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MalariaPhase 3NCT00541385

Pyronaridine Artesunate 3:1 Granule Formulation vs. Coartem© Crushed Tablets in P. Falciparum Malaria Pediatric Patients

A Phase 3 study testing pyronaridine artesunate and arthemeter lumefantrine in people with Malaria, run by Medicines for Malaria Venture at 8 sites in 8 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The primary objective of this Phase III clinical study is to demonstrate the efficacy of the fixed combination of pyronaridine artesunate (PA) granule formulation (60:20 mg; pediatric PYRAMAX®) by showing a PCR-corrected adequate clinical and parasitological cure rate (ACPR) of more than 90%. Read more about this study

Who is it for?
Ages Up to 12 years
Conditions the study is for
Malaria
What is being tested?
pyronaridine artesunate and arthemeter lumefantrine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
535 participants
Where
8 sitesin 8 countries
Study dates
Oct 2007to Nov 2008
Phase
Phase 3
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 Up to 12 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Male or female patients ≤12 years of age.
  • Body weight ≥ 5 kg and < 25 kg with no clinical evidence of severe malnutrition (defined as a child whose weight-for-height is below -3 standard deviations or <70% of the median of the NCHS/WHO normalised reference values).
  • Presence of acute uncomplicated P. falciparum mono-infection confirmed by:
  • Fever, as defined by axillary temperature ≥37.5°C or oral/tympanic/rectal temperature ≥38°C, or documented history of fever in the previous 24 hours and,
  • Positive microscopy of P. falciparum with parasite density between 1,000 and 200,000 asexual parasite count/µl of blood.
  • Written informed consent, in accordance with local practice, provided by parent/guardian. If the parent/guardian is unable to write, witnessed consent is permitted according to local ethical considerations. Where possible, patient assent will be sought.
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  • Ability to swallow whole volume of liquid in which medication is suspended.
  • 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.
  • Ability and willingness to participate based on information given to parent or guardian and access to health facility. The patient is to comply with all scheduled follow up visits until D42.

Who cannot join

  • Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization Criteria 2000 [Attachment 3].
  • Mixed Plasmodium infection.
  • Severe vomiting, defined as >3 times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or severe diarrhoea defined as ≥3 watery stools per day.
  • Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTc interval ≥450 milliseconds), respiratory (including active tuberculosis), history of jaundice, hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including recent head trauma).
  • Presence of significant anaemia, as defined by Hb <8 g/dL.
  • Presence of febrile conditions caused by diseases other than malaria.
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  • Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, lumefantrine or artesunate or other artemisinins.
  • Patients with known disturbances of electrolytes balance, e.g. hypokalaemia or hypomagnesaemia.
  • Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by reported patient history.
  • Pregnant or breastfeeding.
  • Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6 (flecainide, metoprol, imipramine, amitriptyline, clomipramine).
  • 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 positive for HIV antibody.
  • Liver function tests [ASAT/ALAT levels] >2.5 times upper limit of normal range.
  • Known significant renal impairment as indicated by serum creatinine of >1.4 mg/dL.
  • Previous participation in any clinical study with pyronaridine artesunate.

Trial locations and contacts

8 sites in 8 countries.

8 sites in 8 countries

Burkina Faso1 site
  • Centre National de Recherche et de Formation sur le Paludisme

    Ouagadougou

Other trials in Burkina Faso

Côte d’Ivoire1 site
  • Unité de Paludologie de l'Institut Pasteur d'Abidjan

    Abidjan

Other trials in Côte d’Ivoire

Democratic Republic of the Congo1 site
  • Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa

    Kinshasa

Other trials in Democratic Republic of the Congo

Gabon1 site
  • Medical Research Unit, Albert Schweitzer Hospital

    Lambaréné

Other trials in Gabon

Kenya1 site
  • Siaya District Hospital, Medical Superintendent's office

    Siaya

Other trials in Kenya

Mali1 site
  • Malaria Research and Training Center, Faculté de Médecine, de Pharmacie et d'Ondonto-stomatologie

    Bamako

Other trials in Mali

Mozambique1 site
  • Instituto Nacional de Saude, Ministero de Saude

    Maputo

Other trials in Mozambique

Philippines1 site
  • Puerto Princesa General Hospital

    Puerto Princesa City

Other trials in Philippines

About this study

Official title: Phase III Comparative, Open-labelled, Randomised, Clinical Study to Assess a Fixed Dose of Oral Pyronaridine Artesunate Granule Formulation vs. Coartem® Crushed Tablets in Infants With Acute Uncomplicated Plasmodium Falciparum Malaria

The primary objective of this Phase III clinical study is to demonstrate the efficacy of the fixed combination of pyronaridine artesunate (PA) granule formulation (60:20 mg; pediatric PYRAMAX®) by showing a PCR-corrected adequate clinical and parasitological cure rate (ACPR) of more than 90%.

Secondary objectives of this clinical study are to compare the efficacy (non-inferiority) and safety of the PA granule formulation compared to Coartem® (ie, the combination of artemether/lumefantrine [AL]) crushed tablets in a paediatric population and to assess the safety of the PA granule formulation.

Read the detailed description

This is a multi-centre, comparative, randomised, open-label, parallel-group study of the efficacy and safety of a 3-day regimen of a fixed combination of PA (3:1) versus AL in the treatment of acute uncomplicated Plasmodium falciparum mono-infection. The study population will include 534 patients, comprising male and female infants and children (body weight ≥5 and <25 kg) recruited from study sites in East, Central, and West Africa and South East Asia (max. 150 patients/site).

Patients will be randomised in a 2:1 ratio to receive either oral PA (60:20 mg granules) once a day for 3 consecutive days (Days 0, 1, and 2) or AL (20:120 mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). The study drug will be administered by a Third Party Investigator unblinded to the study treatment, while the Investigator will remain blinded. For PA, the dose range covered by this regimen is 7.0:2.3 mg to 13.3:4.4 mg, which has been shown to be effective and safe in Phase I and II studies. Posology will be based on body weight ranges for both the PA and AL regimens.

Patients will be confined to the study facility ≥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 earlier.

The primary efficacy end point for this study is the proportion of subjects with PCR-corrected ACPR on Day 28. 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.

Conditions
Malaria
Being tested
pyronaridine artesunate, arthemeter lumefantrine
Keywords
Falciparum malaria, pediatric, Coartem, artesunate, lumefantrine, pyronaridine, Pyramax
Medical subject headings
Malaria, Malaria, Falciparum

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • pyronaridine artesunateDrug

    Also called Pyramax

    The strength of the granule formulation is 60:20 mg pyronaridine artesunate per sachet. Depending on their body weight, patients will receive between 1 to 3 pyronaridine artesunate sachets per day, for 3 consecutive days The actual dose-range covered by this regimen is 7.0:2.3 mg/kg to 13.3:4.4 mg/kg pyronaridine artesunate, which has shown to be effective and safe in the phase II studies conducted in children and adults.

  • arthemeter lumefantrineDrug

    Also called Coartem

    The strength of the tablet is 20 mg artemether and 120 mg lumefantrine. Depending on their body weight, patients will receive either 1 or 2 crushed tablets twice a day (≥5 to <15 = 1 tablet, 15 to <25 kg = 2 tablets), for 3 consecutive days.

Study groups in NCT00541385
Study groupRoleWhat they receive
PA groupExperimentalOral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Receives: Drug: pyronaridine artesunate
AL groupActive comparatorOral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Receives: Drug: arthemeter lumefantrine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With PCR-Corrected ACPR on Day 28

    Percentage of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. The PCR-corrected ACPR on Day 28 is defined as the absence of parasitaemia on Day 28 without the patient's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

    Measured: Day 28

Secondary outcomes (7)
  1. Percentage of Participants With PCR-Corrected ACPR on Day 14

    Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14. The PCR-corrected ACPR on Day 14 is defined as the 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

  2. Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28

    Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 14 and 28, without correction by PCR. Crude ACPR on Day 14 and 28 is defined as the absence of parasitaemia on Day 14 and 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

    Measured: Days 14 and 28

  3. 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 was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart

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

  4. Fever Clearance Time

    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.

    Measured: 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 and as clinically indicated (within the 42-day study period)

  5. Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3

    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

    Measured: Days 1, 2, and 3

  6. Proportion of Subjects With Fever Cleared on Days 1, 2, and 3

    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

    Measured: Days 1, 2, and 3

  7. Number of Subjects With ≥1 Adverse Event

    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.

  1. First posted10 Oct 2007 (estimated)
  2. Study startOct 2007
  3. Primary completionSep 2008
  4. Study completionNov 2008

Resources

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 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
535 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00541385
Sponsor's protocol ID
SP-C-007-07
Status last verified
Oct 2021
First submitted
9 Oct 2007
Last updated
22 Nov 2021
Data monitoring committee
Yes

Publications

  • Kayentao K, Doumbo OK, Penali LK, Offianan AT, Bhatt KM, Kimani J, Tshefu AK, Kokolomami JH, Ramharter M, de Salazar PM, Tiono AB, Ouedraogo A, Bustos MD, Quicho F, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L. Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial. Malar J. 2012 Oct 31;11:364. doi: 10.1186/1475-2875-11-364.

    PubMed 23113947
  • Ramharter M, Djimde AA, Borghini-Fuhrer I, Miller R, Shin J, Aspinall A, Richardson N, Wibberg M, Fleckenstein L, Arbe-Barnes S, Duparc S. Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study. Malar J. 2024 Feb 28;23(1):61. doi: 10.1186/s12936-024-04885-3.

    PubMed 38418982
  • 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.

    PubMed 26666916
  • 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

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing pyronaridine artesunate and arthemeter lumefantrine in people with Malaria, run by Medicines for Malaria Venture at 8 sites in 8 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 9 inclusion and 17 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 22 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 8 sites in Burkina Faso, Côte d’Ivoire, Democratic Republic of the Congo, Gabon, Kenya and 3 more countries. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

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 22 Nov 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?

Percentage of Participants With PCR-Corrected ACPR on 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 NCT00541385, which also lists 4 linked publications.

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 22 Nov 2021.

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