BETTER-B: Better Treatments for Refractory Breathlessness

INTERVENTION: Participants with refractory breathlessness and COPD/ILD will be randomised on a 1:1 basis to receive either oral Mirtazapine (starting dose 15 mg per day) or placebo (one tablet per day), using minimisation incorporating a random element. Minimisation factors used will be: disease (COPD, ILD); HADS anxiety and depression subscale scores; receipt of opioids and recruiting site. Participants will be eligible for dose escalation to 30 mg per day at Day 14 (or two tablets of placebo) and to 45 mg per day at Day 28 (or three tablets of placebo) of the treatment period. Treatment will continue until day 56. Participant follow‐up assessments will take place at days 7, 14, 28 and 56 post start of treatment. Participants will be followed up 7 days after completing trial treatment (including dose tapering) to assess safety and toxicity of treatment. At the end of the day 56 post start of treatment, and after dose tapering, the trial becomes open label. Once the trial is open label, participants may request off trial mirtazapine from their family doctor/clinical team if they wish to do so irrespective of study arm (and maintaining blinding). Participants will be followed‐up at 180 days post start of treatment via phone to complete the final participant reported questionnaires. Participants will be randomised using a central automated 24‐hour telephone/internet service based at the Leeds CTRU. CONDITION: Refractory breathlessness in patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) ; Respiratory ; Chronic obstructive pulmonary disease (COPD) Interstitial lung disease (ILD) PRIMARY OUTCOME: Self‐reported worst breathlessness over the past 24 hours measured at day 56 post start of treatment using a numerical rating scale (NRS, 0=no breathlessness to 10=worst possible breathlessness) SECONDARY OUTCOME: ; 1. Worst breathlessness over the last 24 hours as assessed by NRS (0=no breathlessness to 10=worst possible breathlessness) at days 7, 14, 28 and 180 post start of treatment; 2. Average breathlessness over the last 24 hours assessed by NRS (0=no breathlessness to 10=worst possible breathlessness) at days 7, 14, 28, 56 and 180 post start of treatment; 3. Number and duration of episodes of breathlessness over the last 24 hours; 4. Physical and emotional aspects of breathlessness (Dyspnoea, fatigue, emotional function, mastery) as assessed by the Chronic Respiratory Questionnaire (CRQ) at days 14, 28, 56 and 180 post start of treatment; 5. Physical symptoms as assessed by the Integrated Palliative care Outcome Scale (IPOS) at days 14, 28, 56 and 180 post start of treatment; 6. Quality of Life (QoL) as assessed by the EQ‐5D‐5L and associated VAS at days 14, 28, 56, 180 post start of treatment and Australia‐modified Karnofsky Performance Scale (AKPS) at days 14, 28, 56 and 180 post start of treatment; 7. Anxiety and depression as assessed by the Hospital Anxiety and Depression Scale (HADS) at days 28 and 56 post start of treatment; 8. Perceived self‐efficacy as measured by the Generalized Self‐Efficacy Scale (GSES) at day 56 post start of treatment; 9. The consumption of opioids as measured by opioid medication usage at days 7, 14, 28, 56 and 180 post start of treatment; 10. Healthcare services received, including out of hours care, number of emergency hospital attendances and admissions within 28, 56 and 180 days post start of treatment; 11. Safety as assessed by the occurrence of:; 11.1. SAEs, SARs and SUSARs coded according to the Common Terminology Criteria for Adverse Events (CTCAE) categorisation (v5) as reported at days 7, 14, 28 and 56 post start of treatment; 11.2. Deaths by day 56 and day 180 post start of treatment; 12. Toxicity as assessed by adverse reactions (ARs) coded according to the Common Terminology Criteria for Adverse Events (CTCAE) categorisation (v5) as reported at days 7, 14, 28 and 56 post start of treatment; 13. Tolerability as assessed by the proportion of patients not withdrawing due to adverse reactions; 14. Baseline demographics and characteristics will be measured to enable prognostic evaluation of those factors most associated with benefit from mirtazapine (benefit as measured by worst breathlessness over the last 24 hours at day 56 post start of treatment. Specifically assessing:; 14.1. Age; 14.2. Gender; 14.3. Functional status (as measured by actual functioning using AKPS, mobility using EQ‐5D‐5L, and ‘poor mobility’ using IPOS), aetiology (COPD / ILD); 14.4. Baseline intensity of breathlessness (as measured by worst breathlessness over the last 24 hours at baseline); 14.5. Anxiety and depression (as measured by HADS); 14.6. Concomitant opioid administration; 15. Formal and informal care use over the previous period as measured by the Client Services Receipt Inventory (CSRI) at days 28, 56 and 180 post start of treatment, to examine hours of care and (using country specific unit costs) costs of services; 16. Acceptability of the offered treatment as assessed by the recruitment conversion rate, the number of people withdrawing from treatment, and the number of participants who request mirtazapine from their doctor/clinician after 56 days post start of treatment; 17. Treatment compliance as measured by the:; 17.1. Proportion and type of dropouts over 56 days post start of treatment; 17.2. Proportion of tablets taken over 56 days post start of treatment; 17.3. Proportion of participants who escalate dose at days 14 and 28 post start of treatment; 17.4. Open label treatment compliance to 180 days post start of treatment; 18. Caregiver’s perceived impact on the participant as measured by:; 18.1. Worst and average rating of the participant’s breathlessness over the last 24 hours as assessed by NRS (0=no breathlessness to 10=worst possible breathlessness) at days 28, 56 and 180 post start of treatment;; 18.2. Caregiver assessment of the participant’s number and duration of episodes of breathlessness over the last 24 hours;; 18.3. Informal care hours as measured by the Client Services Receipt Inventory (CSRI) at days 28, 56 and 180 post start of treatment;; 18.4. Caregiver self‐reported burden as measured by the Zarit Burden inventory at days 28, 56 and 180 post start of treatment;; 18.5. Caregiver self‐reported experiences of caregiving as measured by the Positive Aspects of Caregiving Scale (PACS) at days 28, 56 and 180 post start of treatment;; 18.6. Caregiver perspectives on participants’ situation as measured by the Integrated Palliative care outcome scale (IPOS) at days 28, 56 and 180 post start of treatment.; 18.7. Caregiver overall health and wellbeing as measured by EQ‐5D‐5L and associated VAS at days 28, 56 and 180 post start of treatment; INCLUSION CRITERIA: 1. Aged = 18 years old 2. Diagnosed with: 2.1. Chronic obstructive pulmonary disease (COPD), and/or 2.2. Interstitial lung disease (ILD) 3. Breathlessness severity: Modified MRC breathlessness scale of: 3.1. Grade 3 (I stop for breath after walking about 100 yards or after a few minutes on level ground) or 3.2. Grade 4 (I am too breathless to leave the house or I am breathless when dressing or undressing) 4. On optimal treatment of the underlying condition in the opinion of the identifying clinician (see section 0 of protocol for guidance) 5. Management of the underlying condition unchanged for the previous 2 weeks 6. Reversible causes of breathlessness optimally treated in the opinion of the identifying clinician 7. If female, must be (as documented in patien