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

BACKGROUND: Breathlessness frequently becomes severe among people with respiratory disease. Mirtazapine, a widely used antidepressant, has shown promise in the modulation of respiratory sensation and the response to it, as well as reducing feelings of panic, which often accompanies breathlessness. We aimed to determine 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 (Australia, Germany, Ireland, Italy, New Zealand, Poland, and the UK), recruited adults with chronic obstructive pulmonary disease (COPD), interstitial lung diseases, or both, and grade 3 or 4 of the modified Medical Research Council breathlessness scale. Consenting participants were randomly assigned (1:1) to receive oral mirtazapine or matching placebo for 56 days. Randomisation was by minimisation. The initial mirtazapine dose was 15 mg, escalating to a maximum of 45 mg per 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 h measured on a 0-10 numerical rating scale (NRS), at 56 days post-treatment start, with follow-up to 180 days. The primary analysis was performed in the modified intention-to-treat population using multivariable multi-level repeated measures model. This trial was registered with ISRCTN (ISRCTN10487976 and ISRCTN15751764 [Australia and New Zealand]) and EudraCT (2019-002001-21) and is complete. FINDINGS: Between Feb 4, 2021 and March 28, 2023, we enrolled 225 eligible participants (148 men and 77 women, 113 to the mirtazapine group and 112 to the placebo group). The median age was 74 years (IQR 67-78). No evidence of a difference was found in worst breathlessness at day 56 between mirtazapine and placebo (difference in adjusted mean NRS score was 0·105 [95% CI -0·407 to 0·618]; p=0·69). Although the study was underpowered, the primary endpoint effect did not reach the pre-specified treatment effect of 0·55 for worst breathlessness score reduction that the study was powered to detect for the primary analysis. There were 215 adverse reactions in 72 (64%) of 113 participants in the mirtazapine group versus 116 in 44 (40%) of 110 participants in the placebo group; 11 serious adverse events in six (5%) participants in the mirtazapine group versus eight in seven (6%) participants in the placebo group; and one (1%) suspected unexpected serious adverse reaction in the mirtazapine group. At day 56, there were three deaths in the mirtazapine group and two deaths in the placebo group. At day 180, there were seven deaths in the mirtazapine group and 11 deaths in the placebo group. INTERPRETATION: Our findings suggested that mirtazapine of doses 15 to 45 mg daily over 56 days does not improve severe breathlessness among patients with COPD or interstitial lung diseases and might cause adverse reactions. Based on these findings, we do not recommend mirtazapine as a treatment to alleviate severe breathlessness. FUNDING: EU Horizon 2020 (grant agreement No. 825319); Cicely Saunders International Breathlessness Programme; National Institute for Health and Care Research Applied Research Collaboration South London; Australian National Health and Medical Research Council-EU (application ID: APP1170731).

Incidence of Psoriatic Arthritis in a Primary Care Psoriasis Population in the United Kingdom.

OBJECTIVE: To determine the annual incidence of psoriatic arthritis (PsA) in a United Kingdom primary care population with preexisting psoriasis (PsO) followed prospectively over 2 years after excluding baseline prevalence of existing disease. METHODS: Total Burden of Psoriasis (TUDOR; ISRCTN registry: ISRCTN38877516) was a multicenter, prospective, 2-arm parallel-group cluster randomized controlled trial of the early identification of PsA by annual rheumatological assessment (termed "Enhanced Surveillance") vs standard care in people with PsO identified in primary care. Incidence of PsA is reported at 12 months and 24 months using patients from the Enhanced Surveillance arm, which allows for the exclusion of patients with prevalent PsA at baseline. RESULTS: Fourteen of 511 participants attending a 12-month screen developed PsA over that interval, giving an incidence of 2.74/100 patient-years (PYs; 95% CI 1.32-4.16). Another 7/444 participants attending the 24-month visit developed PsA, giving an incidence of 1.58/100 PYs (95% CI 0.42-2.74). The combined incidence over 2 years was 2.20/100 PYs (95% CI 1.27-3.13). CONCLUSION: The estimated annual incidence of PsA over a 2-year period was 2.20/100 PYs, which is in keeping with studies including clinical assessment rather than relying on health records alone. Extended follow-up of the TUDOR cohort with accrual of larger numbers of incident cases will allow risk factors for PsA to be explored in more depth.

Enhanced surveillance for the detection of psoriatic arthritis in a UK primary care psoriasis population: results from the TUDOR trial.

BACKGROUND: Our objective was to determine whether early detection of undiagnosed psoriatic arthritis (PsA) in a primary care psoriasis population improves outcome in physical function at 24 months post-registration. METHODS: A multicentre, prospective, parallel group cluster randomised controlled trial in patients with psoriasis was conducted. Participants with suspected inflammatory arthritis on screening were referred for an assessment of PsA (enhanced surveillance (ES) arm: at baseline, 12 and 24 months; standard care (SC) arm: at 24 months). The primary outcome measure was the Health Assessment Questionnaire Disability Index (HAQ-DI) at 24 months post registration in participants diagnosed with PsA. RESULTS: A total of 2225 participants across 135 GP practices registered: 1123 allocated to ES and 1102 to SC. The primary analysis population consisted of 87 participants with a positive diagnosis of PsA: 64 in ES, 23 in SC. The adjusted odds ratio (OR) for achieving a HAQ-DI score of 0 at 24 months post registration in ES compared with SC was 0.64 (95% CI (0.17, 2.38)), and the adjusted OR of achieving a higher (non-zero) HAQ-DI score at 24 months post registration in ES relative to SC arm was 1.12 (95% CI: 0.67, 1.86), indicating no evidence of a difference between the two treatment groups (p= 0.66). CONCLUSION: The trial was underpowered for demonstrating the prespecified treatment effect; in patients with psoriasis there was no evidence that early diagnosis of PsA by ES in primary care changes physical function at 24 months compared with SC. CLINICAL TRIAL REGISTRATION: The TUDOR trial is registered as ISRCTN38877516.

The comparative performance of three screening questionnaires for psoriatic arthritis in a primary care surveillance study.

OBJECTIVES: The objective of this study was to compare the performance of three PsA screening questionnaires in a primary care psoriasis surveillance study. METHODS: Participants with psoriasis, and not known to have PsA, were identified from general practice databases and invited to attend a secondary care centre for a clinical assessment. The three patient-completed screening questionnaires (PEST, CONTEST and CONTESTjt) were administered, along with other patient-reported measures, and a clinical examination of skin and joints was performed. Participants who demonstrated signs of inflammatory arthritis suggestive of PsA were referred, via their GP, for a further assessment in a secondary care rheumatology clinic. RESULTS: A total of 791 participants attended the screening visit, and 165 participants were judged to have signs and symptoms of inflammatory arthritis, of which 150 were referred for assessment. Of these, 126 were seen and 48 were diagnosed with PsA. The results for each questionnaire were as follows: PEST: sensitivity 0.625 (95% CI 0.482, 0.749), specificity 0.757 (0.724, 0.787); CONTEST: sensitivity 0.604 (0.461, 0.731), specificity 0.768 (0.736, 0.798); and CONTESTjt: sensitivity 0.542 (0.401, 0.676), specificity 0.834 (0.805, 0.859). CONTESTjt demonstrated marginally superior specificity to PEST, though the area under the ROC curve was similar for all three instruments. CONCLUSION: Minimal differences between the three screening questionnaires were found in this study, and no preferred questionnaire is indicated by these results. The choice of which instrument to choose will depend on other factors, such as simplicity and low patient burden.

Long-term effectiveness of a novel intra-oral electro-stimulator for the treatment of dry mouth in patients with Sjogren's syndrome: A randomised sham-controlled feasibility study (LEONIDAS-1).

BACKGROUND: Effective treatments for dry mouth of Sjogren's syndrome are limited and hampered by adverse effects. The aim of LEONIDAS-1 was to explore the feasibility of salivary electrostimulation in individuals with primary Sjogren's syndrome, as well as parameters required to inform the design of a future phase III trial. METHODS: Multicentre, parallel-group, double-blind, randomised sham-controlled trial in two UK centres. Participants were randomised (1:1, computer-generated) to active or sham electrostimulation. The feasibility outcomes included screening/eligibility ratio, consent, and recruitment and drop-out rates. Preliminary efficacy outcome included dry mouth visual analogue scale, Xerostomia Inventory, the EULAR Sjögren's syndrome patient reported index-Q1, and unstimulated sialometry. RESULTS: Forty-two individuals were screened, of whom 30 (71.4%) met the eligibility criteria. All eligible individuals consented to recruitment. Out of the 30 randomised participants (active n = 15, sham n = 15), 4 dropped out and 26 (13 vs. 13) completed all study visits as per protocol. Recruitment rate was 2.73 participants/month. At 6-month post-randomisation the difference in mean reduction in visual analogue scale, xerostomia inventory and EULAR Sjögren's syndrome patient reported index-Q1 scores between groups were 0.36 (95% CI: -0.84, 1.56), 3.31 (0.43, 6.18), and 0.23 (-1.17, 1.63), respectively; unstimulated salivary flow increased by a mean of 0.98 mL/15 min, all in favour of the active group. No adverse events were reported. CONCLUSION: LEONIDAS-1 results support progression to a phase III definitive randomised controlled trial of salivary electrostimulation in individuals with Sjogren's syndrome. Xerostomia inventory could be considered the primary patient-centred outcome measure and the corresponding observed treatment effect could inform the sample size of a future trial.