Plasmodium Falciparum MalariaPhase 2NCT01594931
Phase II Dose-ranging Study of Pyronaridine/Artesunate in Adults Patients With Plasmodium Falciparum Malaria
A Phase 2 study testing pyronaridine/artesunate in people with Plasmodium Falciparum Malaria, run by Medicines for Malaria Venture at 6 sites in 6 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 15 to 60 years
- Conditions the study is for
- Plasmodium Falciparum Malaria
- What is being tested?
- pyronaridine/artesunate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 477 participants
- Where
- 6 sitesin 6 countries
- Study dates
- Jul 2005to Apr 2006
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 to 60 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
6 sites in 6 countries.
6 sites in 6 countries
About this study
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
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.
Read the 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.
- Conditions
- Plasmodium Falciparum Malaria
- Being tested
- pyronaridine/artesunate
- Keywords
- malaria, antimalarial, artemisinin based combination therapy (ACT), pyronaridine artesunate (Pyramax)
- Medical subject headings
- Malaria, Falciparum, Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
pyronaridine/artesunateDrug
Also called Pyramax
Tablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days.
| Study group | Role | What they receive |
|---|---|---|
| pyronaridine/artesunate (6:2 mg/kg) | Experimental | pyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg Receives: Drug: pyronaridine/artesunate |
| pyronaridine/artesunate (9:3 mg/kg) | Experimental | pyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg Receives: Drug: pyronaridine/artesunate |
| pyronaridine/artesunate (12:4 mg/kg) | Experimental | pyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg Receives: Drug: pyronaridine/artesunate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Day 28
Secondary outcomes (6)
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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2012 (estimated)
- Study startJul 2005
- Primary completionMar 2006
- Study completionApr 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Plasmodium Falciparum MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 477 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medicines for Malaria Venture
- Sponsor type
- University, hospital or other
- Collaborators
- Shin Poong Pharmaceutical Co. Ltd.
- Responsible party
- Sponsor
- Investigators
- Sornchai Looareesuwan, MD, Principal investigator, Hospital of Tropical Diseases, Mahidol University, Bangkok, ThailandDuong Socheat, MD, Principal investigator, Nat. Centre for Parasitol., Entomol. and Malaria Control, Phnom Penh, CambodiaEmiliana Tjitra, PhD, Principal investigator, Bethesda Hospital, Tomohon, North Sulawasi, IndonesiaKalifa Bojang, MD, Principal investigator, MRC Laboratories, Faraffeni, The GambiaPatrice Piola, MD, Principal investigator, Epicentre, Mbarara, UgandaOumar Gaye, MD, Principal investigator, Centre de santé Roi Baudouin, Guediawaye, Senegal
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01594931
- Sponsor's protocol ID
- SP-C-002-05
- Status last verified
- Oct 2021
- First submitted
- 7 May 2012
- Last updated
- 2 Nov 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 23433102
Study at a glance
From the registry record, last updated by the sponsor on 2 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01594931
- Acronym / sponsor ID
- SP-C-002-05
- Conditions
- Plasmodium Falciparum Malaria
- Keywords
- malaria, antimalarial, artemisinin based combination therapy (ACT), pyronaridine artesunate (Pyramax)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 477 participants (actual)
- Lead sponsor
- Medicines for Malaria VentureUniversity, hospital or other
- Collaborators
- Shin Poong Pharmaceutical Co. Ltd.
- Study start
- Jul 2005
- Primary completion
- Mar 2006 (actual)
- Study completion
- Apr 2006 (actual)
- First posted
- 9 May 2012 (estimated)
- Results
- Posted 17 Sep 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| pyronaridine/artesunate (6:2 mg/kg) | Experimental | Drug: pyronaridine/artesunatepyronaridine tetraphosphate 6 mg/kg and artesunate 2 mg/kg |
| pyronaridine/artesunate (9:3 mg/kg) | Experimental | Drug: pyronaridine/artesunatepyronaridine tetraphosphate 9 mg/kg and artesunate 3 mg/kg |
| pyronaridine/artesunate (12:4 mg/kg) | Experimental | Drug: pyronaridine/artesunatepyronaridine tetraphsophate 12 mg/kg and artesunate 4 mg/kg |
Who may qualify
- Ages
- 15 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (11 listed)
- 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):
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| pyronaridine/artesunateAlso: PyramaxTablets of fixed dose combination of pyronaridine and artesunate at a ratio of 3:1. The tablets were taken daily for 3 days. | Drug | pyronaridine/artesunate (12:4 mg/kg), pyronaridine/artesunate (6:2 mg/kg), pyronaridine/artesunate (9:3 mg/kg) |
Primary outcome
PCR-Corrected ACPR at Day 28
Time frame: 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
6 secondary outcomes
PCR-Corrected ACPR at Day 14
Time frame: Day 14
Parasite Clearance Time
Time frame: Thick blood slides were examined every 8 hours until at least 72 hours or until a negative smear was recorded
Fever Clearance Time
Time frame: Every 8 hours for at least 72 hours after the first dose
Parasite Clearance
Time frame: Days 1, 2, and 3
Fever Clearance
Time frame: Days 1, 2 and 3
Adverse Events (AEs)
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Nov 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 23433102Duparc 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sornchai Looareesuwan, MD principal investigator
Hospital of Tropical Diseases, Mahidol University, Bangkok, Thailand
Duong Socheat, MD principal investigator
Nat. Centre for Parasitol., Entomol. and Malaria Control, Phnom Penh, Cambodia
Emiliana Tjitra, PhD principal investigator
Bethesda Hospital, Tomohon, North Sulawasi, Indonesia
6 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing pyronaridine/artesunate in people with Plasmodium Falciparum Malaria, run by Medicines for Malaria Venture at 6 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Cambodia, Indonesia, Senegal, Thailand, The Gambia and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Sep 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PCR-Corrected ACPR at Day 28 (time frame: Day 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01594931, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Nov 2021.