E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic breathlessness due to cardiac, respiratory disease or cancer. |
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E.1.1.1 | Medical condition in easily understood language |
Persistent shortness of breath due to heart or lung diseases or cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007554 |
E.1.2 | Term | Cardiac failure |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009026 |
E.1.2 | Term | Chronic obstructive airways disease |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10022611 |
E.1.2 | Term | Interstitial lung disease |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048683 |
E.1.2 | Term | Advanced cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The principal objective is to test the effectiveness and cost-effectiveness of regular low dose oral modified release morphine for patient-reported worst breathlessness in people living with chronic breathlessness due to advanced disease compared with placebo. |
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E.2.2 | Secondary objectives of the trial |
To assess the benefit of modified-release morphine on: i) Placebo-controlled net effects (balance of benefit versus side-effects) beyond 7 days with blinded side-effects data up to 2 months; ii) Net benefit in the population in addition to people with COPD; iii) Net effect on longer term changes in physical activity if chronic breathlessness is reduced; iv) Longer term impact on health service use, especially days as a hospital inpatient; unplanned health service contact and to assess any potential re-distribution of resource consumption between provider organisations; patient and carer financial implications / out of pocket expenses. v) Cost consequence and cost-effectiveness; vi) Any survival differential between groups; vii) To identify influences affecting safe prescribing and monitoring, and develop a clinically usable process for safe prescribing and monitoring of morphine in specialist and generalist settings. viii) To identify informal carer burden ix) To explore impact on bere |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: MABEL trial: implementation sub-study Date and version as for main study
Aims and objectives: Aim 1: To provide an early indication of experiences and attitudes that impact on morphine prescribing, establish a clinician and service user population for later purposive sampling, identify practice issues, and inform the focus of interview and observation data collection and analysis.
Aim 2: To explore in more depth clinicians’, patients’, and carers’ perspectives about safe morphine use, and to identify potential ways to facilitate safe prescribing and monitoring. |
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E.3 | Principal inclusion criteria |
CTIMP trial Patients: 1. Ambulant people with chronic breathlessness due to cardiac, respiratory disease or cancer. Chronic breathlessness is defined as those with persistent disabling breathlessness despite optimum treatment of their underlying disease in the opinion of the identified clinician. 2. Breathlessness severity. Medical Research Council (mMRC) breathlessness scale grade 3 or 4 (i.e. stops for breath after walking about 100 yards or after a few minutes on level ground, or is too breathless to leave the house or is breathless when dressing). A pooled data study shows that people with worse baseline breathlessness are more likely to respond to opoids. A phase 3 trial in people with COPD showed that those with mMRC grade 3 or 4 were more likely to respond to opioids. This approach also concurs with clinical recommendations. 3. Male or female aged ≥ 18 years old 4. Management of the underlying condition unchanged for the previous 7 days. This, and criterion 5, excludes the very unstable patient who is unlikely to complete the 56 day RCT phase. 5. Australia-modified Karnofsky Performance Scale (AKPS) ≥40. This, with criterion 4, is to identify patients most likely to complete the 2 months RCT phase. 6. eGFR of 25 mls/min/1.732 or more, unless the primary diagnosis is heart failure (≥30 mls/min/1.732) within 21 days of consent. Renal clearance of eGFR ≥25 mls/min/1.732 is adequate for the study doses of morphine, however, in heart failure patients are more likely to have fluctuations in renal function for which the higher level will allow. 7. If female and of child-bearing potential, must agree to use adequate contraception when taking IMP and for 7 days following cessation**** 8. Able to complete questionnaires and trial assessments 9. Able to provide written informed consent
Carers: 1. Family or friend providing care for a patient participant (consented) as identified by the patient participant 2. Male or female ≥ 18 years old 3. Able to complete study carer assessments 4. Able to provide written informed consent
Implementation study Clinicians: Prescribers (or those supporting prescribers) at trial sites attending a site clinical training session
Patients and carers: CTIMP participants and their carers where the participant has completed at least 14 days of the trial Those willing to participate in a face-to-face or telephone interview and able to provide informed written consent
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E.4 | Principal exclusion criteria |
CTIMP trial Patient participants 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 opioid medications >5mg morphine-equivalents daily for > 7 out of last 14 days. 5. Have known true morphine or docusate allergies or hypersensitivity to any of the tablet constituents as assessed by a clinician. 6. Have known central hypoventilation syndrome (e.g. Ondine’s curse post stroke) 7. Have been involved in another medicinal trial (CTIMP) within the past 28 days 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 14 days of discontinuation of their use. 11. Are within the first 24 hours post-operatively 12. Are taking more than 20mg diazapam equivalents per day or are not able or willing to safely reduce dose to less or the same as 20mg / day for the duration of the study.
Carer participants 1. Does not meet inclusion criteria
Implementation study: Exclusion criteria: Clinicians: Clinicians not working at a trial site
Patients and carers: Participants with insufficient written or conversational English to be able to provide informed consent or take part in an interview and adequate translation facilities are unavailable
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is worst breathlessness over the previous 24 hours at Day 28, measured by a 0 - 10 numerical rating scale (NRS) where 0 = no breathlessness and 10 = worst possible breathlessness. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
i) Placebo-controlled net effects beyond 7 days with blinded side-effects data up to 2 months; ii) Net benefit in the population in addition to people with COPD; iii) Net effect on longer term changes in physical activity if chronic breathlessness is reduced; iv) Longer term impact on health service use, especially days as a hospital inpatient; unplanned health service contact and to assess any potential re-distribution of resource consumption between provider organisations; patient and carer financial implications / out of pocket expenses. v) Cost consequence and cost-effectiveness; vi) Any survival differential between groups; and vii) To identify influences affecting trial equipoise (especially with regard to morphine side-effects) and safe prescribing/monitoring, and develop a clinically usable process for safe prescribing and monitoring of morphine in specialist and generalist settings. viii) To identify informal carer burden ix) To explore impact on bereavement on the carer if relevant
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 14 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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The end of the trial is defined as the date the last patient has completed their final follow up assessment for the 56 day RCT. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 31 |