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Pyronaridine - Artesunate (3:1) Versus Mefloquine Plus Artesunate in Plasmodium Falciparum Malaria Patients

Primary Purpose

Falciparum Malaria

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Pyronaridine - artesunate
Mefloquine plus artesunate
Sponsored by
Medicines for Malaria Venture
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Falciparum Malaria focused on measuring malaria, antimalarial, P falciparum, pyronaridine, artesunate, artemisinin based combination therapy (ACT), 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 ages 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 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, mefloquine or artesunate or other artemisinins.
  • Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by 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.
  • Presence of significant renal or hepatic impairment.
  • Receipt of an investigational drug within the past 4 weeks.
  • Known active Hepatitis A IgM, Hepatitis B surface antigen or Hepatitis C antibody.
  • Known seropositive HIV antibody.
  • Previous participation in any clinical study with PA.

Sites / Locations

  • RAOTAP2/Centre Muraz
  • Pailin Referral Hospital
  • Institut Pasteur
  • Wentlock District Hospital
  • Bagamoyo Research and Training Centre of Ifakara Health Institute
  • MaeLamad District Hospital
  • MaeSod General Hospital
  • NIMPE
  • Choray Hospital, Dak O

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Pyronaridine - artesunate

Mefloquine plus artesunate

Arm Description

Oral pyronaridine artesunate (180:60mg tablets) once a day for 3 consecutive days (Day 0, 1, and 2). Posology based on body weight ranges.

Mefloquine (250mg tablets) plus artesunate (100mg tablets) once a day for 3 consecutive days (Day 0, 1, and 2). Posology based on body weight ranges.

Outcomes

Primary Outcome Measures

Percentage of Subjects With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) 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 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 on Days 14 and 28
Percentage of subjects with adequate clinical and parasitological response (ACPR) on Days 14 and 28, without correction by PCR, defined as absence of parasitaemia on Days 14 and 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 was defined as the time from first dosing to 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.
Fever Clearance Time
Fever clearance time was defined as the time from first dosing to first normal reading of temperature (<37.5°C taken axillary or tympanic; <38°C taken oral or rectal) for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.
Parasite Clearance at Day 1, 2 and 3
Parasite clearance time was 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.
Fever Clearance at Day 1, 2 and 3
Fever clearance time was defined as the time for at least 2 consecutive normal body temperature measurements (<37.5°C axillary/tympanic or <38.0°C oral/rectal) to be obtained within an interval of 7 to 25 hours post-dosing.
Adverse Events and Clinically Significant Laboratory Results
Cases and severity of adverse events and of clinically significant laboratory results, ECG, vital signs or physical examination abnormalities

Full Information

First Posted
November 22, 2006
Last Updated
October 22, 2021
Sponsor
Medicines for Malaria Venture
Collaborators
Shin Poong Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00403260
Brief Title
Pyronaridine - Artesunate (3:1) Versus Mefloquine Plus Artesunate in Plasmodium Falciparum Malaria Patients
Official Title
A Phase III Comparative, Open-label, Randomised, Multi-centre Study to Assess the Efficacy of Pyronaridine Artesunate (180:60mg) Versus Mefloquine (250mg) Plus Artesunate (100mg) in Children & Adult Patients With Acute Falciparum Malaria
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
January 2007 (Actual)
Primary Completion Date
October 2008 (Actual)
Study Completion Date
December 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 clinical study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (Pyramax®, PA) with that of the combination of mefloquine plus artesunate (MQ + AS) in children and adults with uncomplicated P falciparum malaria in South East Asia, India and Africa.
Detailed Description
This is a multi-centre, comparative, randomised, open-label, parallel-group, non-inferiority study comparing the efficacy and safety of a fixed combination of PA to a loose combination of MQ + AS for patients with acute, symptomatic, uncomplicated P. falciparum malaria. The study population will include 1271 patients, comprising male and female children (≥20 kg body weight) and adults, recruited from study sites in South East Asia, India and Africa. Patients will be randomised in a 2:1 ratio to receive either oral PA (180:60mg tablets) or MQ (250mg tablets) plus AS (100mg tablets) once a day for 3 consecutive days (Days 0, 1, and 2). The study drug will be administered by a Third-Party Investigator unblinded to the study treatment, while the Investigator remains blinded. Patients will be confined to the 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. The primary efficacy end point for the study is the proportion of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28 (defined as the absence of parasitaemia without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure). 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
Falciparum Malaria
Keywords
malaria, antimalarial, P falciparum, pyronaridine, artesunate, artemisinin based combination therapy (ACT), pyronaridine artesunate (Pyramax)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1271 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pyronaridine - artesunate
Arm Type
Experimental
Arm Description
Oral pyronaridine artesunate (180:60mg tablets) once a day for 3 consecutive days (Day 0, 1, and 2). Posology based on body weight ranges.
Arm Title
Mefloquine plus artesunate
Arm Type
Active Comparator
Arm Description
Mefloquine (250mg tablets) plus artesunate (100mg tablets) once a day for 3 consecutive days (Day 0, 1, and 2). Posology based on body weight ranges.
Intervention Type
Drug
Intervention Name(s)
Pyronaridine - artesunate
Other Intervention Name(s)
Pyramax
Intervention Description
once a day for 3 days
Intervention Type
Drug
Intervention Name(s)
Mefloquine plus artesunate
Intervention Description
once a day for 3 days
Primary Outcome Measure Information:
Title
Percentage of Subjects With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) 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 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 on Days 14 and 28
Description
Percentage of subjects with adequate clinical and parasitological response (ACPR) on Days 14 and 28, without correction by PCR, defined as absence of parasitaemia on Days 14 and 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure
Time Frame
Days 14 and 28
Title
Parasite Clearance Time
Description
Parasite clearance time was defined as the time from first dosing to 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
Thick blood films were examined every 8 hours until ≥72 hours or until 2 consecutive negative readings occurred 7 to 25 hours apart, and on Days 3, 7, 14, 21, 28, 35, and 42 (or any other day if the subject returned).
Title
Fever Clearance Time
Description
Fever clearance time was defined as the time from first dosing to first normal reading of temperature (<37.5°C taken axillary or tympanic; <38°C taken oral or rectal) for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.
Time Frame
Every 8 hours over ≥72 hours following first study drug administration or temperature normalisation for ≥2 readings between 7 and 25 hours apart, then at each visit.
Title
Parasite Clearance at Day 1, 2 and 3
Description
Parasite clearance time was 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 and 3
Title
Fever Clearance at Day 1, 2 and 3
Description
Fever clearance time was defined as the time for at least 2 consecutive normal body temperature measurements (<37.5°C axillary/tympanic or <38.0°C oral/rectal) to be obtained within an interval of 7 to 25 hours post-dosing.
Time Frame
Days 1, 2 and 3
Title
Adverse Events and Clinically Significant Laboratory Results
Description
Cases and severity 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 ages 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 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, mefloquine or artesunate or other artemisinins. Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by 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. Presence of significant renal or hepatic impairment. Receipt of an investigational drug within the past 4 weeks. Known active Hepatitis A IgM, Hepatitis B surface antigen or Hepatitis C antibody. Known seropositive HIV antibody. Previous participation in any clinical study with PA.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Isabelle Borghini-Fuhrer, PhD
Organizational Affiliation
Medicines for Malaria Venture
Official's Role
Study Director
Facility Information:
Facility Name
RAOTAP2/Centre Muraz
City
Bobo Dioulasso
State/Province
Houet Province
ZIP/Postal Code
01 BP390
Country
Burkina Faso
Facility Name
Pailin Referral Hospital
City
Pailin
State/Province
Pailin Province
Country
Cambodia
Facility Name
Institut Pasteur
City
Abidjan
Country
Côte D'Ivoire
Facility Name
Wentlock District Hospital
City
Mangalore
Country
India
Facility Name
Bagamoyo Research and Training Centre of Ifakara Health Institute
City
Bagamoyo
Country
Tanzania
Facility Name
MaeLamad District Hospital
City
Mae Ramat
State/Province
Tak Province
Country
Thailand
Facility Name
MaeSod General Hospital
City
Mae Sot
State/Province
Tak Province
Country
Thailand
Facility Name
NIMPE
City
Hanoi
State/Province
Commune Xy
Country
Vietnam
Facility Name
Choray Hospital, Dak O
City
Ho Chi Minh City
Country
Vietnam

12. IPD Sharing Statement

Citations:
PubMed Identifier
22475593
Citation
Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, Penali LK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L; Pyronaridine-Artesunate Study Team. Pyronaridine-artesunate versus mefloquine plus artesunate for malaria. N Engl J Med. 2012 Apr 5;366(14):1298-309. doi: 10.1056/NEJMoa1007125.
Results Reference
result
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 Mefloquine Plus Artesunate in Plasmodium Falciparum Malaria Patients

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