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

NCT04049916 | Completed Phase 2 DMC

• 2 other identifiers: 17507INV-002098
• Study Type: interventional
• Target: 100
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Malaria,Falciparum

Keywords

Primaquine; Pyramax; Euartesim; Dihydroartemisinin-piperaquine; Pyronaridine-artesunate

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (20)

• Change in mosquito infectivity assessed through membrane feeding assays (day 7)

  2 days (day 0 & 7)

• Mosquito infectivity assessed through membrane feeding assays - inter arm

  3 days (day 0, 2 & 7)

• Duration of infectivity

  5-10 days (as described)

• Area under the curve (AUC) of infectivity/time

  5-10 days (as described)

• Haemoglobin level

  11 days

Study Arms (4)

Pyronaridine-artesunate (PA)

ACTIVE COMPARATOR

Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days.

Drug: Pyronaridine Tetraphosphate/Artesunate

PA with single low dose primaquine (PQ)

EXPERIMENTAL

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; Drug: Primaquine Diphosphate

Dihydroartemisinin-piperaquine (DP)

ACTIVE COMPARATOR

Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days.

Drug: Dihydroartemisinin/Piperaquine

DP with single low dose primaquine (PQ)

ACTIVE COMPARATOR

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: Dihydroartemisinin/Piperaquine; Drug: Primaquine Diphosphate

Interventions

Pyronaridine Tetraphosphate/Artesunate DRUG

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.

Also known as: Pyramax

PA with single low dose primaquine (PQ); Pyronaridine-artesunate (PA)

Dihydroartemisinin/Piperaquine DRUG

Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine tablets (Eurartesim, Sigma Tau), administered according to weight.

Also known as: Euartesim

DP with single low dose primaquine (PQ); Dihydroartemisinin-piperaquine (DP)

Primaquine Diphosphate DRUG

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.

Also known as: Primaquine

DP with single low dose primaquine (PQ); PA with single low dose primaquine (PQ)

Eligibility Criteria

• Age: 5 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• London School of Hygiene and Tropical Medicine: lead
• Malaria Research and Training Center, Bamako, Mali: collaborator
• Radboud University Medical Center: collaborator

Study Sites (2)

Malaria Research and Training Centre

Bamako, Mali

Location

Radboud university medical center

Nijmegen, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 35028628 DERIVED

MeSH Terms

Conditions

Malaria, Falciparum

Interventions

pyronaridine; Artesunate; pyronaridine tetraphosphate, artesunate drug combination; artenimol; piperaquine; Primaquine

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Sesquiterpenes; Terpenes; Hydrocarbons; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2019
• First Posted: August 8, 2019
• Study Start: September 12, 2019
• Primary Completion: January 7, 2020
• Study Completion: January 7, 2020
• Last Updated: January 30, 2020

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1); MA (1)