Clinical trial NCT00403260: Pyronaridine - Artesunate (3:1) Versus Mefloquine Plus Artesunate in Plasmodium Falciparum Malaria Patients
Official title: A Phase III Comparative, Open-label, Randomised, Multi-centre Study to Assess the Efficacy of Pyronaridine Artesunate (180:60mg) Versus Mefloquine (250mg) Plus Artesunate (100mg) in Children & Adult Patients With Acute Falciparum Malaria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Falciparum Malaria
Keywords: malaria
antimalarial
P falciparum
pyronaridine
artesunate
artemisinin based combination therapy (ACT)
pyronaridine artesunate (Pyramax)
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
Collaborators: name: Shin Poong Pharmaceuticals
First posted: 2006-11-23
Enrollment: 1271
Sex: ALL
Minimum age (years): 3
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this phase III clinical study is to compare the efficacy and safety of the fixed combination of pyronaridine artesunate (Pyramax®, PA) with that of the combination of mefloquine plus artesunate (MQ + AS) in children and adults with uncomplicated P falciparum malaria in South East Asia, India and Africa.

Detailed description: This is a multi-centre, comparative, randomised, open-label, parallel-group, non-inferiority study comparing the efficacy and safety of a fixed combination of PA to a loose combination of MQ + AS for patients with acute, symptomatic, uncomplicated P. falciparum malaria. The study population will include 1271 patients, comprising male and female children (≥20 kg body weight) and adults, recruited from study sites in South East Asia, India and Africa. Patients will be randomised in a 2:1 ratio to receive either oral PA (180:60mg tablets) or MQ (250mg tablets) plus AS (100mg tablets) once 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 remains blinded.

Patients will be confined to the 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 proportion of patients with PCR-corrected adequate clinical and parasitological response (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.

The primary efficacy end point for the study is the proportion of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28 (defined as the absence of parasitaemia without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure). 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.

Eligibility criteria: Inclusion Criteria:

* Male or female patients between the ages 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. falciparum mono-infection confirmed by:

  1. Fever, as defined by axillary/tympanic temperature ≥37.5°C or oral/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 100,000 asexual parasite count/µl of blood
* Written informed consent provided by patient and/or parent/guardian/spouse.
* Ability to swallow oral medication.

Exclusion Criteria:

* 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 or severe diarrhoea.
* Known history or evidence of clinically significant disorders.
* Presence of significant anaemia, as defined by Hb \<8 g/dL.
* Presence of febrile conditions caused by diseases other than malaria.
* Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, mefloquine or artesunate or other artemisinins.
* Use of any other antimalarial agent within 2 weeks prior to start of the study as evidenced by positive urine test.
* 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.
* Presence of significant renal or hepatic impairment.
* Receipt of an investigational drug within the past 4 weeks.
* Known active Hepatitis A IgM, Hepatitis B surface antigen or Hepatitis C antibody.
* Known seropositive HIV antibody.
* Previous participation in any clinical study with PA.

Primary outcomes:
measure: Percentage of Subjects With PCR-corrected Adequate Clinical and Parasitological Response (ACPR) on Day 28
timeFrame: Day 28
Secondary outcomes:
measure: PCR-corrected ACPR on Day 14
timeFrame: Day 14
measure: Crude ACPR on Days 14 and 28
timeFrame: Days 14 and 28
measure: Parasite Clearance Time
timeFrame: Thick blood films were examined every 8 hours until ≥72 hours or until 2 consecutive negative readings occurred 7 to 25 hours apart, and on Days 3, 7, 14, 21, 28, 35, and 42 (or any other day if the subject returned).
measure: Fever Clearance Time
timeFrame: Every 8 hours over ≥72 hours following first study drug administration or temperature normalisation for ≥2 readings between 7 and 25 hours apart, then at each visit.
measure: Parasite Clearance at Day 1, 2 and 3
timeFrame: Days 1, 2 and 3
measure: Fever Clearance at Day 1, 2 and 3
timeFrame: Days 1, 2 and 3
measure: Adverse Events and Clinically Significant Laboratory Results
timeFrame: 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
Other outcomes:
Locations:
city: Bobo Dioulasso
country: Burkina Faso
facility: RAOTAP2/Centre Muraz
state: Houet Province
city: Pailin
country: Cambodia
facility: Pailin Referral Hospital
state: Pailin Province
city: Abidjan
country: Côte D'Ivoire
facility: Institut Pasteur
city: Mangalore
country: India
facility: Wentlock District Hospital
city: Bagamoyo
country: Tanzania
facility: Bagamoyo Research and Training Centre of Ifakara Health Institute
city: Mae Ramat
country: Thailand
facility: MaeLamad District Hospital
state: Tak Province
city: Mae Sot
country: Thailand
facility: MaeSod General Hospital
state: Tak Province
city: Hanoi
country: Vietnam
facility: NIMPE
state: Commune Xy
city: Ho Chi Minh City
country: Vietnam
facility: Choray Hospital, Dak O
Study officials:
affiliation: Medicines for Malaria Venture
name: Isabelle Borghini-Fuhrer, PhD
role: STUDY_DIRECTOR
References:
citation: Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, Penali LK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L; Pyronaridine-Artesunate Study Team. Pyronaridine-artesunate versus mefloquine plus artesunate for malaria. N Engl J Med. 2012 Apr 5;366(14):1298-309. doi: 10.1056/NEJMoa1007125.
citation: 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.
citation: 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.