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

Malaria Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00422084
• Other study ID #: SP-C-005-06
• Status: Completed
• Phase: Phase 3
• Start date: January 2007
• Est. completion date: May 2008

Study information

• Verified date: October 2021
• Source: Medicines for Malaria Venture
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1272
• Est. completion date: May 2008
• Est. primary completion date: April 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum

Intervention

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)
• 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)

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Medicines for Malaria Venture	Shin Poong Pharmaceuticals

Countries where clinical trial is conducted

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

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Medicines for Malaria Venture