Phase II Dose-ranging Study of Pyronaridine/Artesunate in Adults Patients With Plasmodium Falciparum Malaria

A Randomised, Multi-Centre, Phase II, Dose-ranging Clinical Study to Assess the Safety and Efficacy of Fixed Dose, Orally Administered Pyronaridine and Artesunate (3:1) in Adult Patients With Acute Uncomplicated Plasmodium Falciparum Malaria

The primary trial objective is to determine the clinically effective dose of orally administered pyronaridine/artesunate (Pyramax®, PA) with a 3:1 ratio to treat adults with acute, symptomatic, uncomplicated P. falciparum malaria in South East Asia and Africa. Secondary trial objectives are to determine the safety of once-daily dosing for 3 days of PA and to explore possible ethnic differences in safety or efficacy.

Study Overview

• Status: Completed
• Conditions: Plasmodium Falciparum Malaria
• Intervention / Treatment: Drug: pyronaridine/artesunate

Detailed Description

This is a double-blind, multicentre, randomized, parallel group, dose-finding study of the efficacy, safety and tolerability of a once-daily 3-day regimen of PA with a 3:1 weight/weight ratio for patients with acute, symptomatic, uncomplicated P. falciparum malaria. Patients will be recruited from 5 to 7 study sites in endemic regions of South East Asia and Africa and will be randomized to 1 of 3 treatment groups differing in dosage, with 160 patients per group (n-480). Randomization will be balanced within each study site across all 3 study groups in pre-assigned treatment blocks.

The first dose will be administered on Day 0 and patients will remain hospitalized for at least 4 days whilst undertaking the 3-day regimen. Patients will remain near the study site for a minimum of 7 days or once fever and parasite clearance is confirmed (assessed by 3 negative readings of fever and/or slide).

The primary efficacy end point is the cure rate on Day 28 - the proportion of patients with PCR-corrected adequate clinical and parasitological response (ACPR). Despite this Day 28 end point, the relatively long half-life of pyronaridine necessitates follow-up until Day 42. In the case of adverse events reported and unresolved at Day 42, patients will be followed up for a further 30 days, or until resolution of the event.

• Study Type: Interventional
• Enrollment (Actual): 477
• Phase: Phase 2

Contacts and Locations

Study Locations

• Cambodia
  • Pailin, Cambodia
    • Pailin General Hospital
• Gambia
  • Farafenni, Gambia
    • Farafenni Field Station, c/o MRC Laboratories
• Indonesia
  • North Sulawesi
    • Tomohon, North Sulawesi, Indonesia
      • Bethesday Hospital
• Senegal
  • Guediawaye, Senegal
    • Centre de santé du roi Baudoin
• Thailand
  • Bangkok, Thailand
    • Faculty of Tropical Medicine, Mahidol University
• Uganda
  • Mbarara, Uganda
    • MSF Epicentre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 58 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients between the age of 15 and 60 years of age inclusive
2. Written informed consent, in accordance with local practice, provided by patient and/or parent/guardian/spouse. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations
3. Absence of severe malnutrition (defined as the weight-for-height being below -3 standard deviations or <70% of the median of the NCHS/WHO normalized reference values)
4. Weight of between 35 kg and 75 kg inclusive

5. Presence of acute symptomatic uncomplicated P. falciparum malaria with a diagnosis confirmed by a positive blood smear with asexual forms of P. falciparum only (i.e. no mixed infection) plus history of fever within the previous 24 hours or a measured temperature of ≥37.5°C (depending on method of measurement):

   • the acceptable range is between 1,000 and 100,000 asexual parasite count/μl of blood and
   • axillary/tympanic temperature of ≥ 37.5°C or oral/rectal temperature of ≥ 38.0°C
6. Ability to swallow oral medication
7. Ability to comply with study visit schedule: patients will be hospitalised for at least 4 days and will be required to remain in the vicinity of the trial site for a minimum of 7 days or until clearance of fever and parasite for at least 24 hours, whichever is the later. The patient is to return to the study site or to make themselves available for all scheduled follow up visits, until discharge at Day 42.
8. Females must not be pregnant or lactating and be willing to take measures to not become pregnant during the study period
9. Willingness and ability to comply with the study protocol for the duration of the study

Exclusion Criteria:

1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000
2. Mixed Plasmodium infection
3. Severe vomiting, defined as >3 times in the 24 hours prior to inclusion in the trial or inability to tolerate oral treatment
4. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other clinically important abnormality (including head trauma).
5. Presence of febrile conditions caused by diseases other than malaria
6. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins
7. Evidence of use of any other antimalarial agent within 2 weeks prior to the start of the study confirmed by a negative urine test or using Eggelte dipsticks
8. Positive urine pregnancy test or lactating
9. Received an investigational drug within the past 4 weeks
10. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab)
11. Known seropositive HIV antibody
12. Liver function tests [ASAT/ALAT levels] >2.5 times upper limit of normal values
13. Known significant renal impairment as indicated by a serum creatinine of ≥ 1.4 mg/dl
14. Previous participation in this clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: pyronaridine/artesunate (6:2 mg/kg); pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.; Other Names: Pyramax
Experimental: pyronaridine/artesunate (9:3 mg/kg); pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.; Other Names: Pyramax
Experimental: pyronaridine/artesunate (12:4 mg/kg); pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.; Other Names: Pyramax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR-Corrected ACPR at Day 28	Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28, defined as absence of parasitaemia on Day 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR-Corrected ACPR at Day 14	Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14, defined as absence of parasitaemia on Day 14 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure	Day 14
Parasite Clearance Time	Parasite clearance time was defined as the time (in hours) from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of parasites for two consecutive negative readings eight hours apart, with confirmed negative reading at 24 hours after the first negative slide	Thick blood slides were examined every 8 hours until at least 72 hours or until a negative smear was recorded
Fever Clearance Time	Fever clearance time was defined as the time (in hours) from first dosing to the first normal reading with fever clearance (2 consecutive assessments without fever (<37.5°C)). The method of temperature measurement was the same (ie, axillary, tympanic, oral or rectal) for each subject. Any subjects with a documented history of fever at inclusion, but who did not subsequently have a documented temperature reading >37.5°C during the 24 hours after initial dosing, were not included in this end point analysis.	Every 8 hours for at least 72 hours after the first dose
Parasite Clearance	Parasite clearance is defined as zero presence of parasites for 2 consecutive negative readings 8 hours apart, with confirmed negative reading at 24 hours after the first negative slide. The proportion of subjects with parasite clearance was summarized at Days 1, 2, and 3.	Days 1, 2, and 3
Fever Clearance	Fever clearance was defined as a subject without fever for 2 consecutive assessments, plus confirmed normal temperature at 24 hours. The proportion of subjects with fever clearance was summarized at Days 1, 2, and 3.	Days 1, 2 and 3
Adverse Events (AEs)	An AE was defined as any unfavourable and unintended sign, symptom, syndrome, or illness that developed or worsened during the period of observation in the clinical study	Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier

Collaborators and Investigators

• Sponsor: Medicines for Malaria Venture
• Collaborators: Shin Poong Pharmaceutical Co. Ltd.
• Investigators: Principal Investigator: Sornchai Looareesuwan, MD, Hospital of Tropical Diseases, Mahidol University, Bangkok, Thailand; Principal Investigator: Duong Socheat, MD, Nat. Centre for Parasitol., Entomol. and Malaria Control, Phnom Penh, Cambodia; Principal Investigator: Emiliana Tjitra, PhD, Bethesda Hospital, Tomohon, North Sulawasi, Indonesia; Principal Investigator: Kalifa Bojang, MD, MRC Laboratories, Faraffeni, The Gambia; Principal Investigator: Patrice Piola, MD, Epicentre, Mbarara, Uganda; Principal Investigator: Oumar Gaye, MD, Centre de santé Roi Baudouin, Guediawaye, Senegal

Publications and helpful links

General Publications

• Duparc S, Borghini-Fuhrer I, Craft CJ, Arbe-Barnes S, Miller RM, Shin CS, Fleckenstein L. Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. Malar J. 2013 Feb 21;12:70. doi: 10.1186/1475-2875-12-70.

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): March 1, 2006
• Study Completion (Actual): April 1, 2006

Study Registration Dates

• First Submitted: May 7, 2012
• First Submitted That Met QC Criteria: May 8, 2012
• First Posted (Estimate): May 9, 2012

Study Record Updates

• Last Update Posted (Actual): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 22, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: malaria; antimalarial; artemisinin based combination therapy (ACT); pyronaridine artesunate (Pyramax)
• 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; Artesunate; Pyronaridine
• Other Study ID Numbers: SP-C-002-05