Clinical Trial Results:
Neuroprotection with Dexmedetomidine in patients undergoing elective cardiac or abdominal surgery
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Summary
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EudraCT number |
2013-000823-15 |
Trial protocol |
DE |
Global end of trial date |
30 Jul 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Oct 2020
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First version publication date |
29 Oct 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NEUPRODEX
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02096068 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Charité - Universitätsmedizin Berlin
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Sponsor organisation address |
Charitéplatz 1, Berlin, Germany, 10117
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Public contact |
Univ.-Prof. Dr. C. Spies, Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), +49 30450 551001 , claudia.spies@charite.de
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Scientific contact |
Univ.-Prof. Dr. C. Spies, Department of Anesthesiology and Operative Intensive Care Medicine (CCM/CVK), +49 30450 551001 , claudia.spies@charite.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Jan 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jul 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Incidence of postoperative delirium measured with the Confusion Assessment Method for the ICU (CAM-ICU)“or the „Confusion Assessment Method (CAM) and/or Chart Review and/or DSM V/ICD-10 “
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Protection of trial subjects |
During anesthesia changes of hemodynamic parameters in the intraoperative transoseophageal echocardiography and in the processive electroencephalography and eletromyography were measured. Incidence of adverse events which start after the application of the study drug were evaluated for five postoperative days.
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Background therapy |
Surgical patients received standard of care in the university hospital. | ||
Evidence for comparator |
not applicable, Placebo use | ||
Actual start date of recruitment |
13 Jul 2014
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Scientific research | ||
Long term follow-up duration |
3 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 75
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Worldwide total number of subjects |
75
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EEA total number of subjects |
75
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
17
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From 65 to 84 years |
57
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85 years and over |
1
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Recruitment
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Recruitment details |
Study group: 13.07.2014 - 08.03.2016 (Last study patient in) POCD control group: 17.10.2015 - 20.04.2018 (Last control subject in) | ||||||||||||
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Pre-assignment
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Screening details |
n= 484 patients were screened, n= 421 screening failure (1. n= 49 refused participation; n= 119 did not meet inclusion criteria; 3. other) n= 63 were included. n=3 patients drop-out criteria occurred after inclusion, reasons: 1. one patient refused study participation; 2. received no heart lung machine surgery, 3. emergency operation | ||||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||
Blinding implementation details |
All role members were unblinded after database closure on May 15, 2019.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Verum | ||||||||||||
Arm description |
Experimental: Study group Application of Dexmedetomidine (Dexdor®) perioperatively for a maximum of 48 hours Dosing Scheme: during operation and mechanical ventilation: 0,7μg/kgABW/h; recovery time until extubation: 0,4μg/kgABW/h; after extubation: 0,2-1,4μg/kgABW/h Dexmedetomidine was supplied in a 2 ml ampoule containing 200 μg (100 μg/ml) dexmedetomidine (as a base) for dilution with 48 ml 0.9% sodium chloride injection (giving a solution containing 4 μg/ml) in 50 ml syringe. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Dexdor 100 Mikrogramm/ml
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Investigational medicinal product code |
ATC code N05CM18
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravascular use
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Dosage and administration details |
Dexmedetomidine was supplied in a 2 ml ampoule containing 200 μg (100 μg/ml) dexmedetomidine (as a base) for dilution with 48 ml 0.9% sodium chloride injection (giving a solution containing 4 μg/ml) in 50 ml syringe.
During operation and mechnical ventilation: 0,7μg/kgABW/h
recovery time until extubation: 0,4μg/kgABW/h
after extubation: 0,2-1,4μg/kgABW/h
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Arm title
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Placebo | ||||||||||||
Arm description |
Placebo Comparator: Control group Application of placebo for a maximum of 48 hours Placebo for dexmedetomidine was a 50 ml syringe containing 0.9% sodium chloride isotonic infusion solution/0.9 % sodium chloride injection solution | ||||||||||||
Arm type |
Placebo | ||||||||||||
Investigational medicinal product name |
0.9% sodium chloride isotonic physiological solution
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Investigational medicinal product code |
ATC code: B05BB01
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Placebo for dexmedetomidine was a 50 ml syringe containing 0.9% sodium chloride isotonic infusion solution/0.9 % sodium chloride injection solution
During operation and mechnical ventilation: 0,7μg/kgABW/h
recovery time until extubation: 0,4μg/kgABW/h
after extubation: 0,2-1,4μg/kgABW/h
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Arm title
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Control POCD | ||||||||||||
Arm description |
No Intervention: POCD (postoperative cognitive deficit) control group A non-surgical control group of 15 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. The participants are matched on age, education, and gender to the study patients. | ||||||||||||
Arm type |
No intervention | ||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
The intention-to-treat population includes 28 patients in the dexmedetomidine group and 32 patients in the placebo group. A non-surgical control group of 15 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Verum
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Reporting group description |
Experimental: Study group Application of Dexmedetomidine (Dexdor®) perioperatively for a maximum of 48 hours Dosing Scheme: during operation and mechanical ventilation: 0,7μg/kgABW/h; recovery time until extubation: 0,4μg/kgABW/h; after extubation: 0,2-1,4μg/kgABW/h Dexmedetomidine was supplied in a 2 ml ampoule containing 200 μg (100 μg/ml) dexmedetomidine (as a base) for dilution with 48 ml 0.9% sodium chloride injection (giving a solution containing 4 μg/ml) in 50 ml syringe. | ||
Reporting group title |
Placebo
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Reporting group description |
Placebo Comparator: Control group Application of placebo for a maximum of 48 hours Placebo for dexmedetomidine was a 50 ml syringe containing 0.9% sodium chloride isotonic infusion solution/0.9 % sodium chloride injection solution | ||
Reporting group title |
Control POCD
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Reporting group description |
No Intervention: POCD (postoperative cognitive deficit) control group A non-surgical control group of 15 ASA II/III- patients is collected for measuring the learning experience during the cognitive testings. The participants are matched on age, education, and gender to the study patients. | ||
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End point title |
Delirium [1] | |||||||||||||||
End point description |
Incidence of postoperative delirium measured with the Confusion Assessment Method for the ICU (CAM-ICU) or the Confusion Assessment Method (CAM)
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End point type |
Primary
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End point timeframe |
Unitil the fifth postoperative day
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| Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The primary end point is reporting statistics for all the study arms e.g. verum arm and placebo arm in the baseline period. In the POCD control group no delirium (primary endpoint) was measured. |
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Statistical analysis title |
Primary endpoint | |||||||||||||||
Statistical analysis description |
Fisher-Boschloo-Test
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Comparison groups |
Verum v Placebo
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Number of subjects included in analysis |
60
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Analysis specification |
Post-hoc
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Analysis type |
equivalence [2] | |||||||||||||||
P-value |
< 0.05 | |||||||||||||||
Method |
Fisher-Boschloo-Test | |||||||||||||||
Confidence interval |
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| Notes [2] - For the primary endpoint we found a reduction of delirium incidence measured by CAM-ICU / CAM within the first five postoperative days from 43.8% (n=14) in the placebo group to 17.9% (n=5) in the verum group. According to the Fisher-Boschloo-Test this difference is significant with p=0.038. The Fisher-Boschloo test was used because it constitutes an alternative to the Fisher's Exact Test with larger statistical power, while ensuring the same level of type-I-error. |
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Adverse events information
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Timeframe for reporting adverse events |
Incidence of adverse events which start after the application of the study medication within 5 postoperative days.
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Adverse event reporting additional description |
Every adverse event that started within 5 postoperative days has to be followed up until decrease of the symptoms or stabilisation.
Patients were evaluated regarding their safety profil during ech study visit twice per day.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.1
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Reporting groups
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Reporting group title |
Verum
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Reporting group description |
This group received study medication Dexdor. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
This group received 0.9% NaCl | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 Apr 2014 |
Amendment 01: changes of the protocol 1.0 to 1.1 within the ethical applications, submitted to BfArM again as substantial Amendment 01. |
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14 Aug 2015 |
Amendment 02: Substantial Amendment changes
of the protocol 1.1 to 1.2: Primary reason for
amendment were changes in study design: a
POCD-control group of 15 patients was requested
and three inclusion and exclusion criteria were
specified. Three secondary endpoints were added.
The time schedule of the study was adapted.and
changes of the summary of product characteristics
Dexdor 11/2014, sodium chloride Fresenius
(07/2013), sodiume chloride BBraun (06/2014) were
included in the new protocol version and patient
information sheets. Safety documentation was set
for 5 postoperative days.
Fulfilling conditions of the ethical committee:
Changes of the protocol 1.2 to 1.4: Including to the
safety documentation that every adverse event that
started within 5 postoperative days has to be
followed up until decrease of the symptoms or
stabilisation. |
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02 Mar 2016 |
Amendment 03
changes of the protocol 1.4 to 1.5
Primary reason for amendment were changes in
study design: the study title was changed. The
inclusion criterion was expanded to abdominal
surgery. Specific protocol exceptions to expected
SAE Reporting were added. Measurement of
Cortisol is collected from blood samples and salivary
juice. |
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27 May 2016 |
Amendment 04
changes of the protocol 1.5 to 1.6 to fulfill the
conditions of the BfArM:
The benefit risk evaluation regarding the inclusion of
study patients undergoing hepatic, gastric and
intestinal surgery was added. The safety
documentation and annual reporting was specified in
the study protocol according to ICH Topic E2F and
the importance of the reporting of SUSARS after
unblinding of adverse events which fulfil the criteria
causal relationship and unexspectedness was
emphasized. |
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29 Dec 2016 |
Amendment 05
changes of the protocol 1.6 to 1.7
Primary endpoint time measurement is reduced from
7 to 5 postoperative days. POCD measurements are
specified to baseline, 5 (+/-2) postoperative days and
between 90 postoperative days.
Changes of the summary of product characteristics
Dexdor 05/2016 were updated. The study drug could
patient develops delirium within 2 hours of pausing
be restarted up to 48 hours postoperatively if the patient develops delirium within 2 hours of pausing. |
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05 Jan 2018 |
Amendment 06
changes of the protocol 1.7 to 1.8
Following Changes in study design: Primary and
secondary endpoints Delirium measurement are
expanded by validated Delirium scores. The
enrollment rates are adapted by a current lower
Drop-Out rate. The SUMMARY OF PRODUCT
CHARACTERISTICS of NaCl (Placebo) is updated.
The biometric institute, that has to perform the
statistical analysis, was changed |
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15 May 2018 |
Amendment 07 to fulfill the conditions of the ethical
committee:
changes of the protocol 1.8 to 1.9 Primary and
secondary endpoints Delirium measurement are
reduced to validated Delirium scores according to
protocol V1.7. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| not applicable | |||
