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Malaria,FalciparumPhase 2NCT01992900

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

A Phase 2 study testing Eurartesim dispersible oral tablet and eurartesim film coated tablet in people with Malaria,Falciparum, run by sigma-tau i.f.r. S.p.A. at 7 sites in 5 countries.

Completed

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

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 6 to 12 months
Conditions the study is for
Malaria,Falciparum
What is being tested?
Eurartesim dispersible oral tablet and eurartesim film coated tablet
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
300 participants
Where
7 sitesin 5 countries
Study dates
Nov 2013to Jan 2016
Phase
Phase 2
Are there results?
None posted in the registry

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 6 to 12 months
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 22Show fewer
  • 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.

Trial locations and contacts

7 sites in 5 countries.

7 sites in 5 countries

Burkina Faso2 sites
  • Centre Muraz

    Bobo-Dioulasso

  • Centre National de Recherche et de Formation en Paludisme

    Ouagadougou

Other trials in Burkina Faso

Tanzania2 sites
  • Bagamoyo Research center, Ifakara Heath Institute

    Bagamoyo

  • National Insititute for Medical Research

    Tanga

Other trials in Tanzania

Democratic Republic of the Congo1 site
  • Kinshasa School of Public Health, School of Medicine, University of Kinshasa

    Kinshasa

Other trials in Democratic Republic of the Congo

Mozambique1 site
  • Manica's Health Research Centre

    Manica

Other trials in Mozambique

The Gambia1 site
  • Medical Research Council

    Fajara

Other trials in The Gambia

About this study

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

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.

Read the 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.

Being tested
Eurartesim dispersible oral tablet, eurartesim film coated tablet
Keywords
Plasmodium falciparum Malaria, Eurartesim, ACT
Medical subject headings
Malaria, Falciparum

What participants receive

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

  • Eurartesim dispersible oral tabletDrug

    Also called Piperaquine tetraphosphate plus dihydroartemisinin

    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.

  • eurartesim film coated tabletDrug

    Also called Piperaquine tetraphosphate plus dihydroartemisinin

    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).

Study groups in NCT01992900
Study groupRoleWhat they receive
Eurartesim dispersible oral tabletsExperimentalEach 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).
Receives: Drug: Eurartesim dispersible oral tablet
Eurartesim film coated tabletActive comparatorEach 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).
Receives: Drug: eurartesim film coated tablet

What is being measured

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

  1. 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.

    Measured: 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

  2. 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.

    Measured: 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

  3. 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.

    Measured: 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

  4. 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.

    Measured: 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)
  1. Parasite clearance time

    Blood film for parasite count will be read by two independent microscopists.

    Measured: 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

  2. Fever clearance time

    Body temperature will be recorded to collect information about the fever clearance time

    Measured: 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

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

    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)

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

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

    The evaluated analytes are: Blood Urea Nitrogen, Creatinine, Glucose, Alanine aminotransferase, aspartate aminotransferase, Total Bilirubin, electrolytes (Na+, K+ and Cl-)

    Measured: screening and Day 7

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

    the following parameters are evaluated: Hemoglobin, hematocrit and full blood counts including Red Blood Cell and differential White Blood Cells, Platelet Count

    Measured: screening and day 7

  6. Adverse Events occurrence to calculate percentage of patients experiencing Adverse Events and Serious Adverse Events

    Measured: during all the study period from randomization and up to day 42

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Nov 2013 (estimated)
  2. Study startNov 2013
  3. Primary completionJul 2015
  4. Study completionJan 2016

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
300 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01992900
Sponsor's protocol ID
ST3073-ST3074-DM-12-002
Other IDs
2013-002255-15
Status last verified
Nov 2016
First submitted
11 Nov 2013
Last updated
8 Nov 2016
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 33289099
  • 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.

    PubMed 29061746

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Eurartesim dispersible oral tablet and eurartesim film coated tablet in people with Malaria,Falciparum, run by sigma-tau i.f.r. S.p.A. at 7 sites in 5 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 7 inclusion and 22 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 8 Nov 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Burkina Faso, Tanzania, Democratic Republic of the Congo, Mozambique, The Gambia. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

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). The study lists 4 primary outcomes in all. 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 NCT01992900, which also lists 2 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 8 Nov 2016.

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