Pyronaridine-artesunate With Low Dose Primaquine for Preventing P. Falciparum Transmission (NECTAR1)

The Efficacy and Safety of Pyronaridine-artesunate Combined With Low Dose Primaquine for Preventing Transmission of P. Falciparum Gametocytes in Sub-Saharan Africa

The purpose of this study is to assess the gametocytocidal and transmission reducing activity of pyronaridine-artesunate (PA) and dihydroartemisinin-piperaquine (DP) with and without a single low dose of primaquine (PQ; 0.25mg/kg). Outcome measures will include infectivity at 2 and 7 days after treatment, the duration of infectivity in the artemisinin combination therapy (ACT) only arms, and the production and detectability of histidine rich protein II.

Study Overview

• Status: Completed
• Conditions: Malaria,Falciparum
• Intervention / Treatment: Drug: Pyronaridine Tetraphosphate/Artesunate; Drug: Primaquine Diphosphate; Drug: Dihydroartemisinin/Piperaquine

Detailed Description

Protocol will be shared on request

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Mali
  • Bamako, Mali
    • Malaria Research and Training Centre
• Netherlands
  • Nijmegen, Netherlands
    • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 48 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 5 years and ≤ 50 years
• Absence of symptomatic falciparum malaria, defined by fever on enrolment
• Presence of ≥16 gametocytes/µL (i.e. ≥1 gametocytes recorded in the thick film against 500 white blood cells)
• No allergies to study drugs
• Use of antimalarial drugs over the past 7 days (as reported by the participant)
• Hemoglobin ≥ 9.5 g/dL
• Individuals weighing >< 80 kg
• No evidence of severe or chronic disease
• Written, informed consent

Exclusion Criteria:

• Age < 5 years or > 50 years
• Pregnancy
• Previous reaction to study drugs/known allergy to study drugs
• Signs of severe malaria
• Taking drugs which may be metabolized by cytochrome enzyme CYP2D6 (e.g., flecainide, metoprolol, imipramine, amitriptyline, clomipramine)
• Blood transfusion within the last 90 days
• Patients with clinical signs or symptoms 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).
• Patients with clinical signs or symptoms of renal impairment or known renal impairment
• Family history of congenital prolongation of the QTc interval or sudden death or with any other clinical condition known to prolong the QTc interval such as history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
• Taking drugs that are known to influence cardiac function and to prolong QTc interval, such as class IA and III: neuroleptics, antidepressant agents, certain antibiotics including some agents of the following classes - macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, astemizole) and cisapride.
• Consent not given

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: Pyronaridine-artesunate (PA); Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days.	Drug: Pyronaridine Tetraphosphate/Artesunate; Adults: Tablets containing 180 mg pyronaridine-tetraphosphate/60mg artesunate (Pyramax, Shin Poong Pharmaceutical Co.), administered according to weight. Children: Granules containing 60 mg pyronaridine-tetraphosphate/20mg artesunate, administered according to weight.; Other Names: Pyramax
Experimental: PA with single low dose primaquine (PQ); Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days, and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg.	Drug: Pyronaridine Tetraphosphate/Artesunate; Adults: Tablets containing 180 mg pyronaridine-tetraphosphate/60mg artesunate (Pyramax, Shin Poong Pharmaceutical Co.), administered according to weight. Children: Granules containing 60 mg pyronaridine-tetraphosphate/20mg artesunate, administered according to weight.; Other Names: Pyramax; Drug: Primaquine Diphosphate; Extemporaneous preparation of 1mg/mL primaquine phosphate solution, from tablets containing 30mg primaquine (A-PQ 30®, ACE pharmaceuticals, NL) dissolved in 30mL water with a non-interacting fruit-flavoured syrup. Solution will be given at 0.25mg/kg.; Other Names: Primaquine
Active Comparator: Dihydroartemisinin-piperaquine (DP); Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days.	Drug: Dihydroartemisinin/Piperaquine; Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine tablets (Eurartesim, Sigma Tau), administered according to weight.; Other Names: Euartesim
Active Comparator: DP with single low dose primaquine (PQ); Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days., and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg.	Drug: Primaquine Diphosphate; Extemporaneous preparation of 1mg/mL primaquine phosphate solution, from tablets containing 30mg primaquine (A-PQ 30®, ACE pharmaceuticals, NL) dissolved in 30mL water with a non-interacting fruit-flavoured syrup. Solution will be given at 0.25mg/kg.; Other Names: Primaquine; Drug: Dihydroartemisinin/Piperaquine; Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine tablets (Eurartesim, Sigma Tau), administered according to weight.; Other Names: Euartesim

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mosquito infectivity assessed through membrane feeding assays (day 2)	The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 2 post feed, compared to baseline	2 days (day 0 & 2)

Secondary 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 (day 0 & 7)
Mosquito infectivity assessed through membrane feeding assays - inter arm	Mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 2 and 7 post feed, compared between study arms	3 days (day 0, 2 & 7)
Duration of infectivity	Non PQ arms only: Duration of infectivity will be determined from measures of mosquito infection prevalence, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 0, 2, 7, 10 and 14 post treatment, and then weekly until 2 sequential negative feeds or until day 49.	5-10 days (as described)
Area under the curve (AUC) of infectivity/time	Non PQ arms only: AUC will be determined from measures of mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 0, 2, 7, 10 and 14 post treatment, and then weekly until 2 sequential negative feeds or until day 49.	5-10 days (as described)
Haemoglobin level	Haemolysis will be monitored by measuring haemoglobin levels (g/dL) on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.	11 days
Histidine rich protein 2 (HRP2) concentration	Histidine rich protein 2 (HRP2) protein concentration in plasma will be determined in subsequent lab analysis from samples collected on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.	11 days
Histidine rich protein 2 (HRP2) circulation time	Histidine rich protein 2 (HRP2) protein circulation time will be compared between methods of detection	11 days
Histidine rich protein 2 (HRP2) area under the curve (AUC)	Histidine rich protein 2 (HRP2) area under the curve (AUC) will be determined from measures of HRP2 concentration	11 days
Rapid diagnostic test result	Varied rapid diagnostic tests based on the detection of HRP2 will be used on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment to determine infection prevalence, for comparison between study arms.	11 days
Gametocyte density	Gametocyte density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.	11 days
Gametocyte under the curve (AUC)	Gametocyte area under the curve (AUC) will be determined from measures of density.	11 days
Gametocyte prevalence	Gametocyte prevalence (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.	11 days
Gametocyte circulation time	Gametocyte circulation time (days) will be determined from measures of prevalence.	11 days
Gametocyte 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, 10, 14, 21, 38, 35, 42 and 49 post treatment.	11 days
Asexual parasite density	Asexual parasite density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.	11 days
Asexual parasite area under the curve (AUC)	Asexual parasite area under the curve (AUC) will be determined from measures of density.	11 days
Asexual parasite prevalence	Asexual parasite prevalence (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.	11 days
Asexual parasite circulation time	Asexual parasite circulation time (days) will be determined from measures of prevalence.	11 days
Parasite genotype	Parasite merozoite surface protein 2 (MSP2) allelic diversity (presence of distinct alleles) will be determined in subsequent lab analysis from whole blood samples collected at baseline.	1 day
Histidine rich protein gene deletion	Deletion (presence/absence) of the HRP2/3 genes will be determined from whole blood samples collected at baseline.	1 day

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: Radboud University Medical Center; Malaria Research and Training Center, Bamako, Mali

Publications and helpful links

General Publications

• Stone W, Mahamar A, Sanogo K, Sinaba Y, Niambele SM, Sacko A, Keita S, Youssouf A, Diallo M, Soumare HM, Kaur H, Lanke K, Ter Heine R, Bradley J, Issiaka D, Diawara H, Traore SF, Bousema T, Drakeley C, Dicko A. Pyronaridine-artesunate or dihydroartemisinin-piperaquine combined with single low-dose primaquine to prevent Plasmodium falciparum malaria transmission in Ouelessebougou, Mali: a four-arm, single-blind, phase 2/3, randomised trial. Lancet Microbe. 2022 Jan;3(1):e41-e51. doi: 10.1016/S2666-5247(21)00192-0.

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2019
• Primary Completion (Actual): January 7, 2020
• Study Completion (Actual): January 7, 2020

Study Registration Dates

• First Submitted: July 12, 2019
• First Submitted That Met QC Criteria: August 7, 2019
• First Posted (Actual): August 8, 2019

Study Record Updates

• Last Update Posted (Actual): January 30, 2020
• Last Update Submitted That Met QC Criteria: January 29, 2020
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Dihydroartemisinin-piperaquine; Pyramax; Primaquine; Euartesim; Pyronaridine-artesunate
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Primaquine; Artesunate; Piperaquine; Artenimol; Pyronaridine
• Other Study ID Numbers: 17507; INV-002098 (Other Grant/Funding Number: Bill & Melinda Gates Foundation)

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.: No