Pharmacokinetic Study of Deferiprone in Paediatric Patients

NCT01740713 | Completed Phase 2 Results

• 1 other identifier: DEEP-1
• Study Type: interventional
• Target: 23
• Locations: 3 countries
• Sites: 7

Brief Summary

Deferiprone (DFP) is the most extensively studied oral iron chelator to date. It has been authorised in Europe in 1999 for the treatment of iron overload in patients with beta-thalassaemia major when DFO is contraindicated or inadequate. Despite a wide experience of DFP there are limited experimental data available on DFP in children and no pharmacokinetic data in children under 6 years of age. On the basis of the existing data in adults and adolescent, in the DEEP-1 trial a pharmacokinetic bridging model was developed to support the dose selection in children aged less than 6 years affected by transfusion dependent haemoglobinopathies. The study consisted of two phases, namely an experimental phase, during which patients received a single dose and a modeling phase, during which PK data obtained after single dose in patients \< 6 years of age were analysed in conjunction with historical PK data in adults and older children and adolescents. The model-based analysis of the data obtained after single dose enabled the assessment of the dosing regimen required for the purpose of accurate pharmacokinetic bridging. The ratio between the predicted systemic exposure parameters (AUC and Cmax) in the target population and reference group were used as basis for recommendation of the dose in the target population.

Conditions

Chronic Iron Overload

Keywords

chronic iron overload; hereditary haemoglobinopathy; beta thalassaemia major

Outcome Measures

Primary Outcomes (8)

• CL/F

  Plasma clearance after oral administration. The parameter was estimated through a population pharmacokinetic model, during which concentration data obtained after single oral dose ( at 3 dose levels) of DFP in patients aged from 1 month to less than 6 years of age.

  Day 1 of single dose treatment (6 sampling time range: from predose up to 8h post first administration)

• AUC (0-8h)

  Area under concentration versus time curve from 0 to 8 h post dosing. Secondary pharmacokinetic parameter derived on the basis of the individual predicted concentration vs. time profiles, through the pop-PK model.

  Day 1 of single dose treatment (6 sampling time range: from predose up to 8h post first administration)

• V/F

  volume of distribution after oral administration. The parameter was estimated through a population pharmacokinetic model, during which concentration data obtained after single oral dose ( at 3 dose levels) of DFP in patients aged from 1 month to less than 6 years of age

  Day 1 of single dose treatment (6 sampling time range: from predose up to 8h post first administration)

• Tmax

  Time at which the maximum concentration (Cmax) is reached. Secondary pharmacokinetic parameters such as Cmax, Min, Tmax, Css and AUC (0-8h) were derived based on the individual predicted concentration vs. time profiles.

  Day 1 of single dose treatment (6 sampling time range: from predose up to 8h post first administration)

• Ka

  Absorption rate constant. The parameter was estimated through a population pharmacokinetic model, during which concentration data obtained after single oral dose ( at 3 dose levels) of DFP in patients aged from 1 month to less than 6 years of age.

  Day 1 of single dose treatment (6 sampling time range: from predose up to 8h post first administration)

• Cmax

  Maximum concentration reached in plasma. Secondary pharmacokinetic parameter derived on the basis of the individual predicted concentration vs. time profiles, through the pop-PK model.

  Day 1 of single dose treatment (6 sampling time range: from predose up to 8h post first administration)

• Css

  Plasma concentration reached at steady state. Secondary pharmacokinetic parameter derived on the basis of the individual predicted concentration vs. time profiles, through the pop-PK model.

  Day 1 of single dose treatment (6 sampling time range: from predose up to 8h post first administration)

• Cmin

  Minimum plasma concentration. Secondary pharmacokinetic parameter derived on the basis of the individual predicted concentration vs. time profiles, through the pop-PK model.

  Day 1 of single dose treatment (6 sampling time range: from predose up to 8h post first administration)

Secondary Outcomes (1)

• Adverse Events

  from drug administration up to 8 days post treatment

Study Arms (3)

Deferiprone, dose level 1

EXPERIMENTAL

single dose level of 8.3 mg/kg every 8 hours for a corresponding total daily dose of 25 mg/kg/day.

Drug: Deferiprone, dose level 1

Deferiprone, dose level 2

EXPERIMENTAL

single dose level of 16.7 mg/kg every 8 hours for a corresponding total daily dose of 50 mg/kg/day.

Drug: Deferiprone, dose level 2

Deferiprone, dose level 3

EXPERIMENTAL

single dose level of 33.3 mg/kg every 8 hours for a corresponding total daily dose of 100 mg/kg/day.

Drug: Deferiprone, dose level 3

Interventions

Deferiprone, dose level 1 DRUG

a solution at 80 mg/mL will be administered orally

Also known as: DFP

Deferiprone, dose level 1

Deferiprone, dose level 2 DRUG

a solution at 80 mg/mL will be administered orally

Also known as: DFP

Deferiprone, dose level 2

Deferiprone, dose level 3 DRUG

a solution at 80 mg/mL will be administered orally

Also known as: DFP

Deferiprone, dose level 3

Eligibility Criteria

• Age: 1 Month - 6 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients in a chronic transfusional program who have received at least 150 ml/kg/year of packed red blood cells (corresponding approximately to 12 transfusions) and on current treatment with DFO, DFX, DFP; aged from 1 month to less than 6 years; or
• Patients naïve to any chelation treatment who have received not less than 150 ml/kg of packed red blood cells (corresponding to approximately 12 transfusions) and have ferritin levels \> 800 ng/mL, aged from 1 month to less than 6 years; or
• Patients who meet the transfusion criteria (150 ml/kg/year corresponding approximately to 12 transfusions) and have known intolerance or contraindication to DFO
• And if all of the following criteria apply:
• Patients affected by any hereditary haemoglobinopathies requiring chronic transfusion therapy including but not limited to thalassaemia and sickle cell disease
• Written informed consent obtained from their legal guardian on the patient's behalf in accordance with the national legislations. According to his/her capability, patient's informed assent will be collected

You may not qualify if:

• Patient with known intolerance or contraindication to the trial treatment
• Patient with Hb levels less than 8g/dl (entry may be delayed until values return to normal)
• Patient with platelet count \<100.000/mm3 or absolute neutrophil count \<1.500/mm3 (entry may be delayed until values return to normal)
• Patient with evidence of abnormal liver function (ALT level \>5 times the upper normal limit during six months preceding enrolment; entry may be delayed until values return to normal)
• iron overload from causes other than transfusional haemosiderosis
• severe heart dysfunction secondary to iron overload defined as the occurrence of heart failure or severe arrhythmia or as indicated by cardiac T2\* lower than 10 ms, if recent MRI data is available,
• Patient with serum creatinine level above the upper normal limit at screening; entry may be delayed until values return to normal.
• Serological evidence of chronic hepatitis B (presence of HBe Ag, HBsAg, HBcAb-IgM, in the absence of HBsAb).
• History of significant medical or psychiatric disorder that may impair compliance with the requirements of the protocol.
• The patient has received another investigational drug within 30 days prior to this study.
• Patient with a pre-existing condition or any other surgical or medical condition which might significantly interfere with normal gastrointestinal and hepatic function that could alter the absorption, metabolism, and/or excretion of the study drug.
• Patient with a known history of HIV seropositivity.
• Fever and other signs/symptoms of infection in the 10 days before drug administration(treatment day)
• Concomitant use of other iron chelators or trivalent cation-dependent medicinal products such as aluminium-based antacids.
• Patient with a chronic condition that does not allow suspension of related treatment from starting of washout until drug is administered.

Sponsors & Collaborators

• Consorzio per Valutazioni Biologiche e Farmacologiche: lead
• European Commission: collaborator

Study Sites (7)

Department of Medical and Public Health Services of the Ministry of Health

Nicosia, Cyprus

Location

Cairo Univesity Paediatric Hospital

Cairo, Egypt

Location

Azienda Ospedaliero-Universitaria Consorziale

Bari, Bari, 70124, Italy

Location

Azienda Ospedaliera Antonio Cardarelli

Napoli, Napoli, 80131, Italy

Location

Azienda Ospedaliera Di Padova

Padua, Padova, 35127, Italy

Location

Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello

Palermo, Palermo, 90146, Italy

Location

Clinica Pediatrica Universita' - Asl 1

Sassari, Sassari, 07100, Italy

Location

MeSH Terms

Conditions

beta-Thalassemia

Interventions

Deferiprone; Isoflurophate

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Pyridones; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Organofluorophosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Results Point of Contact

• Title: Clinical Research Coordinator
• Organization: Consorzio per Valutazioni Biologiche e Farmacologiche

mariagraziafelisi@cvbf.net

0039 0382 25075

Study Officials

• Oscar Della Pasqua

  Universiteit Leiden, The Netherlands

  STUDY CHAIR

• Giovanni Carlo Del Vecchio

  Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Italy

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 28, 2012
• First Posted: December 4, 2012
• Study Start: December 1, 2012
• Primary Completion: December 1, 2013
• Study Completion: February 1, 2014
• Last Updated: January 11, 2017
• Results First Posted: January 11, 2017

Record last verified: 2016-11

Locations

EG (1); CY (1); IT (5)