DEEP-2 is a multi-centre, randomised, open-label, non-inferiority active-controlled efficacy-safety trial involving paediatric patients from 1 month to less than 18 years affected by transfusion-dependent haemoglobinopathies (DEEP-2; EudraCT 2012–000353-31; NCT01825512) performed according to a Paediatric Investigation Plan (PIP) agreed by PDCO (P/0357/2016).

The study was part of the EU funded project “DEferiprone Evaluation in Paediatrics” (DEEP, FP7 HEALTH-F4-2010-261483) coordinated by CVBF, also acting as a Sponsor of the study. The DEEP-2 Trial Leader, and CVBF CEO, Donato Bonifazi said that “The study showed that deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment in paediatric patients with transfusion-dependent haemoglobinopathies. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group.”

In particular, the study intended to investigate the changes in terms of ferritin levels and cardiac iron concentration in order to assess the non-inferiority of deferiprone compared to deferasirox in paediatric patients affected by hereditary haemoglobinopaties requiring chronic transfusions and chelation. Overall, the study provided evidence to support the use of DFP in paediatric patients.

As explained also in the article, patients with thalassaemia cannot produce normal haemoglobin and regular blood transfusions are the only treatment available. Nevertheless, iron overload is inevitable, and the use of iron chelator is needed to remove the excess of iron from the blood.

The oral iron chelator deferiprone was authorized in Europe on August 1999 and is currently indicated for the treatment of iron overload in patients with B-thalassemia major when deferoxamine (DFO) is contraindicated or inadequate. Deferiprone is considered very effective in adult patients, although a scarcity in the number of clinical studies in the paediatric population discourages the use in children.

The article published on the EC website underlined the wide efforts and the numerous resources spent by the researchers working in the framework of the DEEP project in order to provide evidence confirming the correct dosage of Deferiprone (DFP) for use in children (DEEP-1 PK study results) and develop a new oral liquid formulation of DFP suitable for the paediatric use.

In particular, the European Commission’s DG Research and Innovation has particularly appreciated the international cooperation aspect characterizing the project. In particular, the collaboration with the Egyptian partner of the DEEP Consortium has been highlighted and a quote of Amal El-Beshlawy, professor at the University of Cairo and chair of the Egyptian Thalassemia Association, regarding the huge relevance of the project and the importance of a global cooperation, has been reported.

The complete article is available at this link.

The DEEP Project has been developed with the specific intent to integrate the existing information on deferiprone use in paediatric patients, thus covering the lack of information and providing a valid support to the use of the drug in this class of age. The aim of DEEP is to provide data on deferiprone pharmacokinetics in younger children, to evaluate the safety of deferiprone in the clinical setting through a long-term observational study and to generate new comparative efficacy/safety data to be used to grant a Marketing Authorisation (MA) of a new liquid formulation of the drug, specifically developed for children use.

The project consisted of three studies, DEEP-1 (PK), DEEP-2 (efficacy and safety) and DEEP-3 (long-term safety).

The DEEP-1 was a multi-centre, oral single dose experimental and modelling study to evaluate the pharmacokinetics of deferiprone in patients under 6 years of age affected by transfusiondependent haemoglobinopathies (NCT01740713, clinicaltrials.gov). It was concluded in 2014, providing scientific evidence that the dosage per kilogram of deferiprone used in adults and older children can provide sufficient exposure to ensure efficacy also in younger children. These results allowed children aged under 6 years to start to be recruited in DEEP-2 Safety/Efficacy Study.

The DEEP-2 was a phase III multicentre, randomised, open label, non-inferiority active-controlled trial aiming at comparing the efficacy, in terms of changes of serum ferritin levels and cardiac iron overload, of deferiprone versus deferasirox in paediatric patients affected by hereditary haemoglobinopathies, requiring chronic transfusions and chelation (NCT01825512, clinicaltrials.gov). It has involved 393 randomized patients with the first patient first visit (FPFV) in January 2015 and the last patient last visit (LPLV) in September 2017.

The DEEP-3 was a long-term observational safety study which evaluated the nature and incidence of adverse effects of deferiprone in children and adolescents with beta-thalassaemia major. Started in 2013, and ended in October 2015, with 297 patients enrolled in the study, it confirmed that the safety profile of deferiprone in children and adolescents is in accordance with the available data in adults.

The meeting held at Hilton hotel and has gathered all the DEEP-2 investigators that have worked hard to solve all the pending issues for the database lock.

The meeting has been organized on occasion of the Rare Disease Day 2018, organized by EURORDIS to raise awareness of rare diseases and their impact on patients’ lives amongst the general public and decision-makers.  The Rare Disease Day has taken place every year since 2008, to call upon researchers, universities, students, companies, policy makers and clinicians to do more research and to make them aware of the importance of research for the rare diseases community.

DEEP considers the promotion and the coordination of research extremely important for health care system, and particularly for Rare Diseases, since they represent the tools to speed up the achievements in research and benefits for patients.

Botzenhardt’s thesis comprises three parts. The first part is a systematic literature review with meta-analyses of published safety data of DFO, DFP, DFX and combination regimens in young patients aged under 25 years with transfusion-dependent haemoglobinopathies. The second part is a retrospective observational cohort study using population-based data from an electronic health record database in Hong Kong. Diagnosis codes, hospital admission data and laboratory results of Chinese thalassaemia patients under the age of 18 years were utilised to identify potential adverse effects (AEs). The third part coincides with the DEEP-3 observational safety study: a multi-national, retro- and prospective cohort study investigating the long-term safety of DFP treatment in paediatric patients aged under 18 years from the Mediterranean region. Medical patient data and possible AEs to DFP were collected between 2012 and 2016 from 16 thalassaemia centres in Albania, Cyprus, Egypt, Greece, Italy and Tunisia. The coordinating centre was the “Azienda Ospedaliera di Padova – AODP”.

Overall, the data collected in these studies highlighted that the safety profile of DFP in children and adolescents obtained from the systematic literature review and the two pharmacoepidemiology studies is in accordance with the latest information in SPCs (Summary of Products Characteristics) and manufacturer post-marketing data. Moreover, there was no evident increased risk for ADRs in children under the age of 10 years or in patients with combined therapy with DFO. The risk for agranulocytosis in children treated with DFP is comparable to older patients.

DEEP (Deferiprone Evaluation in Paediatrics) is funded EU-funded project aimed to investigate safety and efficacy of deferiprone in children and adolescences from the Mediterranean region affected by beta-thalassemia major.

An early iron chelation therapy is crucial in the treatment of the beta-thalassemia major to avoid complication related to the chronic transfusional iron overload. Deferiprone is an iron chelator that showed a superior efficacy in reducing cardiac iron, especially in combination with deferoxamine. Notwithstanding, utilization in children is still limited since studies in paediatric patients are rare.

DEEP-3 is a multi-center, retro- and prospective, non-interventional cohort study aimed to investigate the long-term safety of deferiprone therapy alone and in combination with deferoxamine. The study was conducted in 16 hospitals in six Mediterranean countries between November 2012 and April 2016 – Albania (1), Cyprus (1), Egypt (1), Greece (1), Italy (11) and Tunisia (1) – to assess the nature and incidence of serious and non-serious adverse drug reactions (ADR) to deferiprone and potential risk factors for ADRs and deferiprone withdrawals. Patients treated with deferiprone were followed up throughout their treatment, from its start up to the end of the study or the patient’s withdrawal.

The authors concluded that the safety profile of deferiprone in children and adolescents is in accordance with the available data in adults and no unexpected ADRs were observed. However, agranulocytosis was also present in this paediatric population. Arthropathy, including arthralgia and swelling, mostly in the knee joints, was the most common ADR and needs to be closely monitored.

The full publication is available at the following link: http://www.haematologica.org/content/103/1/e1.long

DEEP is a EU-funded project, developed under the TEDDY umbrella, involving EU and non-EU countries (Albania, Egypt, Tunisia), aimed to study deferiprone in children affected by congenital anaemias requiring chronic transfusion therapy and iron chelation, such as the β-thalassaemia major and the Sickle Cell Disease (SCD), and develop a new formulation suitable for children. To this aim, the project performed three multi-national paediatric studies involving more than 700 paediatric patients, 23 clinical sites and 16 partners.

In the framework of the DEEP project, the QuBo study has been performed with the aim to investigate the quality, the comprehensibility and the likeability of the informative booklets for patients involved in the DEEP-2 trial, an efficacy and safety trial to compare deferiprone versus deferasirox in 388 paediatric patients aged 1 month < 18 years from Mediterranean area countries.  In particular, three informative booklets and two ad hoc assent forms to empower DEEP-2 minor patients were prepared for different ages in six languages thanks to a collaborative effort involving pharmacologists, paediatricians, child psychologists and illustrators, in an easy-to-manage format, a charming graphic including picture, a simple vocabulary and sentences structures.

Two age-tailored questionnaires were developed in the QuBo study and distributed to the patients involved in the trial. The QuBo pilot study has been carried out in Albania and in Italy and has demonstrated that the use of informative booklets in DEEP-2 trial has been appreciated by children and adolescents and has favoured the understanding and participation of children in the clinical trial. As general recommendation, it has highlighted the need to consider children and families’ active participation as a fundamental step to reach consensus and compliance to treatments.

For further information, you can find the poster here.

DEEP project is glad to support The Rare Disease Day 2018, that will take place on the last day of February 28^th, to raise awareness of rare diseases and their impact on patients’ lives amongst the general public and decision-makers. The Rare Disease Day was first launched by EURORDIS and its Council of National Alliances in 2008, but soon this initiative spread all over the world involving 94 countries in 2017.

A disease is defined as rare in Europe when it affects fewer than 1 out of 2000 and the 50% of rare diseases affect children. Patients with rare diseases often face many challenges, from delay in diagnosis to the absence of adequate treatments, which result in heavy social and financial burdens on patients and their families. Nevertheless, enormous progresses have been made in the last years thanks to the international cooperation in the field of clinical and scientific research as well as to the sharing of scientific knowledge about all rare diseases.

Therefore, it is important to continue along this pathway to further support rare disease patients and their families. To this aim, the Rare Disease Day has taken place every year since 2008, to call upon researchers, universities, students, companies, policy makers and clinicians to do more research and to make them aware of the importance of research for the rare diseases community.

DEEP considers the promotion and the coordination of research extremely important for health care system, and particularly for Rare Diseases, since they represent the tools to speed up the achievements in research and benefits for patients.

For this tenth edition of the Rare Disease Day, a special attention will be paid to the crucial role that patients play in research. Patient involvement in research has resulted in more research, which is better targeted to the needs of patients.

When it comes to consider patient involvement in the paediatric field, more challenges have to be faced. To this aim, within the DEEP project, age-tailored information booklets and videos have been developed to inform the participant children on the study objectives and procedures with a language and a wording appropriate to their age, psychological and intellectual maturity.

Therefore, the DEEP Project welcomes this initiative and joins to the Rare Disease Day community becoming a friend of Rare Disease Day and showing its support on its official website and social networks.

For further information on the Rare Disease Day visit the following website: https://www.rarediseaseday.org/