ST3073-ST3074-DM-12-002

Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.

V. le Shakespeare 47, Roma, Italy,

Giovanni Valentini, Alfasigma S.p.A., 0039 0691393916,

Giovanni Valentini, Alfasigma S.p.A., 0039 0691393916,

Yes

No

Yes

Final

27 Jan 2017

Yes

15 May 2015

Yes

02 Jun 2015

No

To assess the PK of the eurartesim (PQP/DHA) new water dispersible formulation, film coated tablet and crushed film coated tablet in venous blood samples during and after a therapeutic course of Eurartesim in paediatric population

The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki (1964) and its subsequent amendments and in accordance with the “ICH Topic E6, Guideline for Good Clinical Practices”.

12 Nov 2013

No

Yes

Congo: 33

Mozambique: 143

Tanzania, United Republic of: 6

Burkina Faso: 104

Gambia: 14

300

0

0

0

0

300

0

0

0

0

0

Overall trial (overall period)

Randomised - controlled

As the primary objective of this study was to determine the pharmacokinetic profile of DHA and PQ of both formulations in a small children population, blinding procedures were considered not mandatory. Therefore, the study used an open label design since the impossibility of establishing a double-blind dosing schedule involving dispersible and crushed tablets.

Yes

Eurartesim

Dispersible tablet

Oral use

Each child received a specific amount of drug according to body weight once a day for 3 consecutive days. Dispersible tablets were completely dispersed in 5 to 10 mL of water. After ingestion, other 5 mL of water were added to the container and consumed by the patient. The 1st dose was administered as soon as the patient was randomized in the study and possibly no food was given in the following 3 hours. For the 2nd and the 3rd doses, the child had to be fed 3 hours before the scheduled drug intake and, possibly, food was not given in the following 3 hours. If children required food during the restricted periods, it consisted of a small amount of porridge with water. Infants who still required breast-feeding only received maternal milk. Patients were observed for 1 h after dosing. If the dose was: a) vomited within 30 min., a further full dose was given; b) vomited between 31 and 60 min., a further half dose was given.

Eurartesim

Dispersible tablet

Oral use

Each child received a specific amount of drug according to body weight once a day for 3 consecutive days. Tablets were crushed to form a powder. The mortar was cleaned with 5-10 mL of water, that was then used to disperse powder. After administration, 5 mL of water were used to rinse the mortar and the container and then administered. The 1st dose was administered as soon as the patient was randomized in the study and possibly no food was given in the following 3 hours. For the 2nd and the 3rd doses, the child had to be fed 3 hours before the scheduled drug intake and, possibly, food was not given in the following 3 hours. If children required food during the restricted periods, it consisted of a small amount of porridge with water. Infants who still required breast-feeding only received maternal milk. Patients were observed for 1 h after dosing. If the dose was: a) vomited within 30 min., a further full dose was given; b) vomited between 31 and 60 min., a further half dose was given.

DHA/PQP Dispersible Tablets

DHA/PQP Crushed Tablets

ITT/Safety Population Dispersible Tablets

The Intention-to-Treat (ITT) population included all patients taking at least one dose of the study drug. This population has been used for the Efficacy and Safety analysis. As for the Safety data presentation, it has been referenced as Safety Population. Note: Two randomized patients assigned to the dispersible treatment group were excluded from all the study populations since one of them did not have parasites at Day 0 (treated with two doses by mistake and then withdrawn) and the other one withdrawn the informed consent before the first study drug intake.

PP Population Dispersible Tablets

The Per Protocol (PP) population included all patients who took the complete treatment and who did not meet any major protocol violations. Note: two randomized patients assigned to the dispersible treatment group were excluded from all the study populations since one of them did not have parasites at Day 0 (treated with two doses by mistake and then withdrawn) and the other one withdrawn the informed consent before the first study drug intake.

ITT/Safety Population Crushed Tablets

The Intention-to-Treat (ITT) population included all patients taking at least one dose of the study drug. This population has been used for the Efficacy and Safety analysis. As for the Safety data presentation, it has been referenced as Safety Population.

PP Population Crushed Tablets

The Per Protocol (PP) population included all patients who took the complete treatment and who did not meet any major protocol violations.

DHA PK Population Dispersible Tablets

The pharmacokinetic analysis population included all the data from samplings taken under regular treatment course with no major PK specific protocol violations (e.g. use of not permitted concomitant medication, violation of major inclusion/exclusion criteria). The PK population has been used for the PK analysis.

PQ PK Population Dispersible Tablets

The pharmacokinetic analysis population included all the data from samplings taken under regular treatment course with no major PK specific protocol violations (e.g. use of not permitted concomitant medication, violation of major inclusion/exclusion criteria). The PK population has been used for the PK analysis.

DHA PK Population Crushed Tablets

The pharmacokinetic analysis population included all the data from samplings taken under regular treatment course with no major PK specific protocol violations (e.g. use of not permitted concomitant medication, violation of major inclusion/exclusion criteria). The PK population has been used for the PK analysis.

PQ PK Population Crushed Tablets

The pharmacokinetic analysis population included all the data from samplings taken under regular treatment course with no major PK specific protocol violations (e.g. use of not permitted concomitant medication, violation of major inclusion/exclusion criteria). The PK population has been used for the PK analysis.

DHA/PQP Dispersible Tablets

DHA/PQP Crushed Tablets

ITT/Safety Population Dispersible Tablets

The Intention-to-Treat (ITT) population included all patients taking at least one dose of the study drug. This population has been used for the Efficacy and Safety analysis. As for the Safety data presentation, it has been referenced as Safety Population. Note: Two randomized patients assigned to the dispersible treatment group were excluded from all the study populations since one of them did not have parasites at Day 0 (treated with two doses by mistake and then withdrawn) and the other one withdrawn the informed consent before the first study drug intake.

PP Population Dispersible Tablets

The Per Protocol (PP) population included all patients who took the complete treatment and who did not meet any major protocol violations. Note: two randomized patients assigned to the dispersible treatment group were excluded from all the study populations since one of them did not have parasites at Day 0 (treated with two doses by mistake and then withdrawn) and the other one withdrawn the informed consent before the first study drug intake.

ITT/Safety Population Crushed Tablets

The Intention-to-Treat (ITT) population included all patients taking at least one dose of the study drug. This population has been used for the Efficacy and Safety analysis. As for the Safety data presentation, it has been referenced as Safety Population.

PP Population Crushed Tablets

The Per Protocol (PP) population included all patients who took the complete treatment and who did not meet any major protocol violations.

DHA PK Population Dispersible Tablets

The pharmacokinetic analysis population included all the data from samplings taken under regular treatment course with no major PK specific protocol violations (e.g. use of not permitted concomitant medication, violation of major inclusion/exclusion criteria). The PK population has been used for the PK analysis.

PQ PK Population Dispersible Tablets

The pharmacokinetic analysis population included all the data from samplings taken under regular treatment course with no major PK specific protocol violations (e.g. use of not permitted concomitant medication, violation of major inclusion/exclusion criteria). The PK population has been used for the PK analysis.

DHA PK Population Crushed Tablets

The pharmacokinetic analysis population included all the data from samplings taken under regular treatment course with no major PK specific protocol violations (e.g. use of not permitted concomitant medication, violation of major inclusion/exclusion criteria). The PK population has been used for the PK analysis.

PQ PK Population Crushed Tablets

The pharmacokinetic analysis population included all the data from samplings taken under regular treatment course with no major PK specific protocol violations (e.g. use of not permitted concomitant medication, violation of major inclusion/exclusion criteria). The PK population has been used for the PK analysis.

The primary endpoint was to estimate the population and individual PK parameters and variability of PQ and DHA in paediatric populations administered with Eurartesim. DHA and PQ were modelled separately in order to determine the sampling schedule for a study to be performed in infants with malaria. In the learn phase, the population PK analysis was performed using plasma data for DHA and PQ from 5 previous studies. Plasma concentrations of DHA and PQ data obtained from the present study were subsequently pooled with the data from the previous studies for the confirmatory aspects of the study. Actual dosing (and dose per kg) and actual blood sampling times were used for the compartmental modelling of DHA and PQ. The DHA Cmax (ng/ml) Geometric Mean Ratio (GMR) of dispersible vs crushed tablets is here reported. In order to complete and validate all mandatory fields, the same GMR value has been reported for both the relevant analyses sets.

Primary

Overall study

The geometric mean ratios (GMR), lower and upper 90%CI for bioequivalence assessment for Cmax and AUCinf obtained from the simulation of the two formulations in paediatric male and female patients are presented. The point estimate for the bioequivalence ratios of the new dispersible formulation over the old crushed formulation were within the 80-125% acceptance range for PQ but not for DHA.

DHA PK Population Dispersible Tablets v DHA PK Population Crushed Tablets

175

Pre-specified

71.6

2-sided

The primary endpoint was to estimate the population and individual PK parameters and variability of PQ and DHA in paediatric populations administered with Eurartesim. DHA and PQ were modelled separately in order to determine the sampling schedule for a study to be performed in infants with malaria. In the learn phase, the population PK analysis was performed using plasma data for DHA and PQ from 5 previous studies. Plasma concentrations of DHA and PQ data obtained from the present study were subsequently pooled with the data from the previous studies for the confirmatory aspects of the study. Actual dosing (and dose per kg) and actual blood sampling times were used for the compartmental modelling of DHA and PQ. The PQ Cmax (ng/ml) Geometric Mean Ratio (GMR) of dispersible vs crushed tablets is here reported. In order to complete and validate all mandatory fields, the same GMR value has been reported for both the relevant analyses sets.

Primary

Overall study

The geometric mean ratios (GMR), lower and upper 90%CI for bioequivalence assessment for Cmax and AUCinf obtained from the simulation of the two formulations in paediatric male and female patients are presented. The point estimate for the bioequivalence ratios of the new dispersible formulation over the old crushed formulation were within the 80-125% acceptance range for PQ but not for DHA.

PQ PK Population Crushed Tablets v PQ PK Population Dispersible Tablets

259

Pre-specified

93.7

2-sided

The primary endpoint was to estimate the population and individual PK parameters and variability of PQ and DHA in paediatric populations administered with Eurartesim. DHA and PQ were modelled separately in order to determine the sampling schedule for a study to be performed in infants with malaria. In the learn phase, the population PK analysis was performed using plasma data for DHA and PQ from 5 previous studies. Plasma concentrations of DHA and PQ data obtained from the present study were subsequently pooled with the data from the previous studies for the confirmatory aspects of the study. Actual dosing (and dose per kg) and actual blood sampling times were used for the compartmental modelling of DHA and PQ. The DHA AUCinf (ng/ml*h) Geometric Mean Ratio (GMR) of dispersible vs crushed tablets is here reported. In order to complete and validate all mandatory fields, the same GMR value has been reported for both the relevant analyses sets.

Primary

Overall study

The geometric mean ratios (GMR), lower and upper 90%CI for bioequivalence assessment for Cmax and AUCinf obtained from the simulation of the two formulations in paediatric male and female patients are presented. The point estimate for the bioequivalence ratios of the new dispersible formulation over the old crushed formulation were within the 80-125% acceptance range for PQ but not for DHA.

DHA PK Population Dispersible Tablets v DHA PK Population Crushed Tablets

175

Pre-specified

69.9

2-sided

The primary endpoint was to estimate the population and individual PK parameters and variability of PQ and DHA in paediatric populations administered with Eurartesim. DHA and PQ were modelled separately in order to determine the sampling schedule for a study to be performed in infants with malaria. In the learn phase, the population PK analysis was performed using plasma data for DHA and PQ from 5 previous studies. Plasma concentrations of DHA and PQ data obtained from the present study were subsequently pooled with the data from the previous studies for the confirmatory aspects of the study. Actual dosing (and dose per kg) and actual blood sampling times were used for the compartmental modelling of DHA and PQ. PQ AUCinf (ng/ml*h) Geometric Mean Ratio (GMR) of dispersible vs crushed tablets is here reported. In order to complete and validate all mandatory fields, the same GMR value has been reported for both the relevant analyses sets.

Primary

Overall study

The geometric mean ratios (GMR), lower and upper 90%CI for bioequivalence assessment for Cmax and AUCinf obtained from the simulation of the two formulations in paediatric male and female patients are presented. The point estimate for the bioequivalence ratios of the new dispersible formulation over the old crushed formulation were within the 80-125% acceptance range for PQ but not for DHA.

PQ PK Population Dispersible Tablets v PQ PK Population Crushed Tablets

259

Pre-specified

93.5

2-sided

Secondary

Day 28

Secondary

Day 28

Secondary

Day 42

Secondary

Day 42

ETF was defined as: 1. Development of danger signs or severe malaria on Days 0, 1, 2 or 3, in the presence of parasitaemia. 2. Parasite density on Day 2 > Day 0 count, irrespective of axillary temperature. 3. Presence of parasitaemia on Day 3 with fever (axillary temperature ≥37.5°C). 4. Parasitaemia on Day 3 ≥ 25% of count on Day 0. LTF at Day 42 was divided into LCF and LPF. -Late Clinical Failure (LCF) was defined as: 1. Development of danger signs or severe malaria from Day 4 to Day 42 in the presence of parasitaemia. 2. Presence of parasitaemia and fever on any day from Day 4 to Day 42, without previously meeting the criteria of ETF. -Late Parasitological Failure (LPF) at Day 42 was defined as reappearance of parasitaemia between Day 4 and Day 42 (identified as recrudescent infection by PCR analysis) in the absence of fever (axillary temperature <37.5°C) without previously meeting the criteria of ETF or LCF.

Secondary

Day 42

True Treatment Failures were both the ETF and malaria recrudescences

Secondary

Day 42

Secondary

Day 7

Secondary

Day 3

Secondary

Day 42

Secondary

Day 42

Secondary

Day 42

Secondary

Day 42

Overall study

17.0

ITT/Safety Population