Pyronaridine Artesunate 3:1 Granule Formulation vs. Coartem© Crushed Tablets in P. Falciparum Malaria Pediatric Patients

NCT00541385 | Completed Phase 3 Results DMC

• 1 other identifier: SP-C-007-07
• Study Type: interventional
• Target: 535
• Locations: 8 countries
• Sites: 8

Brief Summary

The primary objective of this Phase III clinical study is to demonstrate the efficacy of the fixed combination of pyronaridine artesunate (PA) granule formulation (60:20 mg; pediatric PYRAMAX®) by showing a PCR-corrected adequate clinical and parasitological cure rate (ACPR) of more than 90%. Secondary objectives of this clinical study are to compare the efficacy (non-inferiority) and safety of the PA granule formulation compared to Coartem® (ie, the combination of artemether/lumefantrine \[AL\]) crushed tablets in a paediatric population and to assess the safety of the PA granule formulation.

Conditions

Malaria

Keywords

Falciparum malaria; pediatric; Coartem; artesunate; lumefantrine; pyronaridine; Pyramax

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With PCR-Corrected ACPR on Day 28

  Percentage of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. The PCR-corrected ACPR on Day 28 is defined as the absence of parasitaemia on Day 28 without the patient's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

  Day 28

Secondary Outcomes (7)

• Percentage of Participants With PCR-Corrected ACPR on Day 14

  Day 14

• Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28

  Days 14 and 28

• Parasite Clearance Time

  Days 0, 3, 7, 14, 21, 28, 35, and 42 or on any other day if the subject spontaneously returned within the 42-day study period

• Fever Clearance Time

  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 (within the 42-day study period)

• Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3

  Days 1, 2, and 3

Study Arms (2)

PA group

EXPERIMENTAL

Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.

Drug: pyronaridine artesunate

AL group

ACTIVE COMPARATOR

Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.

Drug: arthemeter lumefantrine

Interventions

pyronaridine artesunate DRUG

The strength of the granule formulation is 60:20 mg pyronaridine artesunate per sachet. Depending on their body weight, patients will receive between 1 to 3 pyronaridine artesunate sachets per day, for 3 consecutive days The actual dose-range covered by this regimen is 7.0:2.3 mg/kg to 13.3:4.4 mg/kg pyronaridine artesunate, which has shown to be effective and safe in the phase II studies conducted in children and adults.

Also known as: Pyramax

PA group

arthemeter lumefantrine DRUG

The strength of the tablet is 20 mg artemether and 120 mg lumefantrine. Depending on their body weight, patients will receive either 1 or 2 crushed tablets twice a day (≥5 to \<15 = 1 tablet, 15 to \<25 kg = 2 tablets), for 3 consecutive days.

Also known as: Coartem

AL group

Eligibility Criteria

• Age: Up to 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female patients ≤12 years of age.
• Body weight ≥ 5 kg and \< 25 kg with no clinical evidence of severe malnutrition (defined as a child whose weight-for-height is below -3 standard deviations or \<70% of the median of the NCHS/WHO normalised reference values).
• Presence of acute uncomplicated P. falciparum mono-infection confirmed by:
• Fever, as defined by axillary temperature ≥37.5°C or oral/tympanic/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 200,000 asexual parasite count/µl of blood.
• Written informed consent, in accordance with local practice, provided by parent/guardian. If the parent/guardian is unable to write, witnessed consent is permitted according to local ethical considerations. Where possible, patient assent will be sought.
• Ability to swallow whole volume of liquid in which medication is suspended.
• 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.
• Ability and willingness to participate based on information given to parent or guardian and access to health facility. The patient is to comply with all scheduled follow up visits until D42.

You may not qualify if:

• Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000 \[Attachment 3\].
• Mixed Plasmodium infection.
• Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTc interval ≥450 milliseconds), respiratory (including active tuberculosis), history of jaundice, hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including recent head trauma).
• 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 reported patient history.
• Pregnant or breastfeeding.
• 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 positive for HIV antibody.
• Liver function tests \[ASAT/ALAT levels\] \>2.5 times upper limit of normal range.
• Known significant renal impairment as indicated by serum creatinine of \>1.4 mg/dL.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• Shin Poong Pharmaceuticals: collaborator

Study Sites (8)

Centre National de Recherche et de Formation sur le Paludisme

Ouagadougou, Burkina Faso

Location

Unité de Paludologie de l'Institut Pasteur d'Abidjan

Abidjan, Côte d’Ivoire

Location

Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa

Kinshasa, Democratic Republic of the Congo

Location

Medical Research Unit, Albert Schweitzer Hospital

Lambaréné, Gabon

Location

Siaya District Hospital, Medical Superintendent's office

Siaya, Kenya

Location

Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie

Bamako, Mali

Location

Instituto Nacional de Saude, Ministero de Saude

Maputo, Mozambique

Location

Puerto Princesa General Hospital

Puerto Princesa City, Philippines

Location

Related Publications (4)

• Kayentao K, Doumbo OK, Penali LK, Offianan AT, Bhatt KM, Kimani J, Tshefu AK, Kokolomami JH, Ramharter M, de Salazar PM, Tiono AB, Ouedraogo A, Bustos MD, Quicho F, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L. Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial. Malar J. 2012 Oct 31;11:364. doi: 10.1186/1475-2875-11-364.

  PMID: 23113947 RESULT

• Ramharter M, Djimde AA, Borghini-Fuhrer I, Miller R, Shin J, Aspinall A, Richardson N, Wibberg M, Fleckenstein L, Arbe-Barnes S, Duparc S. Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study. Malar J. 2024 Feb 28;23(1):61. doi: 10.1186/s12936-024-04885-3.

  PMID: 38418982 DERIVED

• 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.

  PMID: 26666916 DERIVED

• 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.

  PMID: 23433102 DERIVED

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Interventions

pyronaridine tetraphosphate, artesunate drug combination; Artemether, Lumefantrine Drug Combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Stephan Duparc, MD, Chief Medical Officer
• Organization: Medicines for Malaria Venture (MMV)

duparcs@mmv.org

+41 22 555 0300

Study Officials

• Claude Oeuvray, PhD

  Medicines for Malaria Venture

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2007
• First Posted: October 10, 2007
• Study Start: October 1, 2007
• Primary Completion: September 1, 2008
• Study Completion: November 1, 2008
• Last Updated: November 22, 2021
• Results First Posted: November 22, 2021

Record last verified: 2021-10

Locations

MA (1); PH (1); MO (1); DE (1); BU (1); CÔ (1); KE (1); GA (1)