Clinical trial NCT01594931: Phase II Dose-ranging Study of Pyronaridine/Artesunate in Adults Patients With Plasmodium Falciparum Malaria
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Plasmodium Falciparum Malaria
Keywords: malaria
antimalarial
artemisinin based combination therapy (ACT)
pyronaridine artesunate (Pyramax)
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
Collaborators: name: Shin Poong Pharmaceutical Co. Ltd.
First posted: 2012-05-09
Enrollment: 477
Sex: ALL
Minimum age (years): 15
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary trial objective is to determine the clinically effective dose of orally administered pyronaridine/artesunate (Pyramax®, PA) with a 3:1 ratio to treat adults with acute, symptomatic, uncomplicated P. falciparum malaria in South East Asia and Africa. Secondary trial objectives are to determine the safety of once-daily dosing for 3 days of PA and to explore possible ethnic differences in safety or efficacy.

Detailed description: This is a double-blind, multicentre, randomized, parallel group, dose-finding study of the efficacy, safety and tolerability of a once-daily 3-day regimen of PA with a 3:1 weight/weight ratio for patients with acute, symptomatic, uncomplicated P. falciparum malaria. Patients will be recruited from 5 to 7 study sites in endemic regions of South East Asia and Africa and will be randomized to 1 of 3 treatment groups differing in dosage, with 160 patients per group (n-480). Randomization will be balanced within each study site across all 3 study groups in pre-assigned treatment blocks.

The first dose will be administered on Day 0 and patients will remain hospitalized for at least 4 days whilst undertaking the 3-day regimen. Patients will remain near the study site for a minimum of 7 days or once fever and parasite clearance is confirmed (assessed by 3 negative readings of fever and/or slide).

The primary efficacy end point is the cure rate on Day 28 - the proportion of patients with PCR-corrected adequate clinical and parasitological response (ACPR). Despite this Day 28 end point, the relatively long half-life of pyronaridine necessitates follow-up until 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.

Eligibility 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 deviations or \<70% of the median of the NCHS/WHO normalized 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 the previous 24 hours or a 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 temperature 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 until clearance of fever and parasite 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 or lactating and be willing to take measures to not become pregnant during the study period
9. Willingness and ability to comply with the 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 Organization Criteria 2000
2. Mixed Plasmodium infection
3. Severe vomiting, defined as \>3 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 the start of the study confirmed by a 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 \[ASAT/ALAT levels\] \>2.5 times upper limit of normal values
13. Known significant renal impairment as indicated by a serum creatinine of ≥ 1.4 mg/dl
14. Previous participation in this clinical trial

Primary outcomes:
measure: PCR-Corrected ACPR at Day 28
timeFrame: Day 28
Secondary outcomes:
measure: PCR-Corrected ACPR at Day 14
timeFrame: Day 14
measure: Parasite Clearance Time
timeFrame: Thick blood slides were examined every 8 hours until at least 72 hours or until a negative smear was recorded
measure: Fever Clearance Time
timeFrame: Every 8 hours for at least 72 hours after the first dose
measure: Parasite Clearance
timeFrame: Days 1, 2, and 3
measure: Fever Clearance
timeFrame: Days 1, 2 and 3
measure: Adverse Events (AEs)
timeFrame: 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
Other outcomes:
Locations:
city: Pailin
country: Cambodia
facility: Pailin General Hospital
city: Farafenni
country: Gambia
facility: Farafenni Field Station, c/o MRC Laboratories
city: Tomohon
country: Indonesia
facility: Bethesday Hospital
state: North Sulawesi
city: Guediawaye
country: Senegal
facility: Centre de santé du roi Baudoin
city: Bangkok
country: Thailand
facility: Faculty of Tropical Medicine, Mahidol University
city: Mbarara
country: Uganda
facility: MSF Epicentre
Study officials:
affiliation: Hospital of Tropical Diseases, Mahidol University, Bangkok, Thailand
name: Sornchai Looareesuwan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nat. Centre for Parasitol., Entomol. and Malaria Control, Phnom Penh, Cambodia
name: Duong Socheat, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bethesda Hospital, Tomohon, North Sulawasi, Indonesia
name: Emiliana Tjitra, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: MRC Laboratories, Faraffeni, The Gambia
name: Kalifa Bojang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Epicentre, Mbarara, Uganda
name: Patrice Piola, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre de santé Roi Baudouin, Guediawaye, Senegal
name: Oumar Gaye, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.