow up visit. AE's will also be recorded and acted upon if present at any other time during follow up.	7 days (Days 0, 1, 2, 7, 14, 21 & 28): 28 day span

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Stone W, Mahamar A, Smit MJ, Sanogo K, Sinaba Y, Niambele SM, Sacko A, Keita S, Dicko OM, Diallo M, Maguiraga SO, Samake S, Attaher O, Lanke K, Ter Heine R, Bradley J, McCall MBB, Issiaka D, Traore SF, Bousema T, Drakeley C, Dicko A. Single low-dose tafenoquine combined with dihydroartemisinin-piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial. Lancet Microbe. 2022 May;3(5):e336-e347. doi: 10.1016/S2666-5247(21)00356-6. Epub 2022 Mar 23. Erratum In: Lancet Microbe. 2022 Aug 11;:

Helpful Links

• Trial report

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 29, 2020
• Primary Completion (ACTUAL): December 2, 2020
• Study Completion (ACTUAL): December 23, 2020

Study Registration Dates

• First Submitted: October 26, 2020
• First Submitted That Met QC Criteria: October 29, 2020
• First Posted (ACTUAL): October 30, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 9, 2022
• Last Update Submitted That Met QC Criteria: June 7, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Piperaquine; Artenimol; Tafenoquine
• Other Study ID Numbers: 21905

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
• product manufactured in and exported from the U.S.: Yes