Pyronaridine Artesunate (3:1) Versus Coartem® in P Falciparum Malaria Patients

A Phase III Comparative (Double-blind, Double-dummy) Randomised, Multi-centre Study to Assess the Efficacy of Pyronaridine Artesunate (180:60mg) Versus Coartem® (Artemether Lumefantrine) in Children & Adult Patients With Falciparum Malaria

The primary objective of this phase III study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (Pyramax®, PA) with that of Coartem® (artemether lumefantrine, AL) in children and adults with uncomplicated P falciparum malaria in Africa and South East Asia.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: Pyronaridine artesunate; Drug: Coartem® (artemether lumefantrine)

Detailed Description

This is a multi-centre, comparative, randomised, (double-blind, double-dummy), parallel-group, non-inferiority study comparing the efficacy and safety of the fixed combination of PA with that of AL in the treatment of acute, uncomplicated P. falciparum malaria. The study population will include 1269 patients, comprising male and female children (≥20 kg body weight) and adults recruited from study sites in Africa and South East Asia.

Patients will be randomised to receive either oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Days 0, 1, and 2) or AL twice a day plus PA-placebo (once a day) for 3 consecutive days (Days 0, 1, and 2) in a 2:1 ratio. The dose range of PA covered by this regimen is 7.2:2.4 mg/kg to 13.8:4.6 mg/kg, respectively, which has been shown to be effective and safe in Phase I and II studies. Posology will be based on body weight ranges for both the PA and AL regimens.

Patients will be confined to the study facility for ≥4 days (Days 0, 1, 2, and 3) and remain near the study site for ≥7 days, or once fever and parasite clearance has been confirmed for ≥24 hours - whichever occurs later.

The primary efficacy end point for the study is the proportion of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. Scheduled follow-up visits will continue until completion of the study at 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): 1272
• Phase: Phase 3

Contacts and Locations

Study Locations

• Congo, The Democratic Republic of the
  • Kinshasa, Congo, The Democratic Republic of the
    • Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa
• Gambia
  • Fajara, Gambia
    • Farafenni Field Station, c/o: MRC Laboratories
• Ghana
  • Kumasi, Ghana
    • Komfo Anoykye Teaching Hospital
• Indonesia
  • Nusa Tenggara Timur
    • Maumere, Nusa Tenggara Timur, Indonesia, 86113
      • RSUD TC Hillers
  • Papua
    • Jayapura, Papua, Indonesia
      • Jayapura General Hospital (RSUD) DOK II
• Kenya
  • Siaya, Kenya
    • Siaya District Hospital, Medical Superintendent's office
• Mali
  • Bamako, Mali
    • Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie
• Mozambique
  • Maputo, Mozambique
    • Instituto Nacional de Saude, Ministero de Saude
• Philippines
  • Puerto Princesa, Philippines
    • Puerto Princesa General Hospital
• Senegal
  • Dakar Fann
    • Dakar, Dakar Fann, Senegal
      • Service de Parasitologie, Faculté de Médecine, Université Cheikh Anta Diop

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 58 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients between the age of 3 and 60 years, inclusive.
• Body weight between 20 kg and 90 kg with no clinical evidence of severe malnutrition.

• Presence of acute uncomplicated P. falciparum mono-infection confirmed by:

  1. Fever, as defined by axillary/tympanic temperature ≥ 37.5°C or oral/rectal temperature ≥ 38°C, or documented history of fever in the previous 24 hours and,
  2. Positive microscopy of P. falciparum with parasite density between 1,000 and 100,000 asexual parasite count/μl of blood.
• Written informed consent, in accordance with local practice, provided by patient and/or parent/guardian/spouse.
• Ability to swallow oral medication.

Exclusion Criteria:

• Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000.
• Mixed Plasmodium infection.
• Severe vomiting or severe diarrhoea.
• Known history or evidence of clinically significant disorders.
• Presence of significant anaemia, as defined by Hb <8 g/dL.
• Presence of febrile conditions caused by diseases other than malaria.
• Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, lumefantrine or artesunate or other artemisinins.
• Patients with known disturbances of electrolytes balance, e.g., hypokalaemia or hypomagnesaemia.
• Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by a positive urine test.
• Female patients of child-bearing potential must be neither pregnant (as demonstrated by a negative pregnancy test) nor lactating, and must be willing to take measures to not become pregnant during the study period.
• Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (flecainide, metoprol, imipramine, amitriptyline, clomipramine).
• Received an investigational drug within the past 4 weeks.
• Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen. (HBsAg) or Hepatitis C antibody (HCV Ab).
• Known seropositive HIV antibody.
• Liver function tests [ASAT/ALAT levels] >2.5 times the upper limit of normal range.
• Known significant renal impairment as indicated by serum creatinine >1.4 mg/dL.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PA group; Pyronaridine artesunate (PA)	Drug: Pyronaridine artesunate; Oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Day 0, 1, and 2); Other Names: Pyramax
Active Comparator: AL group; Arthemether lumefantrine (AL)	Drug: Coartem® (artemether lumefantrine); AL (20:120mg tablets) twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2); Other Names: Coartem

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on 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 Adequate Clinical and Parasitological Response (ACPR) on 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
Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28	Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 28, without correction by PCR, 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 14 and 28
Parasite Clearance Time	Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart.	Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned)
Fever Clearance Time	Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart	Day 0 and every 8 hours over ≥72 hours following first study drug administration or temperature normalization for ≥2 readings between 7 and 25 hours apart, then at each visit and as clinically indicated
Percentage of Patients With Fever Clearance at Day 1, 2 and 3	Fever clearance time is defined as the time from first dosing to first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.	Days 1, 2, 3
Proportion of Patients With Parasite Clearance at Day 1, 2 and 3	Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart.	Days 1, 2, 3
Adverse Events and Clinically Significant Laboratory Results	Incidence of adverse events and of clinically significant laboratory results, ECG, vital signs or physical examination abnormalities.	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 Pharmaceuticals
• Investigators: Study Director: Claude Oeuvray, PhD, Medicines for Malaria Venture

Publications and helpful links

General Publications

• Tshefu AK, Gaye O, Kayentao K, Thompson R, Bhatt KM, Sesay SS, Bustos DG, Tjitra E, Bedu-Addo G, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L; Pyronaridine-artesunate Study Team. Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. Lancet. 2010 Apr 24;375(9724):1457-67. doi: 10.1016/S0140-6736(10)60322-4.
• Pryce J, Taylor M, Fox T, Hine P. Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2022 Jun 21;6:CD006404. doi: 10.1002/14651858.CD006404.pub4. Review.
• Ayyoub A, Methaneethorn J, Ramharter M, Djimde AA, Tekete M, Duparc S, Borghini-Fuhrer I, Shin JS, Fleckenstein L. Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients. Antimicrob Agents Chemother. 2015 Dec 14;60(3):1450-8. doi: 10.1128/AAC.02004-15.
• 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.

Helpful Links

• Medicines for Malaria Venture

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): April 1, 2008
• Study Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: January 12, 2007
• First Submitted That Met QC Criteria: January 12, 2007
• First Posted (Estimate): January 15, 2007

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; P. falciparum; 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; Lumefantrine; Artemether; Artesunate; Artemether, Lumefantrine Drug Combination; Pyronaridine
• Other Study ID Numbers: SP-C-005-06