Clinical Trials Register

Summary
EudraCT Number:	2014-000155-81
Sponsor's Protocol Code Number:	1.0
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-09-26
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2014-000155-81

A.3

Full title of the trial

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).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Morphine for breathlessness in heart failure

A.3.2

Name or abbreviated title of the trial where available

BreatheMOR-HF:Morphine for breathlessness in heart failure Version 1

A.4.1

Sponsor's protocol code number

1.0

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN41349358

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Hull and East Yorkshire Hospitals NHS Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	British Heart Foundation
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The University of Hull
B.5.2	Functional name of contact point	Miriam Johnson
B.5.3	Address:
B.5.3.1	Street Address	Hertford Building, Cottingham Road
B.5.3.2	Town/ city	Hull
B.5.3.3	Post code	HU6 7RX
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01482463482
B.5.6	E-mail	miriam.johnson@hyms.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	MST Continus
D.2.1.1.2	Name of the Marketing Authorisation holder	Napp Pharmaceuticals Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	morphine sulfate prolonged release capsule 10mg
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic refractory breathlessness due to heart failure (NYHA Class III or IV)

E.1.1.1

Medical condition in easily understood language

Breathlessness in heart failure

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Is morphine medication, used over one month better than placebo for the relief of chronic refractory breathlessness in people with stable chronic heart failure?

E.2.2

Secondary objectives of the trial

Is morphine medication, used over three months better than placebo in people with chronic heart failure with regard to the following:
o the distress and unpleasantness due to breathlessness, global impression of change of breathlessness
o other symptoms such as daytime sleepiness, pain and sleep disturbance,
o quality of life,
o daily activity and function (including cognitive function),
o use of health services and costs of health-care
o severity of heart failure
o toxicity over 3 months with placebo control
o toxicity and benefit on breathlessness in the longer term

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with NYHA class III or IV symptoms due to heart failure as evidenced by:
a) Echo: LVSD <40% EF, or at least "moderate" on inspection within last 3 months
OR
b) Echo showing LVEF > 40% plus left ventricular hypertrophy, left atrial dilation or abnormal diastolic function within last 3 months
2. NT-proBNP ≥1000 pg/mL OR BNP ≥250 pg/mL within last 3 months
3. Optimal medical management of heart failure which has not changed in the previous 2 weeks (see below)
4. Adequate renal clearance within previous 2 weeks. GFR ≥30ml/min (see Appendix A of protocol)
5. Grade 2 or more on the modified MRC dyspnoea scale (see Appendix A of protocol)
6. Aged 18 years or over.

Optimal treatment is defined as:
o Reached target dose of (or be on maximally tolerated dose of, or be intolerant of) an inhibitor of the renin-angiotensin system shown to improve prognosis AND
o Reached target dose of (or be on maximally tolerated dose of, or be intolerant of) a beta adrenoceptor antagonist shown to improve prognosis AND
o Reached target dose of (or be on maximally tolerated dose of, or be intolerant of) an aldosterone antagonist
As assessed by the clinician responsible for the usual care of the patient and reviewed by the study doctor at the recruiting centre prior to study entry.

E.4

Principal exclusion criteria

Patients who
1. Are unable to provide informed consent.
2. Are unable to complete baseline study questionnaires even with the assistance of the study nurse
3. Have co-existing malignant disease only if this would affect the study in the investigators’ opinion.
4. Have used morphine-based medications regularly (that is, most days) within the last month above the study dose.
5. Have known true morphine allergies or hypersensitivity to any of the tablet constituents as assessed by a clinician.
6. Have known central hypoventilation syndrome
7. Have been involved in another medicinal trial (CTIMP) within the past four weeks
8. Are pregnant or lactating
9. Have respiratory depression, head injury, paralytic ileus, acute abdomen, acute hepatic disease
10. Have concurrent administration of monoamine oxidase inhibitors or are within two weeks of discontinuation of their use
11. Are within the first 24 hours post-operatively

E.5 End points

E.5.1

Primary end point(s)

Patient-rated average intensity of breathlessness in the past 24 hours using a 0 – 10 numerical rating scale (NRS), where 0 = no breathlessness and 10 = worst imaginable breathlessness, at 28 days.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary end point: 28 days

E.5.2

Secondary end point(s)

• Other aspects of breathlessness: worst intensity of breathlessness over previous 24 hours (NRS); distress and unpleasantness due to breathlessness (NRS); global impression of change
• Assessment of related symptoms: Average pain over previous 24 hours (NRS); daytime sleepiness (Karolinska sleepiness scale)
• Quality of sleep (Epworth Sleep Scale)
• Assessment of activity and function (including cognitive function): 6 minute walk test (6MWT); ActivPAL activity monitoring; Montreal Cognitive Assessment (MoCA); NYHA class; Australia-modified Karnofsky Performance Status (AKPS)
• Quality of life: Kansas City Cardiomyopathy Questionnaire-short form (KCCQ-SF)
• Health economic assessment: The EuroQoL EQ-5D-5L and EQ-VAS; health service use
• Toxicity symptoms (these will be checked at every study contact)

E.5.2.1

Timepoint(s) of evaluation of this end point

Other aspects of breathlessness and pain will be evaluated at day 1, 2,4,7, week 2,3,4,8 and 12;
Karolinska sleepiness at day 1, 2 4,7, week 2, 3, 4;
Epworth Sleep Questionnaire at week 4;
Global impression of change at week 4;
ActivPAL and 6MWT at week 4;
MoCA at day 4, day 7, week 4 (subsections only at day 4 and 7, by phone);
NYHA class at week 4 and 12;
AKPS at week 4 and 12;
KCCQ-SF at week 4 and 12;
Health economic assessments and EQ5D will be at week 4, 8 and 12;
Toxicity will be assessed at every contact over the 3 months trial period

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1