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Pyronaridine Artesunate (3:1) in Children and Adults With Acute Plasmodium Vivax Malaria

Primary Purpose

Malaria

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Pyronaridine artesunate

Chloroquine

About this trial

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

Eligibility Criteria

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

Inclusion Criteria:

Male or female patients between the age of 3 and 60 years, inclusive.
Body weight between 20 kg and 90 kg with no clinical evidence of severe malnutrition.
Presence of acute uncomplicated P. vivax mono-infection confirmed by:
- Fever, as defined by axillary/tympanic temperature ≥37.5°C or oral/rectal temperature ≥38°C, or history of fever in the previous 24 hours (history of fever must be documented) and,
- Positive microscopy of P. vivax with parasite density ≥250/ mcL of blood (including at least 50% of asexual parasites).
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.
Ability to swallow oral medication.
Ability and willingness to participate based on information given to patient or parent or guardian and access to health facility.

Exclusion Criteria:

Presence of a mixed Plasmodium infection.
Presence of other clinical condition requiring hospitalization.
Presence of significant anaemia, as defined by Hb <8 g/dL.
Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTc interval ≥450 msec), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other abnormality (including recent head trauma).
Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, chloroquine or artesunate or other artemisinins.
Known history of hypersensitivity, allergic or adverse reactions to chloroquine, primaquine and related agents.
Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab).
Known seropositive HIV antibody.
Have received any antimalarial treatment in the preceding 2 weeks, as determined by history and, whenever feasible, by screening test.
Have received antibacterial with known antimalarial activity in the preceding 2 weeks.
Have received any investigational drug within the past 4 weeks.
Liver function tests (AST/ALT levels) >2.5 times the upper limit of normal range.
Known significant renal impairment as indicated by serum creatinine levels of >1.4 mg/dL.
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.
Previous participation in the present clinical trial with PA.

Sites / Locations

Pailin Referral Hospital
Wentlock District Hospital
RSUD TC Hillers
MaeLamad District Hospital
MaeSod General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

pyronaridine artesunate

chloroquine

Arm Description

The tablet strength is 180:60 mg oral PA plus chloroquine-placebo. Depending on their body weight, patients receive 1 to 4 tablets once a day, for 3 days. The actual dose-level range covered by this regimen is 7.2: 2.4 mg/kg to 13.8:4.6 mg/kg pyronaridine artesunate.

The tablet strength is 155 mg oral chloroquine plus PA-placebo. Patients receive: For adults: 620 mg (i.e. 4 tablets) on Days 0 and 1 and 310 mg (i.e. 2 tablets) on Day 2. For children: 10 mg/kg on Days 0 and 1 and 5 mg/kg on Day 2.

Outcomes

Primary Outcome Measures

Crude Cure Rate on Day 14

Cure rate on Day 14 is defined as the absence of P. vivax parasitaemia on Day 14 irrespective of temperature (axillary, oral, tympanic, rectal) without previously meeting any of the criteria of treatment failure throughout the follow-up period.

Secondary Outcome Measures

Crude Cure Rate on Days 21 and 28.

Cure on Day 21 and 28 is defined as the absence of P. vivax parasitaemia on Day 21 and 28 irrespective of temperature (axillary, oral, tympanic, rectal) without previously meeting any of the criteria of treatment failure throughout the follow-up period.

Parasite Clearance Time

Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance is defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart.

Fever Clearance Time

Fever clearance time is defined as the time from first dosing to the first normal reading of temperature (<37.5°C for axillary/tympanic or <38°C for oral/rectal) for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.

Percentage of Subjects With Parasite Clearance on Days 1, 2, and 3

Percentage of subjects with parasite clearance on Day 1 (24 hours after first dose), Day 2 (48 hours after first dose), and Day 3 (72 hours after first dose).

Percentage of Subjects With Fever Clearance on Days 1, 2, and 3

Percentage of subjects with fever clearance on Day 1 (24 hours after first dose), Day 2 (48 hours after first dose), and Day 3 (72 hours after first dose).

Number of Participants With Adverse Events

Number of participants with adverse events, including clinically significant laboratory results, ECG, vital signs or physical examination abnormalities.

Full Information

NCT ID

NCT00440999

First Posted

February 26, 2007

Last Updated

October 22, 2021

Sponsor

Medicines for Malaria Venture

Collaborators

Shin Poong Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00440999

Brief Title

Pyronaridine Artesunate (3:1) in Children and Adults With Acute Plasmodium Vivax Malaria

Official Title

A Phase III Comparative (Double-blind, Double-dummy) Randomised Multicentre Study to Assess the Safety & Efficacy of Oral Pyronaridine Artesunate (180:60 mg) Versus Chloroquine (155 mg) in Children & Adult Patients With Acute Vivax Malaria

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Completed

Study Start Date

March 2007 (undefined)

Primary Completion Date

April 2008 (Actual)

Study Completion Date

September 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Medicines for Malaria Venture

Collaborators

Shin Poong Pharmaceuticals

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (Pyramax®, PA) (180:60 mg) with that of standard chloroquine therapy in children and adults with acute, uncomplicated Plasmodium vivax malaria.

Detailed Description

This is a multi-centre, randomised, double-blind, double-dummy, parallel-group, non-inferiority study comparing the efficacy and safety of the fixed combination of pyronaridine/artesunate (ie, PP/AS [PA]) (180:60 mg) with that of standard chloroquine therapy in children and adults with acute uncomplicated P. vivax malaria. The study population will include 456 patients, comprising male and female children (≥20 kg body weight) and adults recruited from study sites in South East Asia and India. Patients will be randomised in a 1:1 ratio to receive either oral PA (180:60 mg tablets) plus chloroquine-placebo or oral chloroquine (155 mg tablets).plus PA-placebo, once a day for 3 consecutive days (Days 0, 1, and 2). For PA, posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The dose range covered by this regimen is 7.2:2.4 mg/kg to 13.8:4.6 mg/kg, which has been shown to be effective and safe in Phase I and II studies. The chloroquine daily dose is 10 mg/kg on Days 0 and 1 and 5 mg/kg on Day 2 for children, and 620 mg on Days 0 and 1 and 310 mg on Day 2 for adults. Patients will be confined to the study facility for ≥4 days (Days 0,1,2 & 3) and ideally remain near the study site for ≥7 days, or once fever and parasite clearance has been confirmed for ≥24 hours - whichever occurs later. The primary efficacy end point for the study is the crude cure rate on Day 14, which is defined as the absence of P. vivax parasitaemia on Day 14. 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. For patients who complete the study up to Day 28 and who have normal glucose-6-phosphate dehydrogenase (G-6-PD) activity, a 14-day course of primaquine (15 mg/day for adults and 0.3 mg/kg/day for children) will be administered starting on Day 28 to complete their radical cure. Subjects who are deficient in G-6-PD and who completed the study up to Day 28 will be treated per country policy.

6. Conditions and Keywords

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

Malaria

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Care ProviderInvestigator

Allocation

Randomized

Enrollment

456 (Actual)

8. Arms, Groups, and Interventions

Arm Title

pyronaridine artesunate

Arm Type

Experimental

Arm Description

Arm Title

chloroquine

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pyronaridine artesunate

Other Intervention Name(s)

Pyramax

Intervention Type

Drug

Intervention Name(s)

Chloroquine

Primary Outcome Measure Information:

Title

Crude Cure Rate on Day 14

Description

Time Frame

Day 14

Secondary Outcome Measure Information:

Title

Crude Cure Rate on Days 21 and 28.

Description

Time Frame

Day 21 and 28

Title

Parasite Clearance Time

Description

Time Frame

Days 0 to 42

Title

Fever Clearance Time

Description

Time Frame

Days 0 to 42

Title

Percentage of Subjects With Parasite Clearance on Days 1, 2, and 3

Description

Percentage of subjects with parasite clearance on Day 1 (24 hours after first dose), Day 2 (48 hours after first dose), and Day 3 (72 hours after first dose).

Time Frame

Days 1, 2, and 3

Title

Percentage of Subjects With Fever Clearance on Days 1, 2, and 3

Description

Percentage of subjects with fever clearance on Day 1 (24 hours after first dose), Day 2 (48 hours after first dose), and Day 3 (72 hours after first dose).

Time Frame

Day 1, 2, and 3

Title

Number of Participants With Adverse Events

Description

Number of participants with adverse events, including clinically significant laboratory results, ECG, vital signs or physical examination abnormalities.

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

Other Pre-specified Outcome Measures:

Title

Percentage of Subjects With PCR-corrected Cure Rate on Days 14, 21, and 28

Description

Cure on Days 14, 21, and 28 is defined as the absence of P. vivax parasitaemia on Days 14, 21, and 28 irrespective of temperature (axillary, oral, tympanic, rectal) without previously meeting any of the criteria of treatment failure throughout the follow-up period.

Time Frame

Day 14, 21, and 28

Title

Percentage of Subjects With Crude and PCR-corrected Cure Rate on Day 42

Description

Cure on Day 42 is defined as the absence of P. vivax parasitaemia on Day 42 irrespective of temperature (axillary, oral, tympanic, rectal) without previously meeting any of the criteria of treatment failure throughout the follow-up period.

Time Frame

Day 42

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female patients between the age of 3 and 60 years, inclusive. Body weight between 20 kg and 90 kg with no clinical evidence of severe malnutrition. Presence of acute uncomplicated P. vivax mono-infection confirmed by: Fever, as defined by axillary/tympanic temperature ≥37.5°C or oral/rectal temperature ≥38°C, or history of fever in the previous 24 hours (history of fever must be documented) and, Positive microscopy of P. vivax with parasite density ≥250/ mcL of blood (including at least 50% of asexual parasites). 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. Ability to swallow oral medication. Ability and willingness to participate based on information given to patient or parent or guardian and access to health facility. Exclusion Criteria: Presence of a mixed Plasmodium infection. Presence of other clinical condition requiring hospitalization. Presence of significant anaemia, as defined by Hb <8 g/dL. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTc interval ≥450 msec), respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric or other abnormality (including recent head trauma). Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, chloroquine or artesunate or other artemisinins. Known history of hypersensitivity, allergic or adverse reactions to chloroquine, primaquine and related agents. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab). Known seropositive HIV antibody. Have received any antimalarial treatment in the preceding 2 weeks, as determined by history and, whenever feasible, by screening test. Have received antibacterial with known antimalarial activity in the preceding 2 weeks. Have received any investigational drug within the past 4 weeks. Liver function tests (AST/ALT levels) >2.5 times the upper limit of normal range. Known significant renal impairment as indicated by serum creatinine levels of >1.4 mg/dL. 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. Previous participation in the present clinical trial with PA.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Isabelle Borghini Fuhrer, PhD

Organizational Affiliation

Medicines for Malaria Venture

Official's Role

Study Director

Facility Information:

Facility Name

Pailin Referral Hospital

City

Pailin

State/Province

Pailin Province

Country

Cambodia

Facility Name

Wentlock District Hospital

City

Mangalore

Country

India

Facility Name

RSUD TC Hillers

City

Maumere

State/Province

Nusa Tenggara Timur

ZIP/Postal Code

86113

Country

Indonesia

Facility Name

MaeLamad District Hospital

City

Mae Ramat

State/Province

Tak Province

Country

Thailand

Facility Name

MaeSod General Hospital

City

Mae Sot

State/Province

Tak Province

Country

Thailand

12. IPD Sharing Statement

Citations:

PubMed Identifier

21267072

Citation

Poravuth Y, Socheat D, Rueangweerayut R, Uthaisin C, Pyae Phyo A, Valecha N, Rao BH, Tjitra E, Purnama A, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L. Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. PLoS One. 2011 Jan 18;6(1):e14501. doi: 10.1371/journal.pone.0014501.

Results Reference

result

PubMed Identifier

26666916

Citation

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.

Results Reference

derived

PubMed Identifier

23433102

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.

Results Reference

derived

Links:

URL

http://www.mmv.org

Description

Medicines for Malaria Venture

Learn more about this trial

Pyronaridine Artesunate (3:1) in Children and Adults With Acute Plasmodium Vivax Malaria

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