Study protocol: a phase III randomised, double-blind, parallel arm, stratified, block randomised, placebo-controlled trial investigating the clinical effect and cost-effectiveness of sertraline for the palliative relief of breathlessness in people with chronic breathlessness

Abstract

IntroductionBreathlessness remains a highly prevalent and distressing symptom for many patients with progressive life-limiting illnesses. Evidence-based interventions for chronic breathlessness are limited, and there is an ongoing need for high-quality research into developing management strategies for optimal palliation of this complex symptom. Previous studies have suggested that selective serotonin reuptake inhibitors such as sertraline may have a role in reducing breathlessness. This paper presents the protocol for a large, adequately powered randomised study evaluating the use of sertraline for chronic breathlessness in people with progressive life-limiting illnesses.Methods and analysisA total of 240 participants with modified Medical Research Council Dyspnoea Scale breathlessness of level 2 or higher will be randomised to receive either sertraline or placebo for 28 days in this multisite, double-blind study. The dose will be titrated up every 3 days to a maximum of 100 mg daily. The primary outcome will be to compare the efficacy of sertraline with placebo in relieving the intensity of worst breathlessness as assessed by a 0–100 mm Visual Analogue Scale. A number of other outcome measures and descriptors of breathlessness as well as caregiver assessments will also be recorded to ensure adequate analysis of participant breathlessness and to allow an economic analysis to be performed. Participants will also be given the option of continuing blinded treatment until either study data collection is complete or net benefit ceases. Appropriate statistical analysis of primary and secondary outcomes will be used to describe the wealth of data obtained.Ethics and disseminationEthics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals and the key findings presented at national and international conferences.Trial registration numberACTRN12610000464066.

Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial

“…This double-blind, dose increment, parallel-arm, multisite, randomised, placebo-controlled, adaptive study was conducted in accordance with International Conference on Harmonisation Good Clinical Practice [17,18] and registered at www.anzctr.org.au (ACTRN 12610000464066).…”

Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial

“…(Pilot study participants did not have the option of the extension study). [18] There were no difference in functional status; nor anxiety or depression scores. Using baseline values for CO 2 , mMRC, CCI, HADS anxiety, rescue medication use and AKPS as predictors of breathlessness response (≥8•9mm change), there was only one significant association: a higher Charlson Comorbidity Index was associated with a greater likelihood of response for VAS average breathlessness in the previous 24 hours alone (p=0•041) and with the other prognostic factors (0•028).…”

“…This double blind, dose increment, parallel arm, multi-site, randomised, placebo-controlled, adaptive study was conducted in accordance with International Committee on Harmonization -Good Clinical Practice (ICH GCP) [17,18] and registered (ACTRN12610000464066). The adaptive design was a blinded phase II / III study where the phase II study was not unblinded (having demonstrated acceptability and feasibility), moving directly to the phase III study.…”

Non-opioid medications for the relief of chronic breathlessness: current evidence

“…[Eudract number 2015-004064 -11] Phase III RCTs are required to give definitive evidence of these agents for the treatment of breathlessness; one is due to report early 2017 (ACTRN12610000464066; sertraline for chronic breathlessness). 41 A safety trial in people with COPD undergoing pulmonary rehabilitation is underway ([NCT02813447]; primary outcomes of breathlessness scores, quality of life and exercise tolerance measures will be primary outcomes.…”