A Healthy Volunteer Safety Study of Pyronaridine Tetraphosphate Taken in Combination With Piperaquine Tetraphosphate

Healthy Clinical Trial

Official title: A Randomised, Double-blind, Placebo Controlled, Parallel Group Study in Healthy Adult Volunteers to Determine the Tolerability and Safety of Pyronaridine (PYR) Co-administered With Piperaquine (PQP) Under Fasted Conditions

Status Completed

Clinical Trial Summary

The study is a clinical trial involving two medicines called piperaquine (PQP) and pyronaridine (PYR) which, in combination with dihydroartemisinin (DHA) and with artesunate (ART) respectively, have been in clinical use for over 20 years to treat acute episodes of malaria. PYR and PQP are both known to be well tolerated and provide effective treatment for malarial infection when administered in their licensed combinations, but have not been administered together in combination before.

This new combination is being considered for development for malaria prevention (i.e. chemoprophylaxis) in sub-Saharan Africa and therefore, the trial participants will be exclusively drawn from a population from that origin.

Clinical Trial Description

In 2019, an estimated 229 million cases of malaria occurred worldwide, with approximately 94 % occurring in WHO African Region, leading to 409 000 deaths, of which about two thirds were in children under five years of age. In addition, there were an estimated 33 million pregnancies in the moderate to high transmission countries of the WHO African Region, of which 35 % (12 million) were exposed to malaria infection during pregnancy.

Case management with highly effective antimalarial drugs has contributed to the decrease in malaria morbidity and mortality. However, preventive administration of antimalarial drugs is also recommended for use in selected high-risk populations, irrespective of malaria infection status, both to treat any unrecognized Plasmodium infections and to prevent new ones. These preventive treatments prevent or cure undetected malarial illness with the goal to achieve therapeutic drug levels in the blood throughout the period of greatest risk (WHO 2021). WHO strongly recommends with a high-certainty evidence the following malaria chemopreventive therapies: seasonal malaria chemoprevention (SMC), intermittent preventive treatment in infants (IPTi), and intermittent preventive treatment of malaria in pregnancy (IPTp).

Despite the strong public health evidence of chemoprevention, only Sulfadoxine-pyrimethamine (SP) and Sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) are currently recommended by WHO for chemoprevention, which use is currently threatened by increasing resistance to SP. The strategy of the study sponsor, Medicines for Malaria Venture (MMV) is to re-combine existing and approved antimalarials used individually for the treatment of malaria, for the purpose of malaria chemoprevention. As part of this strategy, a review of the potential efficacy and duration of protection, the safety and tolerability, as well as the risk of emergence of resistance of currently approved products has been conducted, with a view to identify a new combination of two registered products that may be suitable for malaria chemoprevention.

A combination of pyronaridine tetraphosphate (PYR) and piperaquine tetraphosphate (PQP) was considered to have potential for this purpose. In the European Union, PQP is marketed in a fixed dose combination with the short acting antimalarial dihydroartemisinin (DHA) as Eurartesim® for treatment of acute uncomplicated malaria. PYR in a fixed dose combination with artesunate (AS) received positive scientific opinion from EMA through Article 58 and is marketed in South Korea and in many malaria endemic countries in Africa and South-East Asia as Pyramax® for treatment of acute uncomplicated malaria. The efficacy of both PYR and PQP combined to the artemisinin derivatives have been demonstrated in the treatment of uncomplicated malaria in various clinical trials in different regions and these combinations have been in clinical use for at least 20 and 40 years, respectively.

This study in healthy adults will be the first one to evaluate combined administration of pyronaridine tetraphosphate (PYR) and piperaquine tetraphosphate (PQP) in humans. A parallel group design (n=40) including a placebo cohort will be used to evaluate safety/tolerability and PK of the two treatments either as monotherapy or in combination. To our knowledge, this study will be the first human study with this new combination. The approved adult malaria treatment doses of PQP and PYR have been chosen for this trial and four treatment arms that include the use of matched placebos will facilitate discrimination of the contribution of the treatments to any safety/tolerability signal and determine the pharmacokinetic of PYR and PQP when administered alone and in combination.

Given the ultimate target population, the study will be carried out in healthy black participants of sub-Saharan African origin (defined as participants whose biological parents are both black and are of sub-Saharan African origin). ;

Related Conditions & MeSH terms

• Healthy

• NCT number: NCT05160363
• Study type: Interventional
• Source: Medicines for Malaria Venture
• Status: Completed
• Phase: Phase 1
• Start date: February 14, 2022
• Completion date: May 31, 2022