A Pharmacokinetic/Pharmacodynamic Study of Eurartesim Dispersible Formulation in Infants With P.Falciparum Malaria

NCT01992900 | Completed Phase 2 DMC

• 2 other identifiers: ST3073-ST3074-DM-12-0022013-002255-15
• Study Type: interventional
• Target: 300
• Locations: 5 countries
• Sites: 7

Brief Summary

There is a need for paediatric formulations that permit accurate dosing and enhance patient compliance. However, for the treatment of malaria, scarce paediatric-friendly formulations are available on the market. Thus, a new water dispersible formulation of eurartesim has been developed for oral administration. Aim of this study is to provide data on pharmacokinetic profile, safety and efficacy of this new paediatric formulation and compare it with the crushed film coated tablet in infant patients (6 to ≤12 months of age) suffering from uncomplicated Plasmodium falciparum malaria. Furthermore, a Pharmacokinetic/Pharmacodynamic(PK/PD) modelling will be built up to establish PK/PD relationship in adult and paediatric populations.

Conditions

Malaria,Falciparum

Keywords

Plasmodium falciparum Malaria; Eurartesim; ACT

Outcome Measures

Primary Outcomes (4)

• Comparison of peak plasma concentration of Dihydroartemisinin in the two studied formulations

  In order to minimize the blood sampling in infants, patients will be divided into 10 blood sampling groups for both the treatments (water dispersible and crushed film coated tablet) and only 2 blood draws per group will be taken within the prespecified timepoints. Optimal sampling design was performed by using the appropriate software. The D-optimal design option was used to determine the optimal sampling design.

  DHA plasma samples will be collected on the first day of study drug administration at 20, 30, 40, 60, 100, 200 and 300 minutes post-dose

• Comparison of area under the plasma concentration versus time curve of Dihydroartemisinin in the two studied formulations.

  In order to minimize the blood sampling in infants, patients will be divided into 10 blood sampling groups for both the treatments (water dispersible and crushed film coated tablet) and only 2 blood draws per group will be taken within the pre-specified timepoints. Optimal sampling design was performed by using the appropriate software. The D-optimal design option was used to determine the optimal sampling design.

  DHA plasma samples will be collected on the first day of study drug administration at 20, 30, 40, 60, 100, 200 and 300 minutes post-dose

• Comparison of peak plasma concentration of Piperaquine in the two studied formulations

  In order to minimize the blood sampling in infants, patients will be divided into 10 blood sampling groups for both the treatments (water dispersible and crushed film coated tablet) and only 2 blood draws per group will be taken within the pre-specified timepoints. Optimal sampling design was performed by using the appropriate software. The D-optimal design option was used to determine the optimal sampling design.

  PQP plasma samples will be collected on day 0 of treatment at 40, 80, 280, 720 minutes, then on day 1 at 24 hours and on day 2 at 40, 80, 280, 720 minutes after the last drug administration and then 24, 120, 288 and 456 hours

• Comparison of area under the plasma concentration versus time curve of Piperaquine in the two studied formulations.

  In order to minimize the blood sampling in infants, patients will be divided into 10 blood sampling groups for both the treatments (water dispersible and crushed film coated tablet) and only 2 blood draws per group will be taken within the pre-specified timepoints. Optimal sampling design was performed by using the appropriate software. The D-optimal design option was used to determine the optimal sampling design.

  PQP plasma samples will be collected on day 0 of treatment at 40, 80, 280, 720 minutes, then on day 1 at 24 hours and on day 2 at 40, 80, 280, 720 minutes after the last drug administration and then 24, 120, 288 and 456 hours

Secondary Outcomes (6)

• Parasite clearance time

  At screening and then about every 12 hours until the time of the first negative result, then confirmed by a second negative result or up to three days

• Fever clearance time

  At screening and then about every 12 hours until the time on which body temperature falls down below 37.5 °C, or up to three days

• Change from baseline of electrocardiographic QT interval at 4-6 hours after the last study drug intake

  Before randomization and then at 4-6 hours after the last dose of study drug.

• Blood chemistry: proportion of patients with deterioration of parameters at day 7 respect to screening.

  screening and Day 7

• Hematology: proportion of patients with deterioration of parameters at day 7 respect to screening

  screening and day 7

Study Arms (2)

Eurartesim dispersible oral tablets

EXPERIMENTAL

Each patient will receive a specific amount of drug according to his/her body weight, once a day for three consecutive days (from 5 to \<7 kg: 1 tablet containing 80 mg PQP and 10 mg DHA; from 7 to \< 13 kg: 1 tablet containing 160 mg PQP and 20 mg DHA).

Drug: Eurartesim dispersible oral tablet

Eurartesim film coated tablet

ACTIVE COMPARATOR

Each patient will receive a specific amount of drug according to his/her body weight, once a day for three consecutive days (from 5 to \<7 kg: half tablet equal to 80 mg PQP and 10 mg DHA; from 7 to \< 13 kg: 1 tablet containing 160 mg PQP and 20 mg DHA).

Drug: eurartesim film coated tablet

Interventions

Eurartesim dispersible oral tablet DRUG

The first dose of Eurartesim dispersible oral tablet will be administered immediately after randomization. the other two doses will be administered with an interval of 24 hours. Eurartesim tablet will be dispersed in about 10 mL of water.

Also known as: Piperaquine tetraphosphate plus dihydroartemisinin

Eurartesim dispersible oral tablets

eurartesim film coated tablet DRUG

The first dose of Eurartesim film coated tablet will be administered immediately after randomization. the other two doses will be administered with an interval of 24 hours. tablet will be crushed and dispersed in a few amount of water (about 10 ml).

Also known as: Piperaquine tetraphosphate plus dihydroartemisinin

Eurartesim film coated tablet

Eligibility Criteria

• Age: 6 Months - 12 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and Female infants aged from 6 months to ≤ 12 months included.
• Ability to swallow oral suspension.
• Body weight \>5 kg.
• Uncomplicated malaria, with microscopically confirmed mono-infection by P. falciparum (parasitaemia ≥1000/microL and \<200000/microL).
• History of fever anytime during the preceding 48 hours or presence of fever (axillary temperature ≥37.5 °C or ≥38.0 °C rectally).
• Ability of parents or guardians to understand the nature of the trial and providing signed informed consent.
• Stable residence in the study area during the two months after recruitment and willingness to comply with the study protocol and the study visit schedule.

You may not qualify if:

• Antimalarial treatment with amodiaquine, chloroquine, quinine or lumefantrine-based compounds within the previous 6 weeks, with piperaquine-based compound, or mefloquine, or sulphadoxine pyrimethamine within the previous 3 months and with halofantrine within the 30 days prior to screening.
• Any other antimalarial treatment or antibiotics with antimalarial activity (including cotrimoxazol) and any herbal products, within the 7 days prior to screening.
• Severe malnutrition (defined as weight for height \<70% of the median National Center for Health Statistics(NCHS)/WHO reference).
• Severe vomiting or dehydration.
• Presence of jaundice.
• Known hypersensitivity to the artemisinin-based therapy or piperaquine.
• History of relevant clinical allergic reaction of any origin.
• Clinical and/or laboratory features of severe malaria.
• Known moderate/ severe renal or liver insufficiency.
• Evidence of clinically relevant haematological, pulmonary, metabolic-endocrine, neurological, urogenital diseases as judged by the investigator.
• Already diagnosed HIV infection, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Previous admission for, or evidence of symptomatic cardiac arrhythmias or with clinically relevant bradycardia at screening (bpm \< 90).
• Family history of sudden death, or known congenital prolongation of the QT interval, or any clinical condition known to prolong the QT interval.
• ECG abnormality that requires urgent management.
• Any treatment which can induce a lengthening of QT interval.

Sponsors & Collaborators

• sigma-tau i.f.r. S.p.A.: lead

Study Sites (7)

Centre Muraz

Bobo-Dioulasso, Burkina Faso

Location

Centre National de Recherche et de Formation en Paludisme

Ouagadougou, Burkina Faso

Location

Kinshasa School of Public Health, School of Medicine, University of Kinshasa

Kinshasa, Democratic Republic of the Congo

Location

Manica's Health Research Centre

Manica, Mozambique

Location

Bagamoyo Research center, Ifakara Heath Institute

Bagamoyo, Tanzania

Location

National Insititute for Medical Research

Tanga, Tanzania

Location

Medical Research Council

Fajara, The Gambia

Location

Related Publications (2)

• Belard S, Ramharter M, Kurth F. Paediatric formulations of artemisinin-based combination therapies for treating uncomplicated malaria in children. Cochrane Database Syst Rev. 2020 Dec 8;12(12):CD009568. doi: 10.1002/14651858.CD009568.pub2.

  PMID: 33289099 DERIVED

• Gargano N, Madrid L, Valentini G, D'Alessandro U, Halidou T, Sirima S, Tshefu A, Mtoro A, Gesase S; Eurartesim Dispersible Study Group; Bassat Q. Efficacy and Tolerability Outcomes of a Phase II, Randomized, Open-Label, Multicenter Study of a New Water-Dispersible Pediatric Formulation of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in African Infants. Antimicrob Agents Chemother. 2017 Dec 21;62(1):e00596-17. doi: 10.1128/AAC.00596-17. Print 2018 Jan.

  PMID: 29061746 DERIVED

MeSH Terms

Conditions

Malaria, Falciparum

Interventions

artenimol

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Study Officials

• Enrique O Bassat, MD

  Manica's health Research Centre, centre de investigacao Saude-Manica (CISM)

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 11, 2013
• First Posted: November 25, 2013
• Study Start: November 1, 2013
• Primary Completion: July 1, 2015
• Study Completion: January 1, 2016
• Last Updated: November 8, 2016

Record last verified: 2016-11

Locations

MO (1); TH (1); BU (2); DE (1); TA (2)