• David Currow, Gareth John Watts, Miriam Johnson, Christine F McDonald, John O Miners, Andrew A Somogyi, Linda Denehy, Nicola McCaffrey, Danny J Eckert, Philip McCloud, Sandra Louw, Lawrence Lam, Aine Greene, Belinda Fazekas, Katherine C Clark, Kwun Fong, Meera R Agar, Rohit Joshi, Sharon Kilbreath, Diana Ferreira, Magnus Ekström, and Australian national Palliative Care Clinical Studies Collaborative (PaCCSC).
• Discipline, Palliative and Supportive Services, Flinders University, Adelaide, Australia.
• BMJ Open. 2017 Jul 17; 7 (7): e018100.

IntroductionChronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended- release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD.Methods And AnalysisThe primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used.Ethics And DisseminationEthics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness.Trial Registration NumberNCT02720822; Pre-results.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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