Mirtazapine to alleviate severe breathlessness in patients with COPD or ILD: an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial (BETTER-B)

Higginson, Irene J; Brown, Sarah T; Oluyase, Adejoke O; May, Peter; Maddocks, Matthew; Costantini, Massimo; Bajwah, Sabrina; Normand, Charles; Bausewein, Claudia; Simon, Steffen T; Ryan, Karen; Currow, David C; Johnson, Miriam; Hart, Simon P; Mather, Hannah; Krajnik, Malgorzata; Tanzi, Silvia; Ghirotto, Luca; Bolton, Charlotte; Janowiak, Piotr; Turola, Elena; Jolley, Caroline J; Murden, Geraldine; Wilcock, Andrew; Farsides, Bobbie; Brown, Julia M

Abstract

Background
Breathlessness frequently becomes severe among people with respiratory disease. Mirtazapine, a widely used antidepressant, showed promise. We determined the effectiveness of mirtazapine to alleviate severe persisting breathlessness.
Methods
This international, multicentre, phase 3, parallel-group, double-blind, randomised, placebo-controlled trial across 16 centres in seven countries, recruited adults with Chronic Obstructive Pulmonary Disease (COPD) and/or Interstitial Lung Diseases (ILD), grade 3 or 4 of the Modified MRC (mMRC) breathlessness scale. Consenting
participants were randomly assigned (1:1) to receive orally mirtazapine or matching placebo for 56 days. Randomisation was by minimisation. Initial mirtazapine dose was 15mg; potentially escalating to maximum 45mg /day, tapered at treatment end.
Participants, caregivers, assessors, and investigators were masked to group assignment. The primary outcome was ‘worst breathlessness’ in the preceding 24 hours measured on a 0-10 numerical rating scale (NRS), at 56 days post treatment start, with follow-up to 180 days. Primary analysis was modified intention-to-treat using multivariable multi-level repeated measures model. Trial registration:
ISRCTN10487976.
Findings
Between 4th February 2021 and 28th March 2023, we enrolled 225 eligible participants (148 men, 77 women, 113 mirtazapine, 112 placebo). There was no evidence of difference in ‘worst breathlessness’ at day 56 between mirtazapine and placebo
(difference in adjusted mean NRS score 0·105, 95% CI: -0·407, 0·618, p=0·69). Although the study was underpowered, the primary end point effect did not reach the pre-specified treatment effect of 0.55 ‘worst breathlessness’ score reduction that the study was powered to detect, for the primary and sensitivity analysis. There were 215
and 116 adverse reactions, across 72 (64%) and 44 (40%) participants; 12 and 9 serious adverse events reported on 7 (6%) and 8 (7%) participants receiving mirtazapine and placebo respectively; 1 (1%) suspected unexpected serious adverse reaction for a participant receiving mirtazapine. There were three and two (56 days) and seven and 11 (180 days) deaths for mirtazapine and placebo respectively.
Interpretation
We can conclude, with 95% confidence, that mirtazapine of doses 15-45mg daily over 56 days does not improve severe breathlessness among patients with COPD or ILD and might cause adverse reactions. It is not recommended to alleviate severe breathlessness.

Citation

Higginson, I. J., Brown, S. T., Oluyase, A. O., May, P., Maddocks, M., Costantini, M., Bajwah, S., Normand, C., Bausewein, C., Simon, S. T., Ryan, K., Currow, D. C., Johnson, M., Hart, S. P., Mather, H., Krajnik, M., Tanzi, S., Ghirotto, L., Bolton, C., Janowiak, P., …Brown, J. M. (2024). Mirtazapine to alleviate severe breathlessness in patients with COPD or ILD: an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial (BETTER-B). Lancet, 12(10), 763-774. https://doi.org/10.1016/S2213-2600%2824%2900187-5

• Journal Article Type: Article
• Acceptance Date: Jun 4, 2024
• Online Publication Date: Sep 9, 2024
• Publication Date: Oct 1, 2024
• Deposit Date: Jun 12, 2024
• Publicly Available Date: Feb 14, 2025
• Journal: Lancet
• Print ISSN: 0140-6736
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 10
• Pages: 763-774
• DOI: https://doi.org/10.1016/S2213-2600%2824%2900187-5
• Keywords: Breathlessness; Adult; Chronic Disease; Dyspnea / therapy; palliative care; hospice; dyspneoa; respiratory disease; Lung Diseases; Interstitial; COPD; Pulmonary Disease; Chronic Obstructive; Quality of life; randomised controlled trial; Respiratory Therapy; Double-Blind Method; Treatment Outcome; Safety; Mirtazapine; ILD; Anti- depressant
• Public URL: https://hull-repository.worktribe.com/output/4708181