Pyronaridine Artesunate 3:1 Granule Formulation vs. Coartem© Crushed Tablets in P. Falciparum Malaria Pediatric Patients
Condition: Malaria
MeSH terms: Malaria; Malaria, Falciparum
Intervention: pyronaridine artesunate; arthemeter lumefantrine
Intervention description: 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.; 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.
Intervention MeSH terms: Artesunate; Lumefantrine; Pyronaridine; Pyronaridine tetraphosphate, artesunate drug combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 535.0
Sex: All
Maximum age: 12 Years
Healthy volunteers: No
Keywords: Falciparum malaria; pediatric; Coartem; artesunate; lumefantrine; pyronaridine; Pyramax

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%.

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female patients ≤12 years of age.

          2. 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).

          3. Presence of acute uncomplicated P. falciparum mono-infection confirmed by:

               1. 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,

               2. Positive microscopy of P. falciparum with parasite density between 1,000 and
                  200,000 asexual parasite count/µl of blood.

          4. 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.

          5. Ability to swallow whole volume of liquid in which medication is suspended.

          6. 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.

          7. 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.

        Exclusion Criteria:

          1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral
             treatment according to the World Health Organization Criteria 2000 [Attachment 3].

          2. Mixed Plasmodium infection.

          3. 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.

          4. 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).

          5. Presence of significant anaemia, as defined by Hb <8 g/dL.

          6. Presence of febrile conditions caused by diseases other than malaria.

          7. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine,
             lumefantrine or artesunate or other artemisinins.

          8. Patients with known disturbances of electrolytes balance, e.g. hypokalaemia or
             hypomagnesaemia.

          9. Use of any other antimalarial agent within 2 weeks prior to start of the study as
             evidenced by reported patient history.

         10. Pregnant or breastfeeding.

         11. Patients taking any drug which is metabolised by the cytochrome enzyme CYP2D6
             (flecainide, metoprol, imipramine, amitriptyline, clomipramine).

         12. Received an investigational drug within the past 4 weeks.

         13. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or
             Hepatitis C antibody (HCV Ab).

         14. Known positive for HIV antibody.

         15. Liver function tests [ASAT/ALAT levels] >2.5 times upper limit of normal range.

         16. Known significant renal impairment as indicated by serum creatinine of >1.4 mg/dL.

         17. Previous participation in any clinical study with pyronaridine artesunate.