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

Sigma-Tau Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: Malaria,Falciparum

Treatments: Drug: eurartesim film coated tablet; Drug: Eurartesim dispersible oral tablet

Study type: Interventional

Funder types: Industry

Identifiers

NCT01992900

ST3073-ST3074-DM-12-002

2013-002255-15 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 300 patients

Sex: All

Ages: 6 to 12 months old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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300 participants in 2 patient groups

Eurartesim dispersible oral tablets

Experimental group

Description:

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).

Treatment:

Drug: Eurartesim dispersible oral tablet

Eurartesim film coated tablet

Active Comparator group

Description:

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).

Treatment:

Drug: eurartesim film coated tablet