search
Back to results

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

Primary Purpose

Malaria

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Pyronaridine artesunate
Coartem® (artemether lumefantrine)
Sponsored by
Medicines for Malaria Venture
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria focused on measuring malaria, antimalarial, artemisinin based combination therapy (ACT), P. falciparum, pyronaridine artesunate (Pyramax)

Eligibility Criteria

3 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa
  • Farafenni Field Station, c/o: MRC Laboratories
  • Komfo Anoykye Teaching Hospital
  • RSUD TC Hillers
  • Jayapura General Hospital (RSUD) DOK II
  • Siaya District Hospital, Medical Superintendent's office
  • Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie
  • Instituto Nacional de Saude, Ministero de Saude
  • Puerto Princesa General Hospital
  • Service de Parasitologie, Faculté de Médecine, Université Cheikh Anta Diop

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

PA group

AL group

Arm Description

Pyronaridine artesunate (PA)

Arthemether lumefantrine (AL)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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
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.
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.
Adverse Events and Clinically Significant Laboratory Results
Incidence of adverse events and of clinically significant laboratory results, ECG, vital signs or physical examination abnormalities.

Full Information

First Posted
January 12, 2007
Last Updated
October 22, 2021
Sponsor
Medicines for Malaria Venture
Collaborators
Shin Poong Pharmaceuticals
search

1. Study Identification

Unique Protocol Identification Number
NCT00422084
Brief Title
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

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
January 2007 (undefined)
Primary Completion Date
April 2008 (Actual)
Study Completion Date
May 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Medicines for Malaria Venture
Collaborators
Shin Poong Pharmaceuticals

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria
Keywords
malaria, antimalarial, artemisinin based combination therapy (ACT), P. falciparum, pyronaridine artesunate (Pyramax)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1272 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PA group
Arm Type
Experimental
Arm Description
Pyronaridine artesunate (PA)
Arm Title
AL group
Arm Type
Active Comparator
Arm Description
Arthemether lumefantrine (AL)
Intervention Type
Drug
Intervention Name(s)
Pyronaridine artesunate
Other Intervention Name(s)
Pyramax
Intervention Description
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
Intervention Name(s)
Coartem® (artemether lumefantrine)
Other Intervention Name(s)
Coartem
Intervention Description
AL (20:120mg tablets) twice a day plus PA-placebo (once a day) for 3 consecutive days (Day 0, 1, and 2)
Primary Outcome Measure Information:
Title
PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on Day 28
Description
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.
Time Frame
Day 28
Secondary Outcome Measure Information:
Title
PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 14
Description
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.
Time Frame
Day 14
Title
Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28
Description
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.
Time Frame
Day 14 and 28
Title
Parasite Clearance Time
Description
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.
Time Frame
Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned)
Title
Fever Clearance Time
Description
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
Time Frame
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
Title
Percentage of Patients With Fever Clearance at Day 1, 2 and 3
Description
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.
Time Frame
Days 1, 2, 3
Title
Proportion of Patients With Parasite Clearance at Day 1, 2 and 3
Description
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.
Time Frame
Days 1, 2, 3
Title
Adverse Events and Clinically Significant Laboratory Results
Description
Incidence of adverse events and of clinically significant laboratory results, ECG, vital signs or physical examination abnormalities.
Time Frame
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
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: 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, 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Claude Oeuvray, PhD
Organizational Affiliation
Medicines for Malaria Venture
Official's Role
Study Director
Facility Information:
Facility Name
Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa
City
Kinshasa
Country
Congo, The Democratic Republic of the
Facility Name
Farafenni Field Station, c/o: MRC Laboratories
City
Fajara
Country
Gambia
Facility Name
Komfo Anoykye Teaching Hospital
City
Kumasi
Country
Ghana
Facility Name
RSUD TC Hillers
City
Maumere
State/Province
Nusa Tenggara Timur
ZIP/Postal Code
86113
Country
Indonesia
Facility Name
Jayapura General Hospital (RSUD) DOK II
City
Jayapura
State/Province
Papua
Country
Indonesia
Facility Name
Siaya District Hospital, Medical Superintendent's office
City
Siaya
Country
Kenya
Facility Name
Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie
City
Bamako
Country
Mali
Facility Name
Instituto Nacional de Saude, Ministero de Saude
City
Maputo
Country
Mozambique
Facility Name
Puerto Princesa General Hospital
City
Puerto Princesa
Country
Philippines
Facility Name
Service de Parasitologie, Faculté de Médecine, Université Cheikh Anta Diop
City
Dakar
State/Province
Dakar Fann
Country
Senegal

12. IPD Sharing Statement

Citations:
PubMed Identifier
20417857
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.
Results Reference
result
PubMed Identifier
35726133
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.
Results Reference
derived
PubMed Identifier
26666916
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.
Results Reference
derived
PubMed Identifier
23433102
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.
Results Reference
derived
Links:
URL
http://www.mmv.org
Description
Medicines for Malaria Venture

Learn more about this trial

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

We'll reach out to this number within 24 hrs