Pyronaridine Artesunate (3:1) in Children and Adults With... | NCT00440999

NCT00440999

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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No data is available for this block.

Document Section

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No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Shin Poong Pharmaceuticals	INDUSTRY

Description Module

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
pyronaridine artesunate	Experimental	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.	Drug: Pyronaridine artesunate
chloroquine	Active Comparator	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.	Drug: Chloroquine

Name	Type	Description	Arm Group Labels	Other Names
Pyronaridine artesunate	Drug		pyronaridine artesunate	Pyramax
Chloroquine

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	Day 14

Secondary Outcomes

Measure	Description	Time Frame
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.	Day 21 and 28
Parasite Clearance Time

Other Outcomes

Measure	Description	Time Frame
Percentage of Subjects With PCR-corrected Cure Rate on Days 14, 21, and 28	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.	Day 14, 21, and 28

Eligibility Module

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.

Name	Affiliation	Role
Isabelle Borghini Fuhrer, PhD	Medicines for Malaria Venture	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Pailin Referral Hospital		Pailin	Pailin		Cambodia
Wentlock District Hospital

PubMed Identifier	Type	Citation	Retractions
21267072	Result	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.
26666916

Arm/Group Information

ID	Title	Description
FG000	Pyronaridine - Artesunate	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (D0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.
FG001	Chloroquine	Subjects receive oral active-chloroquine (tablet 155 mg) + pyronaridine artesunate - placebo, once per day for 3 consecutive days (D0, 1, and 2). The 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.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Pyronaridine - Artesunate	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (D0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous		Subjects total and per country/site

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Efficacy evaluable population: completed a full course of study medication, did not miss a dose, did not use a concomitant medication that may have interfered with the treatment outcome up to D14, did not have a concomitant disease which may have interfered with the classification of the treatment outcome, did not have major protocol deviations.

Posted

Count of Participants

Participants

Day 14

ID	Title	Description
OG000	Pyronaridine Artesunate	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (Day 0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Pyronaridine Artesunate	Subjects receive oral active-pyronaridine artesunate (tablet 180:60 mg) + chloroquine-placebo, once a day for 3 consecutive days (D0, 1, and 2). Posology was based on body weight ranges with subjects receiving 1 to 4 tablets depending on their body weight. The actual dose range covered by this regimen was 7.2:2.4 mg/kg to 13.8:4.6 mg/kg.

ID	Term
D011528	Protozoan Infections
D010272	Parasitic Diseases
D007239	Infections
D000096724	Mosquito-Borne Diseases

ID	Term
C000712628	pyronaridine tetraphosphate, artesunate drug combination
D002738	Chloroquine

ID	Term
D000634	Aminoquinolines
D011804	Quinolines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring