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

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ClinicalTrials.gov Identifier: NCT00422084
Recruitment Status : Completed
First Posted : January 15, 2007
Results First Posted : September 20, 2021
Last Update Posted : November 2, 2021
Sponsor:
Collaborator:
Shin Poong Pharmaceuticals
Information provided by (Responsible Party):
Medicines for Malaria Venture

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.

Condition or disease Intervention/treatment Phase
Malaria Drug: Pyronaridine artesunate Drug: Coartem® (artemether lumefantrine) Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1272 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : January 2007
Actual Primary Completion Date : April 2008
Actual Study Completion Date : May 2008

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: PA group
Pyronaridine artesunate (PA)
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)
Other Name: Pyramax

Active Comparator: AL group
Arthemether lumefantrine (AL)
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)
Other Name: Coartem




Primary Outcome Measures :
  1. PCR-Corrected Adequate Clinical and Parasitological Response (ACPR) Rate on Day 28 [ Time Frame: 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 :
  1. PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 14 [ Time Frame: 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.

  2. Crude ACPR (Non-PCR Corrected ACPR) on Day 14 and Day 28 [ Time Frame: Day 14 and 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.

  3. Parasite Clearance Time [ Time Frame: Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned) ]
    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.

  4. Fever Clearance Time [ 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 ]
    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

  5. Percentage of Patients With Fever Clearance at Day 1, 2 and 3 [ Time Frame: Days 1, 2, 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.

  6. Proportion of Patients With Parasite Clearance at Day 1, 2 and 3 [ Time Frame: Days 1, 2, 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.

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



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Ages Eligible for Study:   3 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00422084


Locations
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Congo, The Democratic Republic of the
Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa
Kinshasa, Congo, The Democratic Republic of the
Gambia
Farafenni Field Station, c/o: MRC Laboratories
Fajara, Gambia
Ghana
Komfo Anoykye Teaching Hospital
Kumasi, Ghana
Indonesia
RSUD TC Hillers
Maumere, Nusa Tenggara Timur, Indonesia, 86113
Jayapura General Hospital (RSUD) DOK II
Jayapura, Papua, Indonesia
Kenya
Siaya District Hospital, Medical Superintendent's office
Siaya, Kenya
Mali
Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie
Bamako, Mali
Mozambique
Instituto Nacional de Saude, Ministero de Saude
Maputo, Mozambique
Philippines
Puerto Princesa General Hospital
Puerto Princesa, Philippines
Senegal
Service de Parasitologie, Faculté de Médecine, Université Cheikh Anta Diop
Dakar, Dakar Fann, Senegal
Sponsors and Collaborators
Medicines for Malaria Venture
Shin Poong Pharmaceuticals
Investigators
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Study Director: Claude Oeuvray, PhD Medicines for Malaria Venture
Additional Information:
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Medicines for Malaria Venture
ClinicalTrials.gov Identifier: NCT00422084    
Other Study ID Numbers: SP-C-005-06
First Posted: January 15, 2007    Key Record Dates
Results First Posted: September 20, 2021
Last Update Posted: November 2, 2021
Last Verified: October 2021
Keywords provided by Medicines for Malaria Venture:
malaria
antimalarial
artemisinin based combination therapy (ACT)
P. falciparum
pyronaridine artesunate (Pyramax)
Additional relevant MeSH terms:
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Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Infections
Vector Borne Diseases
Artesunate
Lumefantrine
Artemether
Artemether, Lumefantrine Drug Combination
Pyronaridine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics