Download PDF

Clinical Trial Results:
A parallel group, double-blind, randomised placebo-controlled trial comparing the efficacy and cost-effectiveness of 20mg daily oral modified release morphine (MRM) versus placebo on the intensity of dyspnoea in patients with stable symptomatic chronic heart failure (CHF).

Summary
EudraCT number	2014-000155-81
Trial protocol	GB
Global end of trial date	24 Aug 2017

Results information
Results version number	v2(current)
This version publication date	29 Nov 2018
First version publication date	31 Aug 2018
Other versions	v1
Version creation reason	New data added to full data set Additional adverse event included for one participant.
Summary report(s)	Additional summary attachment

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

R1730

ISRCTN number

ISRCTN41349358

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Hull and East Yorkshire Hospitals NHS Trust

Sponsor organisation address

R&D Department, Office 13, 2nd Floor Daisy Building, Castle Hill Hospital, Castle Road, Cottingham, East Yorkshire, United Kingdom, HU16 5JQ

Public contact

Prof Miriam Johnson, The University of Hull, +44 1482 463482, miriam.johnson@hyms.ac.uk

Scientific contact

Prof Miriam Johnson, The University of Hull, +44 1482 463482, miriam.johnson@hyms.ac.uk

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

24 Aug 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

24 Aug 2017

Global end of trial reached?

Yes

Global end of trial date

24 Aug 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

Our primary objective was to determine whether medium-term morphine therapy is superior to placebo for the relief of chronic breathlessness in people with stable heart failure and symptomatic despite maximally tolerated medical therapy.

Protection of trial subjects

Participants were telephoned by the research nurse to check toxicity and adverse events in the first week of the study. This included a call within 24 hours of the participant’s first study dose, midweek, and at the end of the week. Safety data were reviewed at IDMC meetings held on 26 July 2016, 26 Jan 2017, 24 July 2017 and 1 Dec 2017. No safety issues were noted from any meeting. A telephone call was made to patients after they stopped taking study drug to check for potential withdrawal symptoms.

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Jan 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 45

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

Top of page

Recruitment details

Thirteen sites in the UK were opened to recruitment between 10 Dec 2015 and 18 April 2017. Seven sites recruited at least one participant. The first participant was randomised on 14 Jan 2016 and the last on 15 May 2017. Recruitment was closed early, on 24 May 2017.

Screening details

386 patients were screened for participation between December 2015 and May 2017 across the 13 sites (median 27 per site, range 0 to 55), of which 175 (45%) were ineligible, 165 (43%) declined, one (0.3%) was eligible and consenting but the trial closed to recruitment before they could be randomised, and 45 (12%) were randomised

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Blinding implementation details

Modified release morphine (MRM) capsules (the Investigational Medicinal Product) and placebo IMP capsules were over-encapsulated, so as to be identical in appearance to maintain blinding. As constipation is a common side-effect of morphine, an overencapsulated laxative (docusate) capsule (the Non-Investigational Medicinal Product), or identical overencapsulated placebo NIMP capsule, was given to the IMP or comparator groups respectively, to prevent unblinding due to development of constipation.

Are arms mutually exclusive

Yes

Morphine

Arm description

Subjects received 10mg twice daily oral modified release morphine (IMP) and 100mg twice daily oral docusate (NIMP).

Arm type

Experimental

Investigational medicinal product name

Modified release morphine (MRM)

Investigational medicinal product code

ATC code: N02A A01

Other name

MST® CONTINUS®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects took one 10mg capsule oral MRM plus one 100mg capsule oral docusate on waking in the morning, and one 10mg capsule MRM plus one 100mg capsule docusate on going to bed at night for 12 weeks.

Placebo

Arm description

Subjects received twice daily oral placebo IMP and twice daily oral placebo NIMP.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

twice daily placebo capsule.

Number of subjects in period 1	Morphine	Placebo
Started	21	24
Reached primary time point of 4 weeks	20	24
Completed	20	22
Not completed	1	2
Consent withdrawn by subject	1	2

Baseline characteristics

Top of page

Reporting group title

Morphine

Reporting group description

Subjects received 10mg twice daily oral modified release morphine (IMP) and 100mg twice daily oral docusate (NIMP).

Reporting group title

Placebo

Reporting group description

Subjects received twice daily oral placebo IMP and twice daily oral placebo NIMP.

Reporting group values	Morphine	Placebo	Total
Number of subjects	21	24	45
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	1	7	8
From 65-84 years	19	16	35
85 years and over	1	1	2
Age continuous
Units: years
arithmetic mean (standard deviation)	74.4 ± 6	70.1 ± 14	-
Gender categorical
Units: Subjects
Female	3	4	7
Male	18	20	38
Ethnicity
Units: Subjects
White	21	24	45
New York Heart Association (NYHA) Class
Class I – no symptoms; Class II – breathless and/or fatigue on moderate exertion; Class III – breathless and/or fatigue on mild exertion; Class IV – breathless and/or fatigue at rest
Units: Subjects
III	20	24	44
IV	1	0	1
modified MRC Breathlessness Scale
0=Not troubled by breathlessness except on strenuous exercise, 1=Short of breath when hurrying or walking up a slight hill, 2=Walks slower than contemporaries on the level because of breathlessness, or has to stop for breath when walking at own pace, 3=Stops for breath after about 100m or after a few minutes on the level, 4=Too breathless to leave the house, or breathless when dressing or undressing
Units: Subjects
score=0	0	0	0
score=1	0	0	0
score=2	7	3	10
score=3	11	21	32
score=4	3	0	3
estimated Glomerular Filtration Rate (eGFR)
Units: ml/min
arithmetic mean (standard deviation)	53.0 ± 18.2	62.2 ± 21.4	-
Resting pulse rate (radial)
Units: Pulse rate per minute
arithmetic mean (standard deviation)	77.0 ± 24.0	77.0 ± 11.2	-
Resting diastolic blood pressure
Units: mmHg
arithmetic mean (standard deviation)	69.4 ± 12.3	68.0 ± 11.6	-
Resting respiratory rate
Units: per minute
arithmetic mean (standard deviation)	17.9 ± 6.8	15.6 ± 4.4	-
Pulse Oximetry %
Units: percentage
arithmetic mean (standard deviation)	97.1 ± 2.1	96.7 ± 1.6	-
Charlson Co-morbidity Index
A scoring system whereby a score is assigned to each of 18 medical conditions, plus a score for patient's age, to provide a total score for the patient.
Units: Score between 0 and 46
arithmetic mean (standard deviation)	6.7 ± 1.4	6.2 ± 2.3	-
NT-proBNP
NT-proBNP (N-Terminal pro-Brain Natriuretic Peptide) was only measured at certain sites (Morphine arm: N=20; Placebo arm: N=22). If not available BNP was measured instead.
Units: pg/mL
arithmetic mean (standard deviation)	3666.7 ± 2459.1	3926.4 ± 3729.3	-
Australia-modified Karnofsky Performance Status (AKPS)
AKPS score, between 0 and 100, in increments of 10, based on ability to perform activities of daily living. Hgher scores imply better function; 100 signifies normal physical activities.
Units: Score from 0 to 100
median (inter-quartile range (Q1-Q3))	70 (60 to 80)	70 (60 to 70)	-
Kansas City Cardiomyopathy Questionnaire-short form (KCCQ-SF)
12-item, self-administered instrument quantifying physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Higher scores indicate better functioning, fewer symptoms, and better disease-specific quality of life.
Units: Score between 0 and 100
arithmetic mean (standard deviation)	36.6 ± 14.7	40.2 ± 11.9	-
Epworth Sleepiness Scale
Screening tool for sleep-disordered breathing. Specifically distinguishes reports of daytime dozing behaviour from fatigue and drowsiness/sleepiness. Higher scores indicate excessive sleepiness (11-12 mild; 13-16 moderate; >16 severe).
Units: Score between 0 to 24
arithmetic mean (standard deviation)	9.6 ± 4.1	9.5 ± 4.8	-
Karolinska Sleepiness Scale
9-point Likert scale of the patient’s level of drowsiness (1=very alert to 9=very sleepy)
Units: Score 1 to 9
arithmetic mean (standard deviation)	3.0 ± 1.5	3.3 ± 1.6	-
Montreal Cognitive Assessment
30-item questionnaire assessing cognitive function. Scores between 0 and 30; ≥ 26 implies no cognitive impairment; lower scores indicate greater cognitive impairment.
Units: Score between 0 and 30
arithmetic mean (standard deviation)	25.1 ± 1.9	25.4 ± 3.1	-
Six minute walk test
Recorded distance walked in metres. Morphine N=18; Placebo: N=24.
Units: Distance walked in metres
arithmetic mean (standard deviation)	177.1 ± 98.8	195.0 ± 101.5	-
Six minute walk test
Oxygen saturation at rest. Morphine N=18; Placebo: N=24.
Units: Percentage
arithmetic mean (standard deviation)	97.2 ± 2.1	96.8 ± 1.7	-
Six minute walk test
Oxygen saturation post-test. Morphine N=18; Placebo: N=24.
Units: Percentage
arithmetic mean (standard deviation)	97.4 ± 1.9	97.2 ± 2.1	-
activPAL™ Average steps per day
Physical activity monitor, activPAL™ , worn for 7 days at baseline prior to randomisation. Average daily step count documented. Morphine: N=20; Placebo: N=22.
Units: Steps per day
arithmetic mean (standard deviation)	2384.5 ± 1661.0	2402.4 ± 2180.8	-
Average breathlessness intensity score over the past 24 hours
Average numerical rating scale (NRS) breathlessness intensity score over the past 24 hours, measured from 0 to 10 where 0 indicates no breathlessness and 10 indicates worst imaginable breathlessness, at Baseline.
Units: NRS from 0 to 10
arithmetic mean (standard deviation)	5.8 ± 2.0	5.0 ± 1.9	-
Average worst breathlessness score over the past 24 hours
Average numerical rating scale (NRS) for worst breathlessness score over the past 24 hours, measured from 0 to 10 where 0 indicates no breathlessness and 10 indicates worst imaginable breathlessness, at Baseline.
Units: NRS from 0 to 10
arithmetic mean (standard deviation)	7.2 ± 2.4	6.2 ± 1.9	-
Average unpleasantness of breathlessness over the past 24 hours
Average numerical rating scale (NRS) for how unpleasant breathlessness has been over the past 24 hours, measured from 0 to 10 where 0 indicates not unpleasant at all and 10 indicates worst unpleasantness imaginable, at Baseline.
Units: NRS from 0 to 10
arithmetic mean (standard deviation)	5.6 ± 2.4	4.5 ± 2.0	-
Average distress breathlessness has caused over the past 24 hours
Average numerical rating scale (NRS) for how much distress breathlessness has caused over the past 24 hours, measured from 0 to 10 where 0 indicates no distress and 10 indicates worst distress imaginable, at Baseline.
Units: NRS from 0 to 10
arithmetic mean (standard deviation)	5.7 ± 2.4	4.1 ± 2.3	-
Average pain experienced over the past 24 hours
Average numerical rating scale (NRS) for pain experienced over the past 24 hours, measured from 0 to 10 where 0 indicates no pain and 10 indicates worst pain imaginable, at Baseline.
Units: NRS from 0 to 10
arithmetic mean (standard deviation)	1.9 ± 3.1	1.2 ± 2.1	-
Resting systolic blood pressure
Units: mmHG
arithmetic mean (standard deviation)	119.8 ± 24.2	116.1 ± 14.5	-
BNP
If NT-proBNP measurement was not available, then BNP was measured (Morphine arm: N=1; Placebo arm: N=2)
Units: pg/ml
arithmetic mean (standard deviation)	528 ± 0	844 ± 526.1	-

End points

Top of page

Reporting group title

Morphine

Reporting group description

Subjects received 10mg twice daily oral modified release morphine (IMP) and 100mg twice daily oral docusate (NIMP).

Reporting group title

Placebo

Reporting group description

Subjects received twice daily oral placebo IMP and twice daily oral placebo NIMP.

Primary: Average breathlessness intensity score over the past 24 hours

Top of page

End point title

Average breathlessness intensity score over the past 24 hours

End point description

The primary outcome measure was the average numerical rating scale (NRS) breathlessness intensity score over the past 24 hours, measured from 0 to 10 where 0 indicates no breathlessness and 10 indicates worst imaginable breathlessness, at 4 weeks.

End point type

Primary

End point timeframe

Measured at 4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	23
Units: numerical rating scale measured 0 to 10
arithmetic mean (standard deviation)	5.3 ± 2.3	4.6 ± 2.4

Primary analysis

Statistical analysis description

NRS at W4 was compared among patients randomly allocated to MRM/placebo. This result was extracted from a covariance pattern linear mixed model in which NRS at each timepoint was nested within patients. NRS at baseline, trial arm, each follow-up timepoint, a time-by-trial arm interaction were included as fixed effects with participant and site as random effect. An exchangeable covariance structure for the repeated measurements was used; this provided the smallest Akaike’s information criterion.

Comparison groups

Placebo v Morphine

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.65

Method

Mixed-effect linear regression

Parameter type

Mean difference (net)

Point estimate

0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.86

upper limit

1.37

Secondary: Average worst breathlessness score over the past 24 hours

Top of page

End point title

Average worst breathlessness score over the past 24 hours

End point description

Average numerical rating scale (NRS) for worst breathlessness score over the past 24 hours, measured from 0 to 10 where 0 indicates no breathlessness and 10 indicates worst imaginable breathlessness, at 4 weeks.

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	23
Units: NRS measured from 0 to 10
arithmetic mean (standard deviation)	5.9 ± 2.5	5.3 ± 2.6

Secondary analysis

Statistical analysis description

A covariance pattern linear mixed model in which NRS at each time point (D2, D4, D7, W2, W3, W4, W8, W12) was nested within patients. NRS at baseline, trial arm, each time point of follow-up, a time-by-trial arm interaction were included as fixed effects with participant and site as random effect.

Comparison groups

Morphine v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.82

Method

Mixed-effect linear regression

Parameter type

Mean difference (net)

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-1.13

upper limit

1.44

Secondary: Average unpleasantness of breathlessness over the past 24 hours

Top of page

End point title

Average unpleasantness of breathlessness over the past 24 hours

End point description

Average numerical rating scale (NRS) for how unpleasant breathlessness has been over the past 24 hours, measured from 0 to 10 where 0 indicates not unpleasant at all and 10 indicates worst unpleasantness imaginable, at 4 weeks.

End point type

Secondary

End point timeframe

Measured at 4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	23
Units: numerical rating scale from 0 to 10
arithmetic mean (standard deviation)	4.7 ± 2.8	4.3 ± 2.1

Secondary analysis

Statistical analysis description

Comparison groups

Placebo v Morphine

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.82

Method

Mixed-effect linear regression

Parameter type

Mean difference (net)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-1.48

upper limit

1.17

Secondary: Average distress breathlessness has caused over the past 24 hours

Top of page

End point title

Average distress breathlessness has caused over the past 24 hours

End point description

Average numerical rating scale (NRS) for how much distress breathlessness has caused over the past 24 hours, measured from 0 to 10 where 0 indicates no distress and 10 indicates worst distress imaginable, at 4 weeks.

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	23
Units: numerical rating scale from 0 to 10
arithmetic mean (standard deviation)	4.2 ± 3.3	3.8 ± 2.6

Secondary analysis

Statistical analysis description

Comparison groups

Morphine v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.45

Method

Mixed-effect linear regression

Parameter type

Mean difference (net)

Point estimate

-0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-1.99

upper limit

0.88

Secondary: Average pain experienced over the past 24 hours

Top of page

End point title

Average pain experienced over the past 24 hours

End point description

Average numerical rating scale (NRS) for pain experienced over the past 24 hours, measured from 0 to 10 where 0 indicates no pain and 10 indicates worst pain imaginable, at 4 weeks.

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	23
Units: numerical rating scale from 0 to 10
arithmetic mean (standard deviation)	1.5 ± 2.8	1.1 ± 1.9

Secondary analysis

Statistical analysis description

Comparison groups

Morphine v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.94

Method

Mixed-effect linear regression

Parameter type

Mean difference (net)

Point estimate

-0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.29

upper limit

1.2

Secondary: Australia-modified Karnofsky Performance Status (AKPS)

Top of page

End point title

Australia-modified Karnofsky Performance Status (AKPS)

End point description

Australia-modified Karnofsky Performance Status score, between 0 and 100, in increments of 10, based on ability to perform activities of daily living. Hgher scores imply better function; 100 signifies normal physical activities

End point type

Secondary

End point timeframe

week 4 post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	22
Units: score, between 0 and 100
median (inter-quartile range (Q1-Q3))	70 (60 to 75)	70 (70 to 70)

No statistical analyses for this end point

Secondary: Kansas City Cardiomyopathy Questionnaire-short form (KCCQ-SF)

Top of page

End point title

Kansas City Cardiomyopathy Questionnaire-short form (KCCQ-SF)

End point description

Kansas City Cardiomyopathy Questionnaire-short form score from 0 to 100, where a higher score indicates better disease-specific quality of life, at week 4

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	22
Units: score from 0 to 100
arithmetic mean (standard deviation)	37.2 ± 16.0	44.1 ± 12.9

No statistical analyses for this end point

Secondary: Epworth Sleepiness Scale

Top of page

End point title

Epworth Sleepiness Scale

End point description

Epworth Sleepiness Scale score from 0 to 24, where a higher score indicates excessive sleepiness, at week 4

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	22
Units: score from 0 to 24
arithmetic mean (standard deviation)	10.6 ± 5.2	9.4 ± 4.3

No statistical analyses for this end point

Secondary: Karolinska Sleepiness Scale

Top of page

End point title

Karolinska Sleepiness Scale

End point description

Karolinska Sleepiness Scale score from 1 to 9, where a higher score indicates excessive sleepiness, at week 4

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	23
Units: score from 1 to 9
arithmetic mean (standard deviation)	3.3 ± 1.5	3.0 ± 1.6

No statistical analyses for this end point

Secondary: Global impression of change

Top of page

End point title

Global impression of change

End point description

The Global Impression of Change question related to the patients' breathing; it asked whether there had been any overall change in breathing since taking the trial medicine that week.

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	21
Units: Patients
About the same	13	9
Better - almost the same, hardly any better at all	0	0
Better - a little better	3	4
Better - somewhat better	1	2
Better - moderately better	0	2
Better - a good deal better	2	2
Better - a great deal better	0	1
Better - a very great deal better	0	0
Worse - almost the same, hardly any worse at all	0	0
Worse - a little worse	0	0
Worse - somewhat worse	0	1
Worse - moderately worse	0	0
Worse - a good deal worse	1	0
Worse - a great deal worse	0	0
Worse - a very great deal worse	0	0

No statistical analyses for this end point

Secondary: Montreal Cognitive Assessment

Top of page

End point title

Montreal Cognitive Assessment

End point description

30-item questionnaire assessing cognitive function. Scores between 0 and 30. Lower scores indicates greater cognitive impairment.

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	20	21
Units: Score from 0 to 30
arithmetic mean (standard deviation)	26.2 ± 3.3	26.8 ± 2.3

No statistical analyses for this end point

Secondary: Six minute walk test - distance walked (m)

Top of page

End point title

Six minute walk test - distance walked (m)

End point description

Distance walked (m)

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	13	17
Units: Distance walked in metres
arithmetic mean (standard deviation)	184.2 ± 87.7	191.5 ± 137.1

No statistical analyses for this end point

Secondary: Six minute walk test - Oxygen saturation at rest (%)

Top of page

End point title

Six minute walk test - Oxygen saturation at rest (%)

End point description

Oxygen saturation at rest (%)

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	13	16
Units: Oxygen saturation %
arithmetic mean (standard deviation)	96.5 ± 1.7	96.9 ± 2.1

No statistical analyses for this end point

Secondary: Six minute walk test - Oxygen saturation at end (%)

Top of page

End point title

Six minute walk test - Oxygen saturation at end (%)

End point description

Oxygen saturation at end of 6MWT (%)

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	13	16
Units: Oxygen saturation %
arithmetic mean (standard deviation)	97.1 ± 1.6	97.2 ± 1.7

No statistical analyses for this end point

Secondary: activPAL™ Average number of steps per day

Top of page

End point title

activPAL™ Average number of steps per day

End point description

Physical activity monitor, activPAL™ , worn for 7 days prior to week 4. Average daily step count documented.

End point type

Secondary

End point timeframe

4 weeks post-randomisation

End point values	Morphine	Placebo
Number of subjects analysed	19	17
Units: Steps per day
arithmetic mean (standard deviation)	1812.9 ± 1425.9	2926.0 ± 2002.2

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

The adverse event (AE) reporting period began as soon as patients were consented to the trial and ended one month after the patient’s final study assessment (week 12) .

Adverse event reporting additional description

Participants’ health status was checked at each study assessment and the local investigator recorded all directly observed AEs and all AEs reported by participants. AEs were recorded in a trial AE form and in patients’ medical notes. AEs reported as possibly, probably or definitely related to morphine are listed here as related to treatment.

Assessment type

Non-systematic

Dictionary name

CTCAE

Dictionary version

Reporting group title

Morphine

Reporting group description

Subjects received 10mg twice daily oral modified release morphine (IMP) and 100mg twice daily oral docusate (NIMP). One participant withdrew from the study immediately after randomisation and did not receive any study medication. Therefore they have been removed from the denominator for this group.

Reporting group title

Placebo

Reporting group description

Subjects received twice daily oral placebo IMP and twice daily oral placebo NIMP.

Serious adverse events	Morphine	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 20 (35.00%)	10 / 24 (41.67%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0	1
Surgical and medical procedures
Pacemaker update
Additional description: Admission to hospital for pacemaker update
subjects affected / exposed	1 / 20 (5.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Dyspnoea
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Heart failure
subjects affected / exposed	1 / 20 (5.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Acute coronary syndrome
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vasovagal reaction
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cognitive disturbance
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stroke
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary retention
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Skin infection
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder infection
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	1 / 20 (5.00%)	2 / 24 (8.33%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Morphine	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 20 (70.00%)	12 / 24 (50.00%)
Investigations
Chronic kidney disease
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	1
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 20 (5.00%)	2 / 24 (8.33%)
occurrences all number	1	2
Alcohol intoxication
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	1
Cardiac disorders
Unconfirmed presyncope
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	1
Dyspnoea
subjects affected / exposed	1 / 20 (5.00%)	1 / 24 (4.17%)
occurrences all number	1	1
Heart failure
subjects affected / exposed	1 / 20 (5.00%)	2 / 24 (8.33%)
occurrences all number	1	2
Ventricular tachycardia
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0
Dizziness
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0
Nervous system disorders
Seizure
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0
Cognitive disturbance
subjects affected / exposed	3 / 20 (15.00%)	0 / 24 (0.00%)
occurrences all number	5	0
Memory impairment
subjects affected / exposed	1 / 20 (5.00%)	1 / 24 (4.17%)
occurrences all number	1	1
Social circumstances
Respite care
subjects affected / exposed	0 / 20 (0.00%)	1 / 24 (4.17%)
occurrences all number	0	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	5 / 20 (25.00%)	1 / 24 (4.17%)
occurrences all number	6	1
Vomiting
subjects affected / exposed	2 / 20 (10.00%)	1 / 24 (4.17%)
occurrences all number	2	1
Diarrhoea
subjects affected / exposed	0 / 20 (0.00%)	3 / 24 (12.50%)
occurrences all number	0	3
Dyspepsia
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0
Dry mouth
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0
Anorexia
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0
Constipation
subjects affected / exposed	4 / 20 (20.00%)	0 / 24 (0.00%)
occurrences all number	4	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0
Arthralgia
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0
Infections and infestations
Lung infection
subjects affected / exposed	1 / 20 (5.00%)	4 / 24 (16.67%)
occurrences all number	1	4
Upper respiratory tract infection
subjects affected / exposed	1 / 20 (5.00%)	1 / 24 (4.17%)
occurrences all number	1	1
Skin infection
subjects affected / exposed	0 / 20 (0.00%)	2 / 24 (8.33%)
occurrences all number	0	2
Metabolism and nutrition disorders
Gout
subjects affected / exposed	1 / 20 (5.00%)	0 / 24 (0.00%)
occurrences all number	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

08 Oct 2014

During the CTA approval process, MHRA requested a change to the emergency unblinding procedure as part of their review. This Substantial Amendment (SA1) to the protocol was submitted to the NHS National Research Ethics Service (NRES) Research Ethics Committee (REC).

18 Feb 2015

Substantial Amendment 2; submitted to REC only: A new patient information sheet regarding the law on driving after certain drugs; a new “as-needed” opioids patient diary; amendments to two new GP letters regarding patients in the study; removal of the "within 3 months" time-limit for the echocardiogram for eligibility; removal of the Day 1 assessments.

13 Apr 2015

Substantial Amendment 3; submitted to REC only: Patient Information Sheet and consent form amended to indicate anonymised data may be held on 3rd party database, that capsules contact gelatin and text regarding driving amended; a new patient information created - List of morphine side-effects; addition of 2 study sites.

06 Jul 2015

Substantial Amendment 4; submitted to REC only: Addition of a Study Experience survey for all participants and a Study Experience telephone interview in a sample of participants

15 Jul 2015

Substantial Amendment 5; submitted to REC only: Addition of 4 new NHS sites.

02 Feb 2016

Substantial Amendment 6; submitted to REC only: Minor amendment to Patient Information Sheet and patient invitation letter templates; both made more flexible to allow sites to enter number of clinic visits needed by participants.

29 Mar 2016

Substantial Amendment 7; submitted to both MHRA and REC: For sites where pharmacy are unable to emergency unblind, the CI or her deputy will do it via an online system. Approved by REC 29/02/16; approved by MHRA 29/03/16.

13 Sep 2016

Substantial Amendment 9; submitted to REC only: addition of 2 new NHS study sites.

22 Dec 2016

Substantial Amendment 10; submitted to REC only: Study site Christmas hamper incentive.

28 Jul 2017

Substantial Amendment 8, submitted to REC only: addition of 3 new NHS study sites.

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.

The major limitation of this study was the early termination due to poor recruitment and subsequent lack of power. Thus these data can only be interpreted as preliminary.

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A parallel group, double-blind, randomised placebo-controlled trial comparing the efficacy and cost-effectiveness of 20mg daily oral modified release morphine (MRM) versus placebo on the intensity of dyspnoea in patients with stable symptomatic chronic heart failure (CHF).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Average breathlessness intensity score over the past 24 hours

Primary: Average breathlessness intensity score over the past 24 hours

Secondary: Average worst breathlessness score over the past 24 hours

Secondary: Average worst breathlessness score over the past 24 hours

Secondary: Average unpleasantness of breathlessness over the past 24 hours

Secondary: Average unpleasantness of breathlessness over the past 24 hours

Secondary: Average distress breathlessness has caused over the past 24 hours

Secondary: Average distress breathlessness has caused over the past 24 hours

Secondary: Average pain experienced over the past 24 hours

Secondary: Average pain experienced over the past 24 hours

Secondary: Australia-modified Karnofsky Performance Status (AKPS)

Secondary: Australia-modified Karnofsky Performance Status (AKPS)

Secondary: Kansas City Cardiomyopathy Questionnaire-short form (KCCQ-SF)

Secondary: Kansas City Cardiomyopathy Questionnaire-short form (KCCQ-SF)

Secondary: Epworth Sleepiness Scale

Secondary: Epworth Sleepiness Scale

Secondary: Karolinska Sleepiness Scale

Secondary: Karolinska Sleepiness Scale

Secondary: Global impression of change

Secondary: Global impression of change

Secondary: Montreal Cognitive Assessment

Secondary: Montreal Cognitive Assessment

Secondary: Six minute walk test - distance walked (m)

Secondary: Six minute walk test - distance walked (m)

Secondary: Six minute walk test - Oxygen saturation at rest (%)

Secondary: Six minute walk test - Oxygen saturation at rest (%)

Secondary: Six minute walk test - Oxygen saturation at end (%)

Secondary: Six minute walk test - Oxygen saturation at end (%)

Secondary: activPAL™ Average number of steps per day

Secondary: activPAL™ Average number of steps per day

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A parallel group, double-blind, randomised placebo-controlled trial comparing the efficacy and cost-effectiveness of 20mg daily oral modified release morphine (MRM) versus placebo on the intensity of dyspnoea in patients with stable symptomatic chronic heart failure (CHF).