Sedation in Intensive CarePhase 3CloSed1NCT02509273
Efficacy, Safety and Pharmacokinetic Study of Intravenous Clonidine Versus Midazolam for Sedation in Paediatric Patients
A Phase 3 study testing Clonidine and Midazolam in people with Sedation in Intensive Care, run by University of Erlangen-Nürnberg Medical School at 10 sites in 7 countries.
Trial summary
Closed1 aims to compare the efficacy, safety and pharmacokinetics of clonidine (hydrochloride) to midazolam in the sedation of ventilated children and adolescents (0-18 years) admitted to a paediatric intensive care unit (PICU) and requiring mechanical ventilation and sedation for at least 24 hours. Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Sedation in Intensive Care
- What is being tested?
- Clonidine and Midazolam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 10 sitesin 7 countries
- Study dates
- May 2016to 22 Oct 2018
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Male or Female
- Aged from birth (≥34 weeks gestational age [GA]) to <17 years, 11 months, 1 week old
- Admitted or expected to be admitted (post-operatively) to PICU
- Existing or expected indication for invasive or non-invasive ventilation (except Continuous Positive Airway Pressure, CPAP)
- Anticipated need for continuous sedation for at least 24 hours
- Informed consent (or deferred consent) obtained from the subject's parent(s) or legal guardian(s)
- Where applicable, assent obtained from the subject to participate in the clinical trial
Who cannot join
- Body weight less than 1500 g
- Gestational age [GA] of <34 weeks
- Body weight 3 kg or less AND aged 28 days or older
- Body weight less than 10 kg AND aged 2 years old or older
- Body weight greater than 85 kg
- Subjects who will be 18 years old in less than 3 weeks
Show all 22Show fewer
- Known hypersensitivity to the IMP (clonidine) or comparator (midazolam), or Non Investigational Medicinal Product (morphine, propofol) or any of their formulation ingredients and their rescue medication
- Subjects anticipated to be treated with forbidden concomitant medications during IMP administration
- Subjects less than 24 hours post-resuscitation
- Subjects who have been under sedation for more than 72 hours immediately prior to assessment
- Subjects currently being treated with Extra Corporeal Membrane Oxygenation (ECMO)
- Subjects with treatment-induced whole body hypothermia
- Subjects with severe organ insufficiencies
- Subjects whose condition is assessed by the investigator to have an effect on the level of consciousness which impairs the assessment of sedation (COMFORT-B/NISS)
- Subjects with phaeochromocytoma
- Subjects with severe bradyarrhythmia resulting from either sick-sinus syndrome or atrioventricular (AV) block of 2nd or 3rd degree
- Known arterial hypertension requiring chronic treatment in medical history
- Females who are pregnant, lactating or planning to become pregnant or who return a positive result to a urine pregnancy test (a dipstick and serum pregnancy test will be performed at the screening visit).
- Employee or direct relative of an employee or any member of the study site staff or the Sponsor/ study management staff (applies to subject and/ or subject's parent(s)
- Participation in a clinical intervention study using drugs within the last 3 weeks
- Previous participation in this clinical study at any time
- Parent(s)/ legal guardian(s) decline to give informed consent. If parent(s)/ legal guardian(s) are not present
Trial locations and contacts
10 sites in 7 countries.
10 sites in 7 countries
Italy3 sites
Azienda Ospedaliero Universitaria Policlinico di Bari
Bari, 70124
ARNAS Civico Di Cristina Benfratelli
Palermo, 90127
Bambino Gesù Hospital and Research Institute
Rome, 00165
Germany2 sites
University of Erlangen-Nürnberg Medical School
Erlangen, 91054
Diakonie Neuendettelsau - Cnopf'sche Kinderklinik Nürnberg
Nuremberg
Netherlands1 site
Erasmus Medical Center
Rotterdam, South Holland, 3015 CN
About this study
Official title: A Double Blind, Randomised, Multicentre, Active Controlled, Parallel-group, Phase III Trial to Evaluate the Efficacy, Safety and Pharmacokinetics of Intravenous Clonidine (Hydrochloride) Compared to Midazolam for Sedation in Children From Birth to Less Than 18 Years of Age
Closed1 aims to compare the efficacy, safety and pharmacokinetics of clonidine (hydrochloride) to midazolam in the sedation of ventilated children and adolescents (0-18 years) admitted to a paediatric intensive care unit (PICU) and requiring mechanical ventilation and sedation for at least 24 hours.
In particular, the proportion of subjects with sedation failure at the maximum possible dose (defined within the study protocol) will be measured. Additionally, the safety and tolerability (including withdrawal effects) of clonidine compared to midazolam will be evaluated. A pharmacokinetic-pharmacodynamic relationship of clonidine for sedation in PICU will be established. Genetic polymorphisms of clinical relevance affecting pharmacokinetics, pharmacodynamics and metabolism will be also identified.
Read more
Ad hoc paediatric parenteral formulations of clonidine hydrochloride and midazolam will be manufactured. At least 300 subjects will be enrolled from study centres in five European member countries (Czech Republic, Germany, Italy, the Netherlands, and Sweden).
The clinical study will enrol critically ill paediatric patients who require mechanical ventilation and sedation.
Subjects will be closely followed using standard PICU monitoring of vital functions (continuous assessment of heart rate and peripheral arterial oxygen saturation, intermittent assessment of systolic and diastolic blood pressure), intermittent assessment of pain and depth of sedation, documentation of parameters of mechanical ventilation and intermittent arterial blood gas analysis.
The study will be conducted in compliance with the study protocol, Good Clinical Practice (ICH-GCP) and the applicable regulatory requirement(s). In addition, qualified PICU staff will be monitoring subjects around the clock, thus minimising reaction time in case of alarms or deterioration of clinical parameters.
This project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement n° 602453.
- Conditions
- Sedation in Intensive Care
- Being tested
- Clonidine, Midazolam
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ClonidineDrug
MidazolamDrug
| Study group | Role | What they receive |
|---|---|---|
| CLONIDINE HYDROCHLORIDE | Experimental | solution for i.v. infusion (maximum 55 μg/kg per day; maximum 7 day treatment) Receives: Drug: Clonidine |
| MIDAZOLAM | Active comparator | solution for i.v. infusion (maximum 5.5 mg/kg per day; maximum 7 day treatment) Receives: Drug: Midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Sedation failure
measured by pain score Numerical Rating Scale (NRS), sedation score COMFORT-B and sedation score Nurse's Interpretation of Sedation (NISS)
Measured: ≤ 7 days
Secondary outcomes (7)
Pharmacokinetics/Pharmacodynamics (PKPD) modeling (measured by plasma concentrations and sedation score results (COMFORT-B)
measured by plasma concentrations and sedation score results (COMFORT-B)
Measured: ≤ 7 days treatment period
Safety assessment (number of patients with adverse events)
measured by number of patients with adverse events
Measured: ≤ 21 ± 2 days (treatment period, completion visit, post dose monitoring and follow-up visit) in all subjects
Extent of withdrawal effects
measured by score Sophia Observation Withdrawal Symptoms-Paediatric Delirium (SOS-PD)
Measured: post dose ≥ 1 day, ≤ 5 days
Extent of rebound hypertension
measured by blood pressure assessment for at least 72 hours after IMP cessation
Measured: post dose ≥ 3 days, ≤ 5 days
Percentage of respiratory depression per group
Number of reintubations / number extubation failures ratio %
Measured: during re-intubation apnoea in treatment period (≤ 7 days), post dose monitoring every 24 hours up to 10 days
Neurodevelopment (Bayley Scales of Infant Development, Second Edition (Bayley-II) score)
Bayley Scales of Infant Development, Second Edition (Bayley-II) score
Measured: 1 year (in neonates only)
Pharmacogenomic assessment (measured by plasma concentrations and candidate gene polymorphisms/genotyping)
measured by plasma concentrations and candidate gene polymorphisms/genotyping
Measured: On 1 day of treatment period (≤7 days) only
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2015 (estimated)
- Study startMay 2016
- Primary completionOct 2018
- Study completion22 Oct 2018
Why it stopped: lack of recruitment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Sedation in Intensive CareStudies of the same condition, open and under way.
- More trials run by University of Erlangen-Nürnberg Medical SchoolThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Erlangen-Nürnberg Medical School
- Sponsor type
- University, hospital or other
- Collaborators
- Erasmus Medical Center, University of Tartu, Therakind Ltd, Gianni Benzi Pharmacological Research Foundation, University College, London, Karolinska Institutet, Univerzita Karlova v Praze, Vereniging Samenwerkende Ouder- En Patientenorganisaties, Bambino Gesù Hospital and Research Institute, European Commission, ARNAS Civico Di Cristina Benfratelli Hospital, Servicio Madrileño de Salud, Madrid, Spain
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02509273
- Sponsor's protocol ID
- CLON01
- Other IDs
- 2014-003582-24, 2014
- Acronym
- CloSed1
- Status last verified
- Jan 2019
- First submitted
- 27 Apr 2015
- Last updated
- 9 Jan 2019
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
Neubert A, Baarslag MA, Dijk MV, Rosmalen JV, Standing JF, Sheng Y, Rascher W, Roberts D, Winslade J, Rawcliffe L, Hanning SM, Metsvaht T, Giannuzzi V, Larsson P, Pokorna P, Simonetti A, Tibboel D; CLOSED Consortium. The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial. BMJ Open. 2017 Jun 21;7(6):e016031. doi: 10.1136/bmjopen-2017-016031.
PubMed 28637741
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double Blind, Randomised, Multicentre, Active Controlled, Parallel-group, Phase III Trial to Evaluate the Efficacy, Safety and Pharmacokinetics of Intravenous Clonidine (Hydrochloride) Compared to Midazolam for Sedation in Children From Birth to Less Than 18 Years of Age
- ClinicalTrials.gov ID
- NCT02509273
- Acronym / sponsor ID
- CloSed1 / CLON01
- Conditions
- Sedation in Intensive Care
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: lack of recruitment
- Enrolment
- 28 participants (actual)
- Lead sponsor
- University of Erlangen-Nürnberg Medical SchoolUniversity, hospital or other
- Collaborators
- Erasmus Medical Center, University of Tartu, Therakind Ltd, Gianni Benzi Pharmacological Research Foundation, University College, London, Karolinska Institutet, Univerzita Karlova v Praze, Vereniging Samenwerkende Ouder- En Patientenorganisaties, Bambino Gesù Hospital and Research Institute, European Commission, ARNAS Civico Di Cristina Benfratelli Hospital, Servicio Madrileño de Salud, Madrid, Spain
- Study start
- May 2016 (actual)
- Primary completion
- Oct 2018 (actual)
- Study completion
- 22 Oct 2018 (actual)
- First posted
- 28 Jul 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Closed1 aims to compare the efficacy, safety and pharmacokinetics of clonidine (hydrochloride) to midazolam in the sedation of ventilated children and adolescents (0-18 years) admitted to a paediatric intensive care unit (PICU) and requiring mechanical ventilation and sedation for at least 24 hours.
In particular, the proportion of subjects with sedation failure at the maximum possible dose (defined within the study protocol) will be measured. Additionally, the safety and tolerability (including withdrawal effects) of clonidine compared to midazolam will be evaluated. A pharmacokinetic-pharmacodynamic relationship of clonidine for sedation in PICU will be established. Genetic polymorphisms of clinical relevance affecting pharmacokinetics, pharmacodynamics and metabolism will be also identified.
Ad hoc paediatric parenteral formulations of clonidine hydrochloride and midazolam will be manufactured. At least 300 subjects will be enrolled from study centres in five European member countries (Czech Republic, Germany, Italy, the Netherlands, and Sweden).
The clinical study will enrol critically ill paediatric patients who require mechanical ventilation and sedation.
Subjects will be closely followed using standard PICU monitoring of vital functions (continuous assessment of heart rate and peripheral arterial oxygen saturation, intermittent assessment of systolic and diastolic blood pressure), intermittent assessment of pain and depth of sedation, documentation of parameters of mechanical ventilation and intermittent arterial blood gas analysis.
The study will be conducted in compliance with the study protocol, Good Clinical Practice (ICH-GCP) and the applicable regulatory requirement(s). In addition, qualified PICU staff will be monitoring subjects around the clock, thus minimising reaction time in case of alarms or deterioration of clinical parameters.
This project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement n° 602453.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| CLONIDINE HYDROCHLORIDE | Experimental | Drug: Clonidinesolution for i.v. infusion (maximum 55 μg/kg per day; maximum 7 day treatment) |
| MIDAZOLAM | Active comparator | Drug: Midazolamsolution for i.v. infusion (maximum 5.5 mg/kg per day; maximum 7 day treatment) |
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (7 listed)
- Male or Female
- Aged from birth (≥34 weeks gestational age [GA]) to <17 years, 11 months, 1 week old
- Admitted or expected to be admitted (post-operatively) to PICU
- Existing or expected indication for invasive or non-invasive ventilation (except Continuous Positive Airway Pressure, CPAP)
- Anticipated need for continuous sedation for at least 24 hours
Key exclusion criteria (22 listed)
- Body weight less than 1500 g
- Gestational age [GA] of <34 weeks
- Body weight 3 kg or less AND aged 28 days or older
- Body weight less than 10 kg AND aged 2 years old or older
- Body weight greater than 85 kg
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Clonidine | Drug | CLONIDINE HYDROCHLORIDE |
| Midazolam | Drug | MIDAZOLAM |
Primary outcome
Sedation failure
Time frame: ≤ 7 days
measured by pain score Numerical Rating Scale (NRS), sedation score COMFORT-B and sedation score Nurse's Interpretation of Sedation (NISS)
7 secondary outcomes
Pharmacokinetics/Pharmacodynamics (PKPD) modeling (measured by plasma concentrations and sedation score results (COMFORT-B)
Time frame: ≤ 7 days treatment period
Safety assessment (number of patients with adverse events)
Time frame: ≤ 21 ± 2 days (treatment period, completion visit, post dose monitoring and follow-up visit) in all subjects
Extent of withdrawal effects
Time frame: post dose ≥ 1 day, ≤ 5 days
Extent of rebound hypertension
Time frame: post dose ≥ 3 days, ≤ 5 days
Percentage of respiratory depression per group
Time frame: during re-intubation apnoea in treatment period (≤ 7 days), post dose monitoring every 24 hours up to 10 days
Neurodevelopment (Bayley Scales of Infant Development, Second Edition (Bayley-II) score)
Time frame: 1 year (in neonates only)
Pharmacogenomic assessment (measured by plasma concentrations and candidate gene polymorphisms/genotyping)
Time frame: On 1 day of treatment period (≤7 days) only
Results and safety
The study was stopped early (reason given: lack of recruitment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2019.
- Derived from this study: PubMed 28637741Neubert A, Baarslag MA, Dijk MV, Rosmalen JV, Standing JF, Sheng Y, Rascher W, Roberts D, Winslade J, Rawcliffe L, Hanning SM, Metsvaht T, Giannuzzi V, Larsson P, Pokorna P, Simonetti A, Tibboel D; CLOSED Consortium. The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial. BMJ Open. 2017 Jun 21;7(6):e016031. doi: 10.1136/bmjopen-2017-016031.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
10 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Clonidine and Midazolam in people with Sedation in Intensive Care, run by University of Erlangen-Nürnberg Medical School at 10 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 9 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Italy, Germany, Czechia, Estonia, Netherlands and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: lack of recruitment). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Sedation failure (time frame: ≤ 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02509273, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2019.