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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: pyronaridine/artesunate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients between the age of 15 and 60 years of age inclusive 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 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) Weight of between 35 kg and 75 kg inclusive 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 Ability to swallow oral medication 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. Females must not be pregnant or lactating and be willing to take measures to not become pregnant during the study period Willingness and ability to comply with the study protocol for the duration of the study 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, defined as >3 times in the 24 hours prior to inclusion in the trial or inability to tolerate oral treatment 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). Presence of febrile conditions caused by diseases other than malaria Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins 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 Positive urine pregnancy test or lactating 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 upper limit of normal values Known significant renal impairment as indicated by a serum creatinine of ≥ 1.4 mg/dl Previous participation in this clinical trial

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pyronaridine/artesunate (6:2 mg/kg)<br>pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg | Drug: pyronaridine/artesunate<br>* Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.<br>* Other names: Pyramax;|
| Experimental: pyronaridine/artesunate (9:3 mg/kg)<br>pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg | Drug: pyronaridine/artesunate<br>* Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.<br>* Other names: Pyramax;|
| Experimental: pyronaridine/artesunate (12:4 mg/kg)<br>pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg | Drug: pyronaridine/artesunate<br>* Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.<br>* Other names: Pyramax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR-Corrected ACPR at 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 | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR-Corrected ACPR at 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 | Day 14 | 
| Parasite Clearance Time | Parasite clearance time was defined as the time (in hours) from first dosing to the 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 | Thick blood slides were examined every 8 hours until at least 72 hours or until a negative smear was recorded | 
| Fever Clearance Time | Fever clearance time was defined as the time (in hours) from first dosing to the first normal reading with fever clearance (2 consecutive assessments without fever (<37.5°C)). The method of temperature measurement was the same (ie, axillary, tympanic, oral or rectal) for each subject. Any subjects with a documented history of fever at inclusion, but who did not subsequently have a documented temperature reading >37.5°C during the 24 hours after initial dosing, were not included in this end point analysis. | Every 8 hours for at least 72 hours after the first dose | 
| Parasite Clearance | Parasite clearance is defined as zero presence of parasites for 2 consecutive negative readings 8 hours apart, with confirmed negative reading at 24 hours after the first negative slide. The proportion of subjects with parasite clearance was summarized at Days 1, 2, and 3. | Days 1, 2, and 3 | 
| Fever Clearance | Fever clearance was defined as a subject without fever for 2 consecutive assessments, plus confirmed normal temperature at 24 hours. The proportion of subjects with fever clearance was summarized at Days 1, 2, and 3. | Days 1, 2 and 3 | 
| Adverse Events (AEs) | An AE was defined as any unfavourable and unintended sign, symptom, syndrome, or illness that developed or worsened during the period of observation in the clinical study | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, antimalarial, artemisinin based combination therapy (ACT), pyronaridine artesunate (Pyramax)