Clinical trial NCT00422084: Pyronaridine Artesunate (3:1) Versus Coartem® in P Falciparum Malaria Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: malaria
antimalarial
artemisinin based combination therapy (ACT)
P. falciparum
pyronaridine artesunate (Pyramax)
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
Collaborators: name: Shin Poong Pharmaceuticals
First posted: 2007-01-15
Enrollment: 1272
Sex: ALL
Minimum age (years): 3
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on Day 28
timeFrame: Day 28
Secondary outcomes:
measure: PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 14
timeFrame: Day 14
measure: Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28
timeFrame: Day 14 and 28
measure: Parasite Clearance Time
timeFrame: Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned)
measure: Fever Clearance Time
timeFrame: 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
measure: Percentage of Patients With Fever Clearance at Day 1, 2 and 3
timeFrame: Days 1, 2, 3
measure: Proportion of Patients With Parasite Clearance at Day 1, 2 and 3
timeFrame: Days 1, 2, 3
measure: Adverse Events and Clinically Significant Laboratory Results
timeFrame: 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
Other outcomes:
Locations:
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa
city: Fajara
country: Gambia
facility: Farafenni Field Station, c/o: MRC Laboratories
city: Kumasi
country: Ghana
facility: Komfo Anoykye Teaching Hospital
city: Maumere
country: Indonesia
facility: RSUD TC Hillers
state: Nusa Tenggara Timur
city: Jayapura
country: Indonesia
facility: Jayapura General Hospital (RSUD) DOK II
state: Papua
city: Siaya
country: Kenya
facility: Siaya District Hospital, Medical Superintendent's office
city: Bamako
country: Mali
facility: Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie
city: Maputo
country: Mozambique
facility: Instituto Nacional de Saude, Ministero de Saude
city: Puerto Princesa
country: Philippines
facility: Puerto Princesa General Hospital
city: Dakar
country: Senegal
facility: Service de Parasitologie, Faculté de Médecine, Université Cheikh Anta Diop
state: Dakar Fann
Study officials:
affiliation: Medicines for Malaria Venture
name: Claude Oeuvray, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.