Community Research and Development Information Service - CORDIS


CLOSED Report Summary

Project ID: 602453
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 2 - CLOSED (Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit)

Project Context and Objectives:
The majority of critically ill children admitted to Paediatric Intensive Care Units (PICU) will require sedation and analgesia which is commonly achieved with a combination of a benzodiazepine and an opioid. However, these agents have a significant side-effect profile, including tolerance, withdrawal and respiratory/circulatory depression. Clonidine is commonly used for sedation in PICU and recommended by guidelines in various countries although there is a lack of evidence regarding its safety and efficacy in this setting and therefore used off-label.
The CloSed project aims to fill this gap. As CloSed addresses a vulnerable patient group, i.e. children aged 0 to < 18 years, it is designed to fulfil the requirements for most ethical research in the paediatric population considering risk minimisation for patients, avoiding unnecessary studies and make use of already available data as outlined in the Paediatric Regulation (EC) No 1901/2006.

The objectives of the CloSed project are
a) to develop an age appropriate formulation of clonidine suitable for sedation of children in PICU,
b) to conduct a double blind, randomized, multicentre, active-controlled, parallel group, phase III clinical trial of clonidine vs midazolam in patients from birth to 18 years to establish the efficacy and safety, including long-term outcomes and dose-dependent effects of clonidine,
c) to establish an European consensus guideline for sedation of critically ill children and
d) to obtain a Paediatric Use Marketing Authorisation (PUMA) for clonidine for sedation of paediatric patients in the intensive care unit.

Project Results:
During the first 18 months of the project, the CloSed Consortium finalised the clinical study protocol (CSP), the IB and the IMP Dossiers (IMPDs), while work on the eCRF was well advanced. The dosing schedules for clonidine and midazolam were established, IMP drug concentrations were decided and appropriate IMP formulations developed. Stability data generation was on-going and available for 6 months. The label booklet was finalised and translated into local languages, and import and export documents were developed. The SOP system devised and an audit programme drafted.
A master submission package was developed and submission to the regulatory and ethical authorities in The Netherlands had been carried out and regulatory approval of the CTA obtained. The CTA had also been submitted to the German CA.
A PIP modification based on the finalised CSP was submitted to the PDCO.
Training of nurses has been carried out in all participating centres on the use of the COMFORT Behaviour scale (COMFORT-B). A website ( addressing the COMFORT assessment with further support was created.
The CloSed project website ( was also set up and the site regularly updated.
The main activities related to the first 18 months of the project were completed with some delays, mainly due to the complexity of the clinical study and its procedures. Nevertheless, most of the deliverables and milestones foreseen for the period have been completed and successfully achieved.

Whereas during the first 18 months the focus was on setting up the project and finalising the CSP, the main focus during the second period was on opening the study sites and commence recruitment. Finalisation of submission packages to Competent Authorities (CAs) and Ethics Committees (ECs) continued, and by the end of the reporting period, Ethics submissions to all involved study sites had been carried out. In The Netherlands, Germany and Italy the Clinical Trial Applications are finalised. In the framework of this reporting period, the eCRF was finalised and additional data for quality aspects of the IMP were generated. Import/export of the IMP continued to be tackled.
During the setup of the first site and after initial screening experiences, the need for an amendment of the clinical study protocol (CSP) was identified and tackled. The CloSed Consortium prepared two CSP amendments and updated the corresponding study documents and submissions.
The modified Paediatric Investigation Plan (PIP), submitted during the first reporting period, was agreed with the EMA PDCO.
150 patients were screened with four patients eligible and one patient recruited. Continuous efforts to widen the patient population will be a focus during the next implementation period.
The CloSed project website continues to be updated with news and information about the project.
The activities of this reporting period underwent delays, mainly due to longer-than-expected submission processes and slow recruitment of patients. Nevertheless, almost all deliverables and milestones foreseen for the period have been completed and successfully achieved.

Potential Impact:
The final goal of the CloSed project is to generate sufficient quality, efficacy and safety data to apply for a Paediatric Use Marketing Authorisation (PUMA). On this basis, a PIP agreed by the PDCO at the EMA is already in place.
Furthermore, a European consensus guideline for sedation of critically ill children will be established incorporating the findings from the CloSed trial.

Ultimately, the project is also aimed to increase the availability of paediatric medicines, foster the conduct of clinical trials in children and to establish international paediatric research collaborations.

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