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

Primary Purpose

Plasmodium Falciparum Malaria

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

pyronaridine/artesunate

About this trial

This is an interventional treatment trial for Plasmodium Falciparum Malaria focused on measuring malaria, antimalarial, artemisinin based combination therapy (ACT), pyronaridine artesunate (Pyramax)

Eligibility Criteria

15 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Pailin General Hospital
Farafenni Field Station, c/o MRC Laboratories
Bethesday Hospital
Centre de santé du roi Baudoin
Faculty of Tropical Medicine, Mahidol University
MSF Epicentre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

pyronaridine/artesunate (6:2 mg/kg)

pyronaridine/artesunate (9:3 mg/kg)

pyronaridine/artesunate (12:4 mg/kg)

Arm Description

pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg

pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg

pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

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.

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.

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.

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

Full Information

NCT ID

NCT01594931

First Posted

May 7, 2012

Last Updated

October 22, 2021

Sponsor

Medicines for Malaria Venture

Collaborators

Shin Poong Pharmaceutical Co. Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT01594931

Brief Title

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

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Completed

Study Start Date

July 2005 (undefined)

Primary Completion Date

March 2006 (Actual)

Study Completion Date

April 2006 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Medicines for Malaria Venture

Collaborators

Shin Poong Pharmaceutical Co. Ltd.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Plasmodium Falciparum Malaria

Keywords

malaria, antimalarial, artemisinin based combination therapy (ACT), pyronaridine artesunate (Pyramax)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

477 (Actual)

8. Arms, Groups, and Interventions

Arm Title

pyronaridine/artesunate (6:2 mg/kg)

Arm Type

Experimental

Arm Description

pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg

Arm Title

pyronaridine/artesunate (9:3 mg/kg)

Arm Type

Experimental

Arm Description

pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg

Arm Title

pyronaridine/artesunate (12:4 mg/kg)

Arm Type

Experimental

Arm Description

pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg

Intervention Type

Drug

Intervention Name(s)

pyronaridine/artesunate

Other Intervention Name(s)

Pyramax

Intervention Description

Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.

Primary Outcome Measure Information:

Title

PCR-Corrected ACPR at Day 28

Description

Time Frame

Day 28

Secondary Outcome Measure Information:

Title

PCR-Corrected ACPR at Day 14

Description

Time Frame

Day 14

Title

Parasite Clearance Time

Description

Time Frame

Thick blood slides were examined every 8 hours until at least 72 hours or until a negative smear was recorded

Title

Fever Clearance Time

Description

Time Frame

Every 8 hours for at least 72 hours after the first dose

Title

Parasite Clearance

Description

Time Frame

Days 1, 2, and 3

Title

Fever Clearance

Description

Time Frame

Days 1, 2 and 3

Title

Adverse Events (AEs)

Description

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

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

15 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials: