A Crossover Bioavailability Clinical Trial of Parenteral Pyronaridine and Artesunate

The clinical trial is a Phase I monocentric clinical trial with a two-armed crossover design to evaluate the bioavailability of parenteral Pyronaridine and Artesunate.

Pyronaridine and Artesunate are antimalarial agents with a history of clinical use, and Artesunate has been used clinically in combination with other drugs also. The action of Artesunate is a rapid knock down of the parasites, after which, the drug is quickly cleared as it has a short systemic half-life. Pyronaridine is also rapidly effective in the short term but has a long blood half-life thus providing a more sustained schizonticidal effect.

12 study subjects will be included into the clinical trial after having signed the informed consent, being screened and judged to be eligible. 6 of them (group 1) will, on Day 0, be injected intravenously with 4 mg base/kg of Pyronaridine together with 4 mg/kg of Artesunate. The group 2 (the other 6 subjects) will on the same day (Day 0) be injected intramuscularly with the 4 mg base/kg of Pyronaridine together with 4 mg/kg of Artesunate (into separate sites) 8 weeks later group 1 will be injected intramuscularly with the same amount of Pyronaridine and Artesunate as on Day 0. Group 2 will also get the same amount as on Day 0 but this time the injection will be intravenously for group 2.

The primary objective is to assess the safety and tolerability by measuring (a) the proportion of subjects with adverse events (AEs) and serious adverse events (SAEs) throughout the study; (b) the proportion of subjects with solicited AEs 15 days after IMP injection; (c) the proportion of subjects with unsolicited AEs throughout the clinical trial. Further, the pharmacokinetics of both drugs will be determined.

Study Overview

• Status: Not yet recruiting
• Conditions: Severe Malarial Treatment
• Intervention / Treatment: Drug: artesunate-pyronaridine

Detailed Description

The clinical trial is a Phase I monocentric clinical trial with a two-armed crossover design to evaluate the bioavailability of parenteral Pyronaridine and Artesunate.

Pyronaridine and Artesunate are antimalarial agents with a history of clinical use, and Artesunate has been used clinically in combination with other drugs also. The action of Artesunate is a rapid knock down of the parasites, after which, the drug is quickly cleared as it has a short systemic half-life. Pyronaridine is also rapidly effective in the short term but has a long blood half-life thus providing a more sustained schizonticidal effect.

12 study subjects will be included into the clinical trial after having signed the informed consent, being screened and judged to be eligible. 6 of them (group 1) will, on Day 0, be injected intravenously with 4 mg base/kg of Pyronaridine together with 4 mg/kg of Artesunate. The group 2 (the other 6 subjects) will on the same day (Day 0) be injected intramuscularly with the 4 mg base/kg of Pyronaridine together with 4 mg/kg of Artesunate (into separate sites) 8 weeks later group 1 will be injected intramuscularly with the same amount of Pyronaridine and Artesunate as on Day 0. Group 2 will also get the same amount as on Day 0 but this time the injection will be intravenously for group 2.

The primary objective is to assess the safety and tolerability by measuring (a) the proportion of subjects with adverse events (AEs) and serious adverse events (SAEs) throughout the study; (b) the proportion of subjects with solicited AEs 15 days after IMP injection; (c) the proportion of subjects with unsolicited AEs throughout the clinical trial. Further, the pharmacokinetics of both drugs will be determined.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ayola Akim Adegnika, M.D.; Ph.D.; Phone Number: +24177406464; Email: aadegnika@gmail.com
• Study Contact Backup: Name: Diane Egger-Adam, Ph.D.; Phone Number: +49 7071 2982191; Email: diane.egger-adam@uni-tuebingen.de

Study Locations

• Gabon
  • Moyen- Ogooué
    • Lambaréné, Moyen- Ogooué, Gabon, 1437
      • Centre de Recherches Médicales de Lammbaréné

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Male and female volunteers aged 18-45 years with an asymptomatic Plasmodium falciparum infection.
• Able and willing (in the investigator's opinion) to comply with all trial requirements.
• General good health based on medical history and clinical examination.
• Written informed consent.
• Available to participate in follow-up for the duration of the trial (4 months in total).
• Reachable by phone during the whole trial period.
• Women only: Must agree to practice continuous effective contraception for the duration of the trial.

Exclusion Criteria:

• Pregnancy, lactation, or intention to become pregnant during the trial.
• Known HIV-, HBV- and HCV-infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Artesunate-pyronaridine intravenous	Drug: artesunate-pyronaridine; Pyronaridine and Artesunate are antimalarial agents with a history of clinical use, and Artesunate has been used clinically in combination with other drugs also. The action of Artesunate is a rapid knock down of the parasites, after which, the drug is quickly cleared as it has a short systemic half-life. Pyronaridine is also rapidly effective in the short term but has a long blood half-life thus providing a more sustained schizonticidal effect.
Active Comparator: Artesunate-pyronaridine intramuscular	Drug: artesunate-pyronaridine; Pyronaridine and Artesunate are antimalarial agents with a history of clinical use, and Artesunate has been used clinically in combination with other drugs also. The action of Artesunate is a rapid knock down of the parasites, after which, the drug is quickly cleared as it has a short systemic half-life. Pyronaridine is also rapidly effective in the short term but has a long blood half-life thus providing a more sustained schizonticidal effect.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of injectable artesunate-pyronaridine	To assess the safety and tolerability by measuring (a) the proportion of subjects with adverse events (AEs) and serious adverse events (SAEs) throughout the study; (b) the proportion of subjects with solicited AEs 15 days after IMP injection; (c) the proportion of subjects with unsolicited AEs throughout the clinical trial	within the two week post injection
Plasma level of Pyronaridine	Change in concentration of post IV/IM injection whole blood and plasma level of Pyronaridine will be summarized over time	iwithin the two week post injection
Plasma level of Artesunate/dihydroartemisinin	Change in concentration of post IV/IM injection plasma level of Artesunate/dihydroartemisinin will be summarized over time	within the two week post injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pyronaridine area under the curve	Pyronaridine area under the whole blood and plasma concentration versus time curves (AUC), over a 24-hour period, following dosing	within the two week post injection
Artesunate/dihydroartemisinin area under the curve	Artesunate/dihydroartemisinin area under the plasma concentration versus time curve (AUC) , over a 24-hour period, following dosing	within the two week post injection

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pyronaridine distribution	Distribution of pyronaridine between red cells and plasma (calculated from whole blood and plasma concentration measurements) will be interesting to look at during and after infection (after the crossover point)	within the two week post injection
Pyronaridine metabolites	If possible, Pyronaridine metabolites will be measured in the PK analysis, apart from the parent compound	within the two week post injection

Collaborators and Investigators

• Sponsor: Centre de Recherche Médicale de Lambaréné
• Collaborators: Institute of Tropical Medicine, University of Tuebingen

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2023
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: June 16, 2023
• First Submitted That Met QC Criteria: June 26, 2023
• First Posted (Actual): July 3, 2023

Study Record Updates

• Last Update Posted (Estimated): July 24, 2023
• Last Update Submitted That Met QC Criteria: July 20, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Artesunate; Pyronaridine
• Other Study ID Numbers: parP&A_22_1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No