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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by sigma-tau i.f.r. S.p.A.
Sponsor:
Information provided by (Responsible Party):
sigma-tau i.f.r. S.p.A.
ClinicalTrials.gov Identifier:
NCT01992900
First received: November 11, 2013
Last updated: April 9, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Plasmodium Falciparum Malaria.
Drug: Eurartesim dispersible oral tablet
Drug: eurartesim film coated tablet
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II, Open-label, Multicentre, Pharmacokinetic, Pharmacodynamics and Safety Study of a New Paediatric Eurartesim Dispersible Formulation and Crushed Film Coated Eurartesim Tablet, in Infant Patients With P. Falciparum Malaria

Resource links provided by NLM:


Further study details as provided by sigma-tau i.f.r. S.p.A.:

Primary Outcome Measures:
  • Comparison of peak plasma concentration of Dihydroartemisinin in the two studied formulations [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Comparison of area under the plasma concentration versus time curve of Dihydroartemisinin in the two studied formulations. [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Comparison of peak plasma concentration of Piperaquine in the two studied formulations [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Comparison of area under the plasma concentration versus time curve of Piperaquine in the two studied formulations. [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Parasite clearance time [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Blood film for parasite count will be read by two independent microscopists.

  • Fever clearance time [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Body temperature will be recorded to collect information about the fever clearance time

  • Change from baseline of electrocardiographic QT interval at 4-6 hours after the last study drug intake [ Time Frame: Before randomization and then at 4-6 hours after the last dose of study drug. ] [ Designated as safety issue: No ]

    Triplicate ECGs will be undertaken on screening (before study drug administration)as well as 4-6 hours after the last drug administration.

    The triplicate ECG values will be averaged in order to obtain one single value per patient and time point. These averages will be used for the statistical analysis.

    From the collected values the heart rate corrected QT intervals will be derived according to Fridericia's correction (QTcF)


  • Blood chemistry: proportion of patients with deterioration of parameters at day 7 respect to screening. [ Time Frame: screening and Day 7 ] [ Designated as safety issue: No ]
    The evaluated analytes are: Blood Urea Nitrogen, Creatinine, Glucose, Alanine aminotransferase, aspartate aminotransferase, Total Bilirubin, electrolytes (Na+, K+ and Cl-)

  • Hematology: proportion of patients with deterioration of parameters at day 7 respect to screening [ Time Frame: screening and day 7 ] [ Designated as safety issue: No ]
    the following parameters are evaluated: Hemoglobin, hematocrit and full blood counts including Red Blood Cell and differential White Blood Cells, Platelet Count

  • Adverse Events occurrence to calculate percentage of patients experiencing Adverse Events and Serious Adverse Events [ Time Frame: during all the study period from randomization and up to day 42 ] [ Designated as safety issue: No ]

Estimated Enrollment: 300
Study Start Date: November 2013
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Eurartesim dispersible oral tablets
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
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.
Other Name: Piperaquine tetraphosphate plus dihydroartemisinin
Active Comparator: Eurartesim film coated tablet
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
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).
Other Name: Piperaquine tetraphosphate plus dihydroartemisinin

Detailed Description:

Although the significant advances made during the last decades in controlling malaria in Africa, morbidity and mortality in sub-Saharan countries remain substantial. It is estimated that around 655.000 deaths a year still occur due to malaria infection and the majority of such deaths occur among young African children.

In response to the emergence and spread of classical drug-resistant Plasmodia strains, the WHO recommends since 2004 the use of artemisinin-based combination therapies (ACTs) in the treatment of uncomplicated malaria episodes.

The artemisinin derivatives are currently the most rapidly acting and potent antimalarial drugs.

Eurartesim is a fixed-dose combination product composed of dihydroartemisinin (DHA) and piperaquine phosphate (PQP). This second compound assures the long-term efficacy of eurartesim completing the whole body cleaning from the parasites. Eurartesim appears to offer benefits over existing licensed malaria treatments and is in line with current WHO treatment policy recommendations.

Eurartesim obtained a centralized marketing authorization by the European Union as film coated tablets containing 160 mg PQP/20 mg DHA and 320 mg PQP/40 mg DHA. The drug, licensed for its use in children (above 6 months of age) and adults has been administered in infants (above 6 months) and young children by crushing the tablets and administering them with a small amount of water.

According to the Guidelines on Clinical Investigation of Medicinal Products in the Paediatric Population (EMA ICH Topic E 11), 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, and this is a particularly blatant problem as young children carry the brunt of the malaria burden. Thus, a new water dispersible formulation of eurartesim has been developed for oral administration, since liquid formulations may be needed or desirable for paediatric patients of smaller ages due to their inability to swallow tablets. Moreover, in order to increase paediatric compliance to treatment, the new formulation is prepared with acceptable flavour and sweetener for children.

Eurartesim is a promising effective ACT treatment for malaria. It provides a simple dosing scheme (a single daily dose over 3 days) and it does not need any concomitant administration of food to improve its absorption. Moreover, eurartesim offers an interesting post-treatment prophylactic effect following therapy, reducing the risk of new infection, an issue of particular relevance in highly endemic malaria countries.

  Eligibility

Ages Eligible for Study:   6 Months to 12 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  • Gastrointestinal dysfunction that could alter absorption or motility (i.e. malabsorption syndromes, intestinal sub-occlusion or previous major gastrointestinal surgery).
  • Any contraindication to blood sampling.
  • Moderate and severe anaemia (Hb < 7 g/dL).
  • Patients who have used any drugs or substances known to be strong inhibitors of Cytochrome P enzymes (formerly known as cytochrome P450 enzymes) within 10 days prior to screening.
  • Patients who have used any drugs or substances known to be strong inducers of CYP enzymes (formerly known as cytochrome P450 enzymes)within 28 days prior to screening.
  • Children lactated by HIV positive women who are undergoing treatment with antiretroviral drugs.
  • Participation in any investigational drug study during the 30 days prior to screening or previously randomised in the present trial.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01992900

Contacts
Contact: Enrique O Bassat, MD +258 21810181 quique.bassat@gmail.com

Locations
Burkina Faso
Centre Muraz Not yet recruiting
Bobo Dioulasso, Burkina Faso
Centre National de Recherche et de Formation en Paludisme Not yet recruiting
Ouagadougou, Burkina Faso
Congo, The Democratic Republic of the
Kinshasa School of Public Health, School of Medicine, University of Kinshasa Recruiting
Kinshasa, Congo, The Democratic Republic of the
Gambia
Medical Research Council Recruiting
Fajara, Gambia
Mozambique
Manica's Health Research Centre Recruiting
Manica, Mozambique
Tanzania
Bagamoyo Research center, Ifakara Heath Institute Not yet recruiting
Bagamoyo, Tanzania
National Insititute for Medical Research Not yet recruiting
Tanga, Tanzania
Sponsors and Collaborators
sigma-tau i.f.r. S.p.A.
Investigators
Study Chair: Enrique O Bassat, MD Manica's health Research Centre, centre de investigacao Saude-Manica (CISM)
  More Information

No publications provided

Responsible Party: sigma-tau i.f.r. S.p.A.
ClinicalTrials.gov Identifier: NCT01992900     History of Changes
Other Study ID Numbers: ST3073-ST3074-DM-12-002, 2013-002255-15
Study First Received: November 11, 2013
Last Updated: April 9, 2014
Health Authority: Burkina Faso: Ministry of Health
Gambia: Department of State for Health and Social Welfare
Mozambique: Ministry of Health (MISAU)
Tanzania: Food & Drug Administration
Congo, Democratic Republic of the: Ministry of Health

Keywords provided by sigma-tau i.f.r. S.p.A.:
Plasmodium falciparum Malaria
Eurartesim
ACT

Additional relevant MeSH terms:
Protozoan Infections
Malaria
Malaria, Falciparum
Parasitic Diseases
Dihydroquinghaosu
Piperaquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014