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Clinical Trial Results:
Comparative evaluation of the effects of dexmedetomidine and propofol on patient/ventilator interaction in difficult-to-wean mechanically ventilated patients; a prospective, open, randomised, multicentre study.

Summary
EudraCT number	2011-001490-40
Trial protocol	IT
Global end of trial date	31 Oct 2013

Results information
Results version number	v1(current)
This version publication date	06 Jul 2016
First version publication date	23 Jul 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

3005019

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Orion Corporation Orion Pharma

Sponsor organisation address

Orionintie 1, Espoo, Finland, 02200

Public contact

Clinical Trials Information Desk, Orion Corporation, +358 10 4261, clinicaltrials@orionpharma.com

Scientific contact

Clinical Trials Information Desk, Orion Corporation, +358 10 4261, clinicaltrials@orionpharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Oct 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Oct 2013

Global end of trial reached?

Yes

Global end of trial date

31 Oct 2013

Was the trial ended prematurely?

Main objective of the trial

The primary objective is to investigate effects of dexmedetomidine on diaphragmatic neural activity (EAdi) over 24 hours after starting study treatment in difficult to wean mechanically ventilated patients.

Protection of trial subjects

Patient’s sedative needs were met exclusively with the study treatments as far as possible. In the event that urgent additional sedation was required a small bolus of midazolam (not >5 mg) was administered. For patients’ analgesia needs, paracetamol and then codeine were used as first-line analgesic agents. In the event that further analgesia was required, intermittent intravenous fentanyl could be administered as clinically required.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Jun 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 26

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Number of subjects started

Number of subjects completed

Period 1 title

Treatment (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

6 run-in subjects were not blinded (dexmedetomidine treated)

Are arms mutually exclusive

Yes

Open-label dexmedetomidine

Arm description

Arm type

Experimental

Investigational medicinal product name

Dexmedetomidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

0.2-1.4 microg/kg/h

Dexmedetomidine randomised

Arm description

Arm type

Experimental

Investigational medicinal product name

Dexmedetomidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

0.2-1.4 microg/kg/h

Propofol, randomised

Arm description

Arm type

Active comparator

Investigational medicinal product name

Propofol

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

0.3-4 mg/kg/h i.v.

Number of subjects in period 1	Open-label dexmedetomidine	Dexmedetomidine randomised	Propofol, randomised
Started	6	10	10
Completed	5	9	9
Not completed	1	1	1
Adverse event, serious fatal	-	-	1
Coma, RASS-value out of range	-	1	-
Unknown	1	-	-

Baseline characteristics

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Reporting group title

Treatment

Reporting group description

Reporting group values	Treatment	Total
Number of subjects	26	26
Age categorical
Units: Subjects
In utero		0
Preterm newborn infants (gestational age < 37 wks)		0
Newborns (0-27 days)		0
Infants and toddlers (28 days-23 months)		0
Children (2-11 years)		0
Adolescents (12-17 years)		0
Adults (18-64 years)		0
From 65-84 years		0
85 years and over		0
Age continuous
Units: years
arithmetic mean (standard deviation)	66.1 ± 17.6	-
Gender categorical
Units: Subjects
Female	10	10
Male	16	16

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

All randomised subjects who receive any study treatment will be included in the FAS.

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All study subjects (including non-randomised run-in patients) who received any study treatment will be included in the evaluation of safety.

Subject analysis set title

Per protocol

Subject analysis set type

Per protocol

Subject analysis set description

All randomised study subject who have received at least 24-hour study treatment, who have completed 24-hour neural assessments and who have had no major protocol deviations during the first 24-hour after starting treatment will be included in the per-protocol (PP) dataset.

Subject analysis sets values	Full analysis set	Safety set	Per protocol
Number of subjects	20	26	20
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	68.8 ± 15.7	66.1 ± 17.6	68.8 ± 15.7
Gender categorical
Units: Subjects
Female	9	10	9
Male	11	16	11

End points

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Reporting group title

Open-label dexmedetomidine

Reporting group description

Reporting group title

Dexmedetomidine randomised

Reporting group description

Reporting group title

Propofol, randomised

Reporting group description

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

All randomised subjects who receive any study treatment will be included in the FAS.

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All study subjects (including non-randomised run-in patients) who received any study treatment will be included in the evaluation of safety.

Subject analysis set title

Per protocol

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Asynchrony index (AI)

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End point title

Asynchrony index (AI) ^[1]

End point description

End point type

Primary

End point timeframe

during 24 hours

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 open arm was included during the baseline period to allow ICU staff to get used to handling patients on dexmedetomidine. It is not a comparative arm in the study.

End point values	Dexmedetomidine randomised	Propofol, randomised
Number of subjects analysed	10	10
Units: proportion
arithmetic mean (full range (min-max))	3.89 (0 to 29.7)	5.81 (0 to 16)

Analysis of covariance

Comparison groups

Dexmedetomidine randomised v Propofol, randomised

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9193 ^[2]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-15.2

Confidence interval

level

95%

sides

2-sided

lower limit

-313

upper limit

282.8

Variability estimate

Standard error of the mean

Dispersion value

149.63

Notes
[2] - observed p-value

Adverse events

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Timeframe for reporting adverse events

From the start of study treatment to 30 days after it.

Adverse event reporting additional description

description1

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Dexmedetomidine

Reporting group description

Reporting group title

Propofol

Reporting group description

Serious adverse events	Dexmedetomidine	Propofol
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 16 (37.50%)	3 / 10 (30.00%)
number of deaths (all causes)	6	3
number of deaths resulting from adverse events
Vascular disorders
Hypotension
subjects affected / exposed	4 / 16 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 4	0 / 1
Haemodynamic instability
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Embolism arterial
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac disorders
Agonal rhythm
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac arrest
subjects affected / exposed	5 / 16 (31.25%)	3 / 10 (30.00%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 5	0 / 3
Bradycardia
subjects affected / exposed	1 / 16 (6.25%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Nervous system disorders
Coma
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 16 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Respiratory distress
subjects affected / exposed	1 / 16 (6.25%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Pulmonary oedema
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Infections and infestations
Sepsis
subjects affected / exposed	2 / 16 (12.50%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Lung infection
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Septic shock
subjects affected / exposed	1 / 16 (6.25%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Dexmedetomidine	Propofol
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 16 (68.75%)	7 / 10 (70.00%)
Injury, poisoning and procedural complications
Gastrointestinal anastomotic leak
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
Surgical and medical procedures
Tracheostomy
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Duodenal ulcer
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Cough decreased
subjects affected / exposed	0 / 16 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Increased bronchial secretion
subjects affected / exposed	0 / 16 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Productive cough
subjects affected / exposed	0 / 16 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Delirium
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
Infections and infestations
Endocarditis bacterial
subjects affected / exposed	0 / 16 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Device related sepsis
subjects affected / exposed	1 / 16 (6.25%)	1 / 10 (10.00%)
occurrences all number	1	1
Pneumonia
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
Urinary tract infection
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0
Metabolism and nutrition disorders
Hyperammonaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 10 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

05 Jan 2011

Sample size adjusted according to additional clinical in-put on reasonable expected treatment differences.

14 Feb 2013

Standard of care safety blood tests acceptable at baseline if taken on same day as start of study treatment to reduce patient burden. If SOC safety blood tests not available, study specific tests to be taken within 2 hrs of starting treatment.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Comparative evaluation of the effects of dexmedetomidine and propofol on patient/ventilator interaction in difficult-to-wean mechanically ventilated patients; a prospective, open, randomised, multicentre study.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Asynchrony index (AI)

Primary: Asynchrony index (AI)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Comparative evaluation of the effects of dexmedetomidine and propofol on patient/ventilator interaction in difficult-to-wean mechanically ventilated patients; a prospective, open, randomised, multicentre study.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Asynchrony index (AI)

Primary: Asynchrony index (AI)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Comparative evaluation of the effects of dexmedetomidine and propofol on patient/ventilator interaction in difficult-to-wean mechanically ventilated patients; a prospective, open, randomised, multicentre study.