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

NCT ID: NCT00422084

Last Updated: 2021-11-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1272 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2008-05-31

Brief Summary

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.

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.

Conditions

Malaria

Keywords

malaria; antimalarial; artemisinin based combination therapy (ACT); P. falciparum; pyronaridine artesunate (Pyramax)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

PA group

Pyronaridine artesunate (PA)

Group Type: EXPERIMENTAL

Pyronaridine artesunate

Intervention Type: DRUG

Oral PA (180:60mg tablets) once a day plus AL-placebo (twice a day) for 3 consecutive days (Day 0, 1, and 2)

AL group

Arthemether lumefantrine (AL)

Group Type: ACTIVE_COMPARATOR

Coartem® (artemether lumefantrine)

Intervention Type: DRUG

AL (20:120mg tablets) twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2)

Interventions

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)

Intervention Type: 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)

Intervention Type: DRUG

Other Intervention Names

Pyramax; Coartem

Eligibility Criteria

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.

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shin Poong Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Medicines for Malaria Venture

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Claude Oeuvray, PhD

Role: STUDY_DIRECTOR

Medicines for Malaria Venture

Locations

Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa

Kinshasa, , Democratic Republic of the Congo

Komfo Anoykye Teaching Hospital

Kumasi, , Ghana

RSUD TC Hillers

Maumere, Nusa Tenggara Timur, Indonesia

Jayapura General Hospital (RSUD) DOK II

Jayapura, Special Region of Papua, Indonesia

Siaya District Hospital, Medical Superintendent's office

Siaya, , Kenya

Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie

Bamako, , Mali

Instituto Nacional de Saude, Ministero de Saude

Maputo, , Mozambique

Puerto Princesa General Hospital

Puerto Princesa City, , Philippines

Service de Parasitologie, Faculté de Médecine, Université Cheikh Anta Diop

Dakar, Dakar Fann, Senegal

Farafenni Field Station, c/o: MRC Laboratories

Fajara, , The Gambia

Countries

Republic of the Congo; Democratic Republic of the Congo; Ghana; Indonesia; Kenya; Mali; Mozambique; Philippines; Senegal; The Gambia

References

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.

Reference Type: RESULT

PMID: 20417857 (View on PubMed)

Pryce J, Taylor M, Fox T, Hine P. Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2022 Jun 21;6(6):CD006404. doi: 10.1002/14651858.CD006404.pub4.

Reference Type: DERIVED

PMID: 35726133 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26666916 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23433102 (View on PubMed)

Other Identifiers

SP-C-005-06

Identifier Type: -

Identifier Source: org_study_id