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Safety and Efficacy of Pyronaridine Artesunate Vs Chloroquine in Children and Adult Patients With Acute Vivax Malaria

Primary Purpose

Malaria

Status

Terminated

Phase

Phase 3

Locations

Korea, Republic of

Study Type

Interventional

Intervention

Pyronaridine - artesunate

Chloroquine

About this trial

This is an interventional treatment trial for Malaria focused on measuring Artemisinin-based combination therapy (ACT), Pyramax, Pyronaridine artesunate, Chloroquine, Children, Adults, Plasmodium vivax, Republic of Korea

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:
1. 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,
2. Positive microscopy of P. vivax with parasite density ≥250/ μL 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 greater than or equal to 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 pyronaridine artesunate.

Sites / Locations

Inje University Ilsan Paik Hospital
Eulji General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Pyronaridine - artesunate

Chloroquine

Arm Description

Oral pyronaridine artesunate (180:60 mg tablets), plus chloroquine-placebo once a day for 3 consecutive days. For patients who complete the study up to Day 28 and who have normal G-6-PD activity, a 14-day course of primaquine (15 mg/day) shall be administered starting on Day 28, after all required assessments have been performed, to complete their radical cure. Patients who are deficient in G-6-PD and who complete the study up to Day 28 will be treated as per country policy.

Oral chloroquine (155 mg tablets), plus pyronaridine artesunate-placebo, once a day for 3 consecutive days. For patients who complete the study up to Day 28 and who have normal G-6-PD activity, a 14-day course of primaquine (15 mg/day) shall be administered starting on Day 28, after all required assessments have been performed, to complete their radical cure. Patients who are deficient in G-6-PD and who complete the study up to Day 28 will be treated as per country policy.

Outcomes

Primary Outcome Measures

Crude Cure Rate on Day 14

Percentage of subjects with crude cure rate at Day 14, defined as absence of parasitaemia on Day 14, irrespective of body temperature without previously meeting any of the criteria of treatment failure

Secondary Outcome Measures

Crude Cure Rate on Day 28

Percentage of subjects with crude cure rate at Day 28, defined as absence of parasitaemia on Day 28, irrespective of body temperature without previously meeting any of the criteria of treatment failure

Parasite Clearance Time (PCT)

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

Fever Clearance Time (FCT)

Fever clearance time is defined as the time from first dosing to the first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart

Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3

Parasite clearance is defined as at least 2 consecutive negative smears for asexual parasites obtained within an interval of 7 to 25 hours post-dosing

Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3

Fever clearance is defined as at least 2 consecutive normal body temperature measurements (<37.5 C axillary/tympanic or <38.0 C oral/rectal) obtained within an interval of 7 to 25 hours postdosing

Number of Participants With Adverse Events (AEs)

Number of Participants with AEs, including clinically significant laboratory results, electrocardiogram (ECG), vital signs or physical examination abnormalities

Full Information

NCT ID

NCT04368910

First Posted

April 23, 2020

Last Updated

November 18, 2021

Sponsor

Medicines for Malaria Venture

Collaborators

Shin Poong Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT04368910

Brief Title

Safety and Efficacy of Pyronaridine Artesunate Vs Chloroquine in Children and Adult Patients With Acute Vivax Malaria

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2021

Overall Recruitment Status

Terminated

Why Stopped

Due to slow recruitment the study was terminated prematurely by the Sponsor after 30 subjects had been included

Study Start Date

September 6, 2007 (Actual)

Primary Completion Date

October 16, 2010 (Actual)

Study Completion Date

November 15, 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Medicines for Malaria Venture

Collaborators

Shin Poong Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

Detailed Description

This is a multi-centre, randomised, double-blind, double-dummy, parallel group, comparative trial. It is a Phase III study designed to meet the regulatory requirements for registration of pyronaridine artesunate (PA) in Korea. Chloroquine will be used as a comparator, which is recognized as an effective and well-tolerated anti-malarial therapy, and is standard blood-stage therapy for patients with P. vivax malaria in Korea. This study will be conducted in a total of 40 male and female children (≥20 kg body weight) and adult patients suffering from acute symptomatic uncomplicated P. vivax malaria recruited from study sites in Korea. 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 will be based on body weight ranges, with patients receiving 1 to 4 tablets per day depending on their body weight. The actual dose range covered by this regimen is 7.2:2.4 mg/kg to 13.8:4.6 mg/kg per day, 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, and 3) and 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. 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. It is anticipated that the study results will be pooled with the results of study SP-C-006-06 entitled "A Phase III Comparative (Double-blind, Double-dummy) Randomized 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 " for a formal non-inferiority analysis.

6. Conditions and Keywords

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

Malaria

Keywords

Artemisinin-based combination therapy (ACT), Pyramax, Pyronaridine artesunate, Chloroquine, Children, Adults, Plasmodium vivax, Republic of Korea

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

30 (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 Description

Oral pyronaridine artesunate (180:60 mg tablets), plus chloroquine-placebo once a day for 3 consecutive days.

Intervention Type

Drug

Intervention Name(s)

Chloroquine

Intervention Description

Oral chloroquine (155 mg tablets), plus pyronaridine artesunate-placebo, once a day for 3 consecutive days.

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 Day 28

Description

Time Frame

Day 28

Title

Parasite Clearance Time (PCT)

Description

Time Frame

Days 0, 3, 7, 14, 21, 28, 35, and 42 (or on any other day if the subject spontaneously returned within the 42-day period)

Title

Fever Clearance Time (FCT)

Description

Fever clearance time is defined as the time from first dosing to the first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart

Time Frame

Day 0 and every 8 hours over ≥72 hours following first study drug administration or temperature normalization for ≥2 readings between 7 and 25 hours apart, then at each visit (Days 7, 14, 28 and 42)

Title

Percentage of Patients Who Had Cleared Parasite on Days 1, 2, and 3

Description

Parasite clearance is defined as at least 2 consecutive negative smears for asexual parasites obtained within an interval of 7 to 25 hours post-dosing

Time Frame

Days 1, 2, and 3

Title

Percentage of Patients Who Had Cleared Fever on Days 1, 2, and 3

Description

Fever clearance is defined as at least 2 consecutive normal body temperature measurements (<37.5 C axillary/tympanic or <38.0 C oral/rectal) obtained within an interval of 7 to 25 hours postdosing

Time Frame

Days 1, 2, and 3

Title

Number of Participants With Adverse Events (AEs)

Description

Number of Participants with AEs, including clinically significant laboratory results, electrocardiogram (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

Other Pre-specified Outcome Measures:

Title

Crude Cure Rate on Day 42

Description

Proportion of subjects with crude cure rate at Day 42, defined as absence of parasitaemia on Day 42, irrespective of body temperature without previously meeting any of the criteria of treatment failure

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/ μL 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 greater than or equal to 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 pyronaridine artesunate.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stephan Duparc, MD

Organizational Affiliation

Medicine for Malaria Venture

Official's Role

Study Director

Facility Information:

Facility Name

Inje University Ilsan Paik Hospital

City

Goyang-si

ZIP/Postal Code

411-706

Country

Korea, Republic of

Facility Name

Eulji General Hospital

City

Seoul

ZIP/Postal Code

139-711

Country

Korea, Republic of

12. IPD Sharing Statement

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Safety and Efficacy of Pyronaridine Artesunate Vs Chloroquine in Children and Adult Patients With Acute Vivax Malaria

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