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

NCT ID: NCT00541385

Last Updated: 2021-11-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 535 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-10-31
• Study Completion Date: 2008-11-30

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.

Detailed Description

This is a multi-centre, comparative, randomised, open-label, parallel-group study of the efficacy and safety of a 3-day regimen of a fixed combination of PA (3:1) versus AL in the treatment of acute uncomplicated Plasmodium falciparum mono-infection. The study population will include 534 patients, comprising male and female infants and children (body weight ≥5 and <25 kg) recruited from study sites in East, Central, and West Africa and South East Asia (max. 150 patients/site).

Patients will be randomised in a 2:1 ratio to receive either oral PA (60:20 mg granules) once a day for 3 consecutive days (Days 0, 1, and 2) or AL (20:120 mg crushed tablets) twice 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 will remain blinded. For PA, the dose range covered by this regimen is 7.0:2.3 mg to 13.3:4.4 mg, 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 ≥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 earlier.

The primary efficacy end point for this study is the proportion of subjects with PCR-corrected 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.

Conditions

Malaria

Keywords

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

PA group

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.

Group Type: EXPERIMENTAL

pyronaridine artesunate

Intervention Type: 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.

AL group

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.

Group Type: ACTIVE_COMPARATOR

arthemeter lumefantrine

Intervention Type: 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.

Interventions

pyronaridine artesunate

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.

Intervention Type: DRUG

arthemeter lumefantrine

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.

Intervention Type: DRUG

Other Intervention Names

Pyramax; Coartem

Eligibility Criteria

Inclusion Criteria

1. Male or female patients ≤12 years of age.

2. 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).

3. Presence of acute uncomplicated P. falciparum mono-infection confirmed by:

1. 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,

2. Positive microscopy of P. falciparum with parasite density between 1,000 and 200,000 asexual parasite count/µl of blood.

4. 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.

5. Ability to swallow whole volume of liquid in which medication is suspended.

6. 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.

7. 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.

Exclusion Criteria

1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000 [Attachment 3].

2. Mixed Plasmodium infection.

3. Severe vomiting, defined as >3 times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or severe diarrhoea defined as ≥3 watery stools per day.

4. 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).

5. Presence of significant anaemia, as defined by Hb <8 g/dL.

6. Presence of febrile conditions caused by diseases other than malaria.

7. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, lumefantrine or artesunate or other artemisinins.

8. Patients with known disturbances of electrolytes balance, e.g. hypokalaemia or hypomagnesaemia.

9. Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by reported patient history.

10. Pregnant or breastfeeding.

11. Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (flecainide, metoprol, imipramine, amitriptyline, clomipramine).

12. Received an investigational drug within the past 4 weeks.

13. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab).

14. Known positive for HIV antibody.

15. Liver function tests [ASAT/ALAT levels] >2.5 times upper limit of normal range.

16. Known significant renal impairment as indicated by serum creatinine of >1.4 mg/dL.

17. Previous participation in any clinical study with pyronaridine artesunate.

• Maximum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shin Poong Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Medicines for Malaria Venture

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Claude Oeuvray, PhD

Role: STUDY_DIRECTOR

Medicines for Malaria Venture

Locations

Centre National de Recherche et de Formation sur le Paludisme

Ouagadougou, , Burkina Faso

Unité de Paludologie de l'Institut Pasteur d'Abidjan

Abidjan, , Côte d’Ivoire

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

Kinshasa, , Democratic Republic of the Congo

Medical Research Unit, Albert Schweitzer Hospital

Lambaréné, , Gabon

Siaya District Hospital, Medical Superintendent's office

Siaya, , Kenya

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

Bamako, , Mali

Instituto Nacional de Saude, Ministero de Saude

Maputo, , Mozambique

Puerto Princesa General Hospital

Puerto Princesa City, , Philippines

Countries

Republic of the Congo; Burkina Faso; Côte d’Ivoire; Democratic Republic of the Congo; Gabon; Kenya; Mali; Mozambique; Philippines

References

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.

Reference Type: RESULT

PMID: 23113947 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38418982 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26666916 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23433102 (View on PubMed)

Other Identifiers

SP-C-007-07

Identifier Type: -

Identifier Source: org_study_id