E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Refractory breathlessness in patients diagnosed with cancer, chronic heart failure, or lung disease (chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD)). |
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E.1.1.1 | Medical condition in easily understood language |
Breathlessness that continues despite optimal management of the underlying causes and current symptom relief measures, in patients suffering from cancer, heart failure or lung disease. |
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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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006345 |
E.1.2 | Term | Breathlessness |
E.1.2 | System Organ Class | 100000004855 |
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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 |
Is a large scale, randomised, double blind, placebo-controlled study of mirtazapine for refractory breathlessness feasible in terms of recruitment? |
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E.2.2 | Secondary objectives of the trial |
1. Is a large-scale randomised, double-blind, placebo-controlled study of mirtazapine for refractory breathlessness feasible in terms of: a)Recruitment in different settings: outpatient, community services and inpatient settings? b) Acceptability of randomisation to patients? c) Ability to deliver placebo-control and maintain the double-blind? d) Ability to assess outcome measures and minimise missing data in a future large-scale trial? e) Patient eligibility to increase the dose of mirtazapine further at 28 days? f) Compliance with treatment? 2. In order to further inform the sample size calculation for the future large-scale trial, what is the expected activity of mirtazapine? 3. What is the toxicity profile of mirtazapine in patients with breathlessness? 4. What is the potential impact on quality of life (QoL) and symptom management of mirtazapine for patients with breathlessness? |
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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 |
The aim of this sub-study is to qualitatively explore patient acceptability of the trial and recruitment processes to assist in optimisation of recruitment and follow-up strategies employed for a future large scale randomised controlled trial. |
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E.3 | Principal inclusion criteria |
1. Male or female aged ≥ 18 years old 2. Modified MRC dyspnoea scale grade 3 or 4 3. Diagnosed with: • Cancer, or • Chronic obstructive pulmonary disease (COPD), or • Interstitial lung disease (ILD), or • Chronic heart failure (New York Heart Association (NYHA) class III or IV) 4. On optimal treatment of the underlying condition in the opinion of the identifying clinician (see section 9.3.3 of protocol for guidance) 5. Management of the underlying condition unchanged for the previous 1 week 6. Reversible causes of breathlessness optimally treated in the opinion of the identifying clinician 7. Expected prognosis of ≥2 months 8. If female must be (as documented in the notes) a) postmenopausal (no menses for 12 months without an alternative medical cause), or b) surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or c) using acceptable contraception ii (which must be continued for 7 days after the last dose of IMP) 9. Able to complete questionnaires and trial assessments 10. Able to provide written informed consent ii Acceptable contraception is defined as one of the following: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; practising true abstinence (when this is in line with the preferred and usual lifestyle of the subject). |
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E.4 | Principal exclusion criteria |
1. Existing antidepressant use, use of linezolid, or St John’s wort 2. Known contraindication to mirtazapine 3. Hypersensitivity to the active substance or to any of the components of the mirtazapine or placebo (e.g. lactose intolerance) 4. Australia modified Karnofsky Performance Scale ≤40 5. Pregnant or breast-feeding women(vi) 6. Patients with acute cardiac events within 3 months of randomisation (myocardial infarction, unstable angina pectoris, or significant cardiac conduction disturbance) 7. Patients with known hepatic impairment 8. Patients with known renal impairment 9. Patients with uncontrolled blood pressure 10. Patients with uncontrolled diabetes mellitus 11. Patients with uncontrolled seizures, epilepsy or organic brain syndrome 12. Patients with severe depression or suicidal thoughts 13. Patients with a history of psychotic illness (schizophrenia, bipolar disorder, mania or hypomania, or other psychotic disturbances) vi for women of childbearing potential (those not post-menopausal or surgically sterile) must be confirmed by a pregnancy test within 7 days prior to randomisation |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the number of patients recruited into the trial across 3 trial sites over a 12-month period. This will be evaluated at the end of the trial.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 12 months recruitment |
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E.5.2 | Secondary end point(s) |
Other outcome measures of feasibility will be assessed to determine whether the design of the future large-scale trial may need to be adapted to improve recruitment or reduce attrition. Physical activity and toxicity outcomes will be used to inform the design of the future trial, however they will not be used to inform the decision as to whether or not to proceed to a future large-scale trial. These are: • Number of patients screened for eligibility and reasons for non-eligibility • Proportion of eligible patients randomised and reasons for non-randomisation • Proportion of participants for which blinding is maintained • Proportion of research assessors for which blinding is maintained • Proportion of participants remaining on study for 28 days • Proportion of, and reasons for, participants with missing data for trial outcomes • Proportion of participants who would be eligible for dose escalation at 28 days • Treatment compliance over the period Feasibility outcome measures relating to recruitment will be assessed by the use of screening logs completed at each site. Blinding will be assessed using the Bang Blinding index. Missing data and study compliance will be assessed based on completed and received CRFs, summarised for each trial outcome measure. Eligibility for dose escalation will be assessed based on breathlessness intensity at day 28 and tolerability of treatment. 3) Safety and Toxicity •Adverse events reported on days 7, 14, 21 and 28. •Safety will be reported based on the occurrence of SAEs, SARs and SUSARs. • Australia-modified KPS and mMRC at days 14 and 28 •Opioid medication: on days 7, 14, 21 and 28. 4) Symptoms and Quality of Life •Coping self-belief assessment on day 28. •Mobility, self-care, usual activities, pain/discomfort and anxiety/depression as assessed on day 28. •Palliative symptoms as assessed days 14 and 28. •Anxiety and depression as assessed on days 14 and 28. •QoL as assessed by CRQ at days 14 and 28.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints will be evaluated when all participants have been followed up for safety i.e. 7 days after last treatment dose. |
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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 | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
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 | 3 |
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 | No |
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 trial is defined as the date of the collection of the last participant’s last data item, i.e. the last participant’s Follow-Up trial phone-call assessment, which will be no earlier than 7 days after the last participant has completed trial treatment. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |