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

Malaria,Falciparum Clinical Trial

— NECTAR1  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04049916
• Other study ID #: 17507
• Secondary ID: INV-002098
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: September 12, 2019
• Est. completion date: January 7, 2020

Study information

• Verified date: July 2019
• 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 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.

Description:

Protocol will be shared on request

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: January 7, 2020
• Est. primary completion date: January 7, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 5 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Malaria, Falciparum
• Malaria,Falciparum

Intervention

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

Locations

Country	Name	City	State
Mali	Malaria Research and Training Centre	Bamako
Netherlands	Radboud university medical center	Nijmegen

Sponsors (3)

Lead Sponsor	Collaborator
London School of Hygiene and Tropical Medicine	Malaria Research and Training Center, Bamako, Mali, Radboud University

Countries where clinical trial is conducted

Mali,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	Histidine rich protein 2 (HRP2) circulation time	Histidine rich protein 2 (HRP2) protein circulation time will be compared between methods of detection	11 days
Secondary	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
Secondary	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
Secondary	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
Secondary	Gametocyte under the curve (AUC)	Gametocyte area under the curve (AUC) will be determined from measures of density.	11 days
Secondary	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
Secondary	Gametocyte circulation time	Gametocyte circulation time (days) will be determined from measures of prevalence.	11 days
Secondary	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
Secondary	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
Secondary	Asexual parasite area under the curve (AUC)	Asexual parasite area under the curve (AUC) will be determined from measures of density.	11 days
Secondary	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
Secondary	Asexual parasite circulation time	Asexual parasite circulation time (days) will be determined from measures of prevalence.	11 days
Secondary	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
Secondary	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