Phase II Dose-ranging Study of Pyronaridine/Artesunate in Adults Patients With Plasmodium Falciparum Malaria

• ClinicalTrials.gov Identifier: NCT01594931
• Recruitment Status: Completed
• First Posted: May 9, 2012
• Last Update Posted: April 1, 2020
• Sponsor: Medicines for Malaria Venture
• Collaborator: Shin Poong Pharmaceutical Co. Ltd.
• Information provided by (Responsible Party): Medicines for Malaria Venture

Study Description

Brief Summary:

This is a double-blind, multicentre, randomised, parallel group, dose-finding study of the safety, tolerability and efficacy of a three day regimen of the combination of pyronaridine/artesunate in the ratio 3:1. The primary trial objective is to determine the clinical effective dose of orally administered pyronaridine/artesunate (3:1 weight/weight) ratio, in the treatment of patients with acute, symptomatic, uncomplicated P. falciparum malaria using the PCR-corrected adequate clinical and parasitological response (ACPR) at Day 28 as primary endpoint. Secondary trial objectives are to determine the safety of once daily dosing for 3 days of pyronaridine/artesunate (3:1) combination in male and female patients with uncomplicated P. falciparum malaria and to explore possible ethnic differences in safety or efficacy in South East Asia and Africa

Condition or disease	Intervention/treatment	Phase
Plasmodium Falciparum Malaria	Drug: pyronaridine/artesunate	Phase 2

Detailed Description:

The study is designed as a double-blind, multicentre, randomised, parallel group,dose-finding study of the efficacy, safety and tolerability of a three day regimen of the combination of pyronaridine/artesunate in the ratio 3:1. Pharmacokinetics of pyronaridine will be estimated in a separate sub-study. Patients will be recruited from between 5 to 7 study sites and will be randomised to one of 3 treatment groups:

Group A: pyronaridine+artesunate PA (PP 6 mg/kg + AS 2 mg/kg) Group B: pyronaridine+artesunate PA (PP 9 mg/kg + AS 3 mg/kg) Group C: pyronaridine+artesunate PA (PP 12 mg/kg + AS 4 mg/kg) Randomisation is planned to be balanced within each study site across all 3 study groups in pre-assigned treatment blocks. Patients who withdraw early for any reason will not be replaced.

Patients will ideally be hospitalised for at least 4 days and will be required to remain in the vicinity of the trial site for a minimum of 7 days from start of treatment, or when fever and parasite has been cleared: 2 negative readings (fever and/or slide) taken 8 hours apart plus another negative (fever and/or slide) 24 hours later. The patient is to return to the study site, or to make themselves available, for all scheduled weekly follow up visits until discharge at Day 42.

Patients will remain in the study for 42 days following first dosing (D0). In the case of adverse events reported and unresolved at visit Day 42, patients will be followed up for a further 30 days, or until resolution of event.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 477 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomised, Multi-Centre, Phase II, Dose-ranging Clinical Study to Assess the Safety and Efficacy of Fixed Dose, Orally Administered Pyronaridine and Artesunate (3:1) in Adult Patients With Acute Uncomplicated Plasmodium Falciparum Malaria
• Study Start Date: July 2005
• Actual Primary Completion Date: March 2006
• Actual Study Completion Date: April 2006

Arms and Interventions

Arm	Intervention/treatment
Experimental: pyronaridine/artesunate (6:2 mg/kg); pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1; Other Name: Pyramax
Experimental: pyronaridine/artesunate (9:3 mg/kg); pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1; Other Name: Pyramax
Experimental: pyronaridine/artesunate (12:4 mg/kg); pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg	Drug: pyronaridine/artesunate; Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1; Other Name: Pyramax

Outcome Measures

Primary Outcome Measures :

1. Cure rate on Day 28 [ Time Frame: 28 days ]
   The primary efficacy endpoint will be the cure rate on Day 28 defined as the proportion of patients with PCR-corrected Adequate Clinical and Parasitological Response (ACPR). PCR-corrected ACPR is defined as patients with clearance of asexual parasitaemia within 7 days of initiation of study treatment and without recrudescence within 28 days of initiation of study treatment.
2. Safety [ Time Frame: 42 days ]
   Incidence of adverse events (including clinically significant laboratory results, ECG, vital signs, of physical examination abnormalities)

Secondary Outcome Measures :

1. Cure rate on Day 14 [ Time Frame: 14 days ]
   Cure rate on Day 14 is defined as the proportion of patients with ACPR on Day 14. The PCR-corrected ACPR is defined as patients with clearance of asexual parasitaemia within 7 days of initiation of study treatment and without recrudescence within 14 days of initiation of study treatment.
2. Parasite Clearance Time [ Time Frame: 3 days ]
   The time from first dosing to time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of parasites for two consecutive negative readings eight hours apart, with confirmed negative reading at 24 hours after the first negative slide
3. Fever Clearance Time [ Time Frame: 3 days ]
   The time to fever clearance is defined as the time from first dosing to first normal reading of temperature (<37.5 °C) for two consecutive normal temperature reading plus confirmed normal temperature at 24 hours.
4. Parasite clearance [ Time Frame: 3 days ]
   The proportion of patients with parasite clearance will be described at Days 1, 2 and 3.
5. Fever clearance [ Time Frame: 3 days ]
   The proportion of patients with fever clearance will be described at Days 1, 2 and 3.

Eligibility Criteria

• Ages Eligible for Study: 15 Years to 60 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female patients between the age of 15 and 60 years of age inclusive
2. Written informed consent, in accordance with local practice, provided by patient and/or parent/guardian/spouse. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations
3. Absence of severe malnutrition (defined as the weight-for-height being below -3 standard deviation or less than 70% of median of the NCHS/WHO normalised reference values)
4. Weight of between 35 kg and 75 kg inclusive

5. Presence of acute symptomatic uncomplicated P. falciparum malaria with a diagnosis confirmed by a positive blood smear with asexual forms of P. falciparum only (i.e. no mixed infection) plus history of fever within previous 24 hours or measured temperature of ≥ 37.5°C (depending on method of measurement):

   • the acceptable range is between 1,000 and 100,000 asexual parasite count/μl of blood and
   • axillary/tympanic of ≥ 37.5°C or oral/rectal temperature of ≥ 38.0°C
6. Ability to swallow oral medication
7. Ability to comply with study visit schedule: patients will be hospitalised for at least 4 days and will be required to remain in the vicinity of the trial site for a minimum of 7 days or when fever and parasite has been cleared for at least 24 hours, whichever is the later. The patient is to return to the study site or to make themselves available for all scheduled follow up visits, until discharge at Day 42.
8. Females must not be pregnant and non-lactating and be willing to take measures not to become pregnant during the study period
9. Willingness and ability to comply with study protocol for the duration of the study

Exclusion Criteria:

1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organisation Criteria 2000
2. Mixed Plasmodium infection
3. Severe vomiting, defined as more than three times in the 24 hours prior to inclusion in the trial or inability to tolerate oral treatment
4. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other clinically important abnormality (including head trauma).
5. Presence of febrile conditions caused by diseases other than malaria
6. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins
7. Evidence of use of any other antimalarial agent within 2 weeks prior to start of the study confirmed by negative urine test or using Eggelte dipsticks
8. Positive urine pregnancy test or lactating
9. Received an investigational drug within the past 4 weeks
10. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab)
11. Known seropositive HIV antibody
12. Liver function tests [ASAT/ALAT levels] more than 2.5 times upper limit of normal values
13. Known significant renal impairment as indicated by serum creatinine of ≥ 1.4 mg/dl
14. Previous participation in this clinical trial

Contacts and Locations

Locations

Cambodia

Pailin General Hospital

Pailin, Cambodia

Gambia

Farafenni Field Station, c/o MRC Laboratories

Farafenni, Gambia

Indonesia

Bethesday Hospital

Tomohon, North Sulawesi, Indonesia

Senegal

Centre de santé du roi Baudoin

Guediawaye, Senegal

Thailand

Faculty of Tropical Medicine, Mahidol University

Bangkok, Thailand

Uganda

MSF Epicentre

Mbarara, Uganda

Sponsors and Collaborators

Medicines for Malaria Venture

Shin Poong Pharmaceutical Co. Ltd.

Investigators

• Principal Investigator: Sornchai Looareesuwan, MD; Hospital of Tropical Diseases, Mahidol University, Bangkok, Thailand
• Principal Investigator: Duong Socheat, MD; Nat. Centre for Parasitol., Entomol. and Malaria Control, Phnom Penh, Cambodia
• Principal Investigator: Emiliana Tjitra, PhD; Bethesda Hospital, Tomohon, North Sulawasi, Indonesia
• Principal Investigator: Kalifa Bojang, MD; MRC Laboratories, Faraffeni, The Gambia
• Principal Investigator: Patrice Piola, MD; Epicentre, Mbarara, Uganda
• Principal Investigator: Oumar Gaye, MD; Centre de santé Roi Baudouin, Guediawaye, Senegal

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Medicines for Malaria Venture
• ClinicalTrials.gov Identifier: NCT01594931
• Other Study ID Numbers: SP-C-002-05
• First Posted: May 9, 2012
• Last Update Posted: April 1, 2020
• Last Verified: March 2020

Keywords provided by Medicines for Malaria Venture:

malaria; antimalarial; artemisinin based combination therapy

Additional relevant MeSH terms:

Malaria; Malaria, Falciparum; Protozoan Infections; Parasitic Diseases; Artesunate; Pyronaridine; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Antineoplastic Agents; Antiviral Agents; Schistosomicides; Antiplatyhelmintic Agents; Anthelmintics