Community Research and Development Information Service - CORDIS

Periodic Report Summary 3 - 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 and
c) to establish an European consensus guideline for sedation of critically ill children.
The ultimate goal is to use these data and to apply for a Paediatric Use Marketing Authorisation (PUMA).
Project Results:
M1-18
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 has been 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 (www.comfortassessment.nl) addressing the COMFORT assessment with further support was created.
The CloSed project website (www.closed-fp7.eu) 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.

M19-36
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 commencing 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.
During the set up 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. The introduction of a series of new aspects in the CSP subsequently led to the update of the Paediatric Investigation Plan (PIP) and the modified PIP was agreed with the EMA PDCO. Additional data for quality aspects of the IMP were generated.
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 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.

M37-54
Whereas during the first 18 months the focus was on setting up the project and finalising the CSP and the second 18 months primarily tackled the activities of opening the study sites and commencing recruitment, the Consortium focused on two main objectives during the third Reporting Period:
1. continuous recruitment and finalisation of remaining site set up activities and
2. the implementation of mitigating measures (identification and set up of additional study sites, CSP amendments to improve slow recruitment, etc.) to overcome slow recruitment and widen the patient population.
SOPs/SSPs are fully issued. The number of study sites was doubled (from 5 to 10) and all sites obtained regulatory approvals. 8 sites were opened for enrolment and 22 patients were enrolled so far. 2 additional study sites are imminent to be opened. In total, 9 SIV’s were held and the 10th is planned for the very beginning of the 4th Period. A total of 17 monitoring visits were realised and remote monitoring was conducted at least once on all 22 patients recruited to the study. DSMB meetings were held in September 2017 and in February 2018.
During site set up activities, the Consortium was particularly challenged by the different bureaucratic frameworks for obtaining import/export licenses for all involved territories.
The IMP’s shelf-life was extended to 36 months, the Statistical Analysis Plan was updated to version 2.0 and a blinded interim PKPD analysis on the first 6 patients was performed.
In accordance with the new General Data Protection regulation (GDPR), PIS and ICF forms were re-assessed.
The CloSed project website continues to be updated with news and information about the project.
Potential Impact:
The expected final results of the CloSed clinical study are
a) an age appropriate formulation of clonidine suitable for sedation of children in PICU,
b) to obtain pharmacokinetic, efficacy and safety data, including long-term outcomes and dose-dependent effects of clonidine and
c) to establish a European consensus guideline for sedation of critically ill children.
The ultimate goal of the CloSed project is to apply for a PUMA. On this basis, a PIP has been approved by the EMA in February 2013 and an update of this has been submitted to the EMA PDCO in March 2015.
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.
List of Websites:
www.closed-fp7.eu

Reported by

UNIVERSITATSKLINIKUM ERLANGEN
Germany

Subjects

Life Sciences
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