Controlled-Release Oxycodone vs. Placebo in the Treatment of Chronic Breathlessness—A Multisite Randomized Placebo Controlled Trial

Journal Pre-proof Controlled-release oxycodone versus placebo in the treatment of chronic breathlessness – a multi-site randomised placebo controlled trial Diana H. Ferreira, MD, MPC, Sandra Louw, BSc, Philip McCloud, PhD, Belinda Fazekas, DipAppSci (Nsg), BN, GradDipCommHealth, Christine F. McDonald, AM, FAHMS, MBBS (Hons), FRACP, PhD, FCCP, FThorSoc, Meera Agar, PhD, FRACP, FAChPM, MPallCare, MBBS, Katherine Clark, MBBS, MMed, PhD, Nikki McCaffrey, PhD, Magnus Ekström, MD, PhD, David C. Currow, FAHMS, BMed, MPH, PhD, FRACP, On behalf of the Australian national Palliative Care Clinical Studies Collaborative (PaCCSC) PII:

S0885-3924(19)30608-6

DOI:

https://doi.org/10.1016/j.jpainsymman.2019.10.017

Reference:

JPS 10278

To appear in:

Journal of Pain and Symptom Management

Received Date: 11 August 2019 Revised Date:

14 October 2019

Accepted Date: 16 October 2019

Please cite this article as: Ferreira DH, Louw S, McCloud P, Fazekas B, McDonald CF, Agar M, Clark K, McCaffrey N, Ekström M, Currow DC, On behalf of the Australian national Palliative Care Clinical Studies Collaborative (PaCCSC), Controlled-release oxycodone versus placebo in the treatment of chronic breathlessness – a multi-site randomised placebo controlled trial, Journal of Pain and Symptom Management (2019), doi: https://doi.org/10.1016/j.jpainsymman.2019.10.017. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of American Academy of Hospice and Palliative Medicine

Controlled-release oxycodone versus placebo in the treatment of chronic breathlessness – a multi-site randomised placebo controlled trial

Diana H. Ferreira , MD, MPC 1 Sandra Louw BSc 2 Philip McCloud PhD 2 Belinda Fazekas DipAppSci (Nsg), BN, GradDipCommHealth 1,3 Christine F. McDonald AM, FAHMS, MBBS (Hons), FRACP, PhD, FCCP, FThorSoc 4,5 Meera Agar PhD, FRACP, FAChPM, MPallCare, MBBS

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Katherine Clark MBBS, MMed, PhD 6,7 Nikki McCaffrey PhD 8 Magnus Ekström MD, PhD 3,9 David C. Currow FAHMS, BMed, MPH, PhD, FRACP1,3 On behalf of the Australian national Palliative Care Clinical Studies Collaborative (PaCCSC)

1 Discipline, Palliative and Supportive Services, Flinders University, Adelaide, South Australia, Australia. 2 McCloud Consulting Group, Narabang Way, Belrose, New South Wales, Australia 3 IMPACCT, Faculty of Health, University of Technology Sydney, Ultimo, New South Wales. Australia. 4 Austin Health, Heidelberg, Victoria. Australia 5 University of Melbourne, Parkville, Victoria. Australia 6 Northern Sydney Local Health District, St Leonards, New South Wales, Australia. 7 University of Sydney, Glebe, New South Wales. Australia 8 Deakin Health Economics, School of Health and Social Development, Deakin University, Victoria, Australia. 9 Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund, Sweden

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Corresponding author: Prof David Currow FAHMS IMPACCT, Faculty of Health University of Technology Sydney P O Box 123 Ultimo, NSW. Australia 2007

Word count

3235

Tables and figures

5

References

32

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Abstract Context: Chronic breathlessness is a clinical syndrome that results in significant distress and disability. Morphine can reduce chronic breathlessness when the contributing aetiologies are optimally treated. Objective: Does oxycodone reduce chronic breathlessness compared with placebo? Methods: A multi-site, randomised, placebo-controlled, double-blind, parallel-arm, fixeddose trial of oral controlled-release oxycodone 15mg (5 mg 8 hourly) or placebo (ACTRN12609000806268 at www.anzctr.org.au). ‘As needed’ immediate-release morphine (2.5mg per dose; ≤6 doses/day) was available for both arms as required by one ethics committee overseeing the trial. Recruitment occurred from 2010 to 2014 in 14 inpatient and outpatient respiratory, cardiology and palliative care services across Australia. Participants were adults, with chronic breathlessness (modified Medical Research Council Scale 3 or 4), who were opioid naïve. The primary endpoint was the proportion of people with >15% reduction from baseline in the intensity of breathlessness now (0-100 mm visual analogue scale) comparing arms days 5-7. Secondary endpoints were ‘average’ and ‘worst’ breathlessness; quality of life; function; and harms. Results: Of 157 participants randomised, 155 were included (74 oxycodone, 81 placebo), but the study did not reach target recruitment. There was no difference between groups for the primary outcome (p=0.489) nor any of the pre-specified secondary outcomes. Placebo participants used more ‘as needed’ morphine (mean 7.0 versus 4.2 doses; p≤0.001). Oxycodone participants reported more nausea (p<0.001). Conclusions: There was no signal of benefit from oxycodone over placebo. Future research should focus on investigating the existence of an opioid class effect on the reduction of chronic breathlessness.

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Key Messages: Does oxycodone off the same symptomatic benefits of regular, low dose, sustained release morphine for reducing chronic breathlessness? This world’s largest double blind, placebo-controlled study of oxycodone for reducing chronic breathlessness is strongly negative. Despite being underpowered, it doesn’t justify larger phase III studeis nor support an opioid class effect.

Key words: Chronic breathlessness, oxycodone, randomised controlled trial, effectiveness study, placebo study, palliative care, symptom control. Running title: Oxycodone for chronic breathlessness

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Background Chronic breathlessness is a debilitating syndrome [1] affecting one percent of the population long-term day-to-day. [2] Seventeen percent of elderly adults experience breathlessness regularly. [2] Increasing age and chronic diseases including chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF) and cancer contribute to the global burden of chronic breathlessness. [3] More than 95% of people with COPD experience breathlessness despite adequate disease management, some of whom will be housebound. [4] Chronic breathlessness is highly distressing. Some people describe “existing rather than living”. [5] Chronic breathlessness often increases as death approaches, becoming more prevalent and intense, particularly in people with cardiorespiratory diagnoses [6] and is one of the most feared aspects of dying. [7] Despite this community-wide symptom burden, pharmacological interventions have been limited. National and international guidelines recommend morphine for the reduction of chronic breathlessness (level I evidence). [8, 9] Doses as low as 10 mg/24 hours were shown to be effective and safe, even in people with COPD. [11-13] It is unclear whether there is a class effect of opioids on the symptomatic reduction of chronic breathlessness as almost all studies have used morphine. [12, 14] Oxycodone, a µ-opioid agonist, is potentially more acceptable to patients due to misconceptions about morphine. [15] A small randomised, placebo-controlled, cross-over trial in participants with CHF showed no improvement in breathlessness scores with oral oxycodone 2.5 mg every 6 hours compared to placebo. [16] However, no adequately powered, blinded randomised, placebocontrolled trials have evaluated oxycodone for the symptomatic reduction of chronic breathlessness in other aetiologies. The aim of this randomised, placebo-controlled trial was to determine the efficacy and safety of regular, oral controlled-release (CR) oxycodone 5 mg every 8 hours, in participants with chronic breathlessness due to a range of causes, over a one-week period. The null hypothesis was that there would be no difference in breathlessness now between study arms. Methods Study Design This study was initially a phase III, multi-centre, double blind, block-randomised (1:1:1), fixed dose, triple arm study of 20 mg oral sustained release (SR) morphine daily compared to 15 mg oral controlled-release (CR) oxycodone daily (5mg every eight hours) compared to placebo for seven days, for the reduction of chronic breathlessness. The lower than expected recruitment rate resulted in a protocol review in order to achieve the study primary objective (comparison between morphine and placebo) in the timeframe. Consequently, the oxycodone arm was ceased before reaching the recruitment target. The results from the main study 5

analysis (SR morphine / placebo) are presented elsewhere. [17] This study presents a findings from oxycodone and placebo until the oxycodone arm deletion (July 2014). Ethics and Consent This trial was approved by the Human Research Ethics Committee at each site and the trial was registered with the Australian New Zealand Clinical Trials Registry before the first participant was recruited (ACTRN12609000806268). All participants provided written informed consent to participate before commencing. Study Subjects Participants were recruited from 14 inpatient and outpatient respiratory, cardiology and palliative care services across Australia. This study included adults with chronic breathlessness (3 or 4 on the modified Medical Research Council (mMRC) breathlessness scale) at screening, which corresponds to “stops for breath after walking 100 metres or after a few minutes on the level” or “too breathless to leave the house or breathless when dressing or undressing”. [18] For every participant, a relevant specialist physician documented that reversible causes of the breathlessness were optimised. Other inclusion criteria were: on stable medication for breathlessness over the previous seven days except routine “as needed” medications; prognosis of at least two months based on the treating clinician’s judgement; and English-speaking with sufficient understanding to complete the study questionnaires. Exclusion criteria were: treatment with any opioid medications ≥ 20 mg oral morphine equivalent daily dose (MEDD) in the previous seven days; blood transfusion for breathlessness-associated anaemia in the previous month; Australia-modified Karnofsky Performance Status (AKPS) of <40 at baseline; [19] uncontrolled nausea, vomiting or gastrointestinal obstruction; renal dysfunction (calculated creatinine clearance of < 25 mls/minute0; severe hepatic impairment (3 times upper limit of normal for 2 or more hepatic enzymes (serum alkaline phosphatase, gamma GT, ALT or AST), or INR >1.2 when not treated with warfarin); respiratory depression (resting respiratory rate <8 breaths/minute); an active respiratory or cardiac event in the previous week, excluding upper respiratory tract infections; documented previous respiratory failure induced by any opioid medication; unable to give informed consent or complete diary entries; or being pregnant or breastfeeding. Randomisation and interventions Strata tables were developed for each site using random number tables, generated at an independent centre (central registry). Treatment for each participant was allocated according to randomisation schedule held by the central registry for oxycodone or identically-appearing placebo for seven days. Randomisation was stratified in blocks of four by site and by dominant cause of breathlessness (COPD, cancer, end-stage CHF, mixed or other). On notification of a participant, the pharmacist at each site consulted the strata table according to the strata determined by the dominant cause of breathlessness, and allocated the next code for 6

the dispensed medicine delivered in individually labelled patient boxes. All participants and assessors were blinded to the treatment assignment until the past participant had completed data collection. One Human Research Ethics Committee (HREC) overseeing this trial required that all participants included in the study had access to take up to six ‘as needed’ doses per 24 hours of immediate release oral morphine solution 2.5 mg per dose (maximum of 15 mg per 24 hours). Participants in the active arm also took blinded docusate with sennosides A and B, and participants in the placebo arm took identical-looking placebo laxative. Open label docusate with sennosides A and B was also available to all participants. After completing the study intervention, participants were followed-up weekly for four weeks. The first three weekly assessments were conducted by telephone, and the fourth faceto-face. Outcomes The primary outcome was the proportion of people in each arm whose breathlessness now decreased ≥15% over baseline, averaging the scores collected on days 5-7. The choice of 15% was based on the magnitude of difference seen in an earlier randomised, placebocontrolled, cross-over study of sustained release morphine. [10] Participants were asked “How is your breathlessness right now?” on a 0-100 mm visual analogue scale (VAS), with the anchors “No breathlessness” and “Worst possible breathlessness”. A sensitivity analysis evaluated the proportion of people with an absolute reduction of >8.9 mm. [24] Secondary outcomes included changes from baseline to averages of days 5-7 using the VAS in: - Scores of self-rated worst, best and average breathlessness in the previous 24 hours and unpleasantness of breathlessness now; and at the end of treatment for: -

-

Participants’ quality of life (European Organization for Research and Treatment of Cancer- Quality of Life Questionnaire core 15-Palliative Care (EORTC-QLQ-C15 PAL) where higher scores reflect poorer quality of life) [20]; Carers’ quality of life (Carer Quality of Life Index - Cancer; CQOLC; with higher scores reflecting better quality of life) [21]; Global impression of change and blinded participant preference to continue the assigned treatment arm [22] measured; Oxyhemoglobin saturation and end-tidal carbon dioxide measurement (ETCO2) [Lifesense Monitor, Nonin Medical Inc, Plymouth MN, USA] as a measure for safety; Functional status using the AKPS [19] as a measure of safety; Frequency and severity of treatment emergent adverse events (TEAE) using the 5point National Cancer Institute Common Terminology Criteria of Adverse Event (NCI CTC AE) reporting version 4.0 [23] where TEAEs were defined as a 1 point worsening over baseline scores. 7

Sample size considerations Assuming a standard deviation (SD) of approximately 22 mm for the primary outcome, [10] a total sample of 120 participants per group would have provided at least 80% power to detect a clinically important change of 8.9 mm between groups, [24] assuming a two tailed pvalue of 5%. Analysis All effectiveness analyses were conducted on an intention-to-treat (ITT) basis using all available data. As sensitivity analyses, missing values for the primary analysis of breathlessness were imputed using Markov Chain Monte Carlo (MCMC) multiple imputation (MI) with 50 samples redrawn. [25] The MI analyses included all subjects in the ITT population except those who did not have any VAS breathlessness assessments recorded in the patient diary at any time point including baseline. The mean differences between arms in the primary and secondary endpoints were also analysed using analysis of covariance (ANCOVA), with change from baseline as the dependent variable; study site, baseline dominant cause of breathlessness, and interaction between stratification factors; baseline score as the baseline covariate; and treatment group as a predictor variable. Response variables were analysed using logistic regression including the same independent variables as the ANCOVA, with estimates expressed as odds ratios (OR). Safety analyses included all participants who received at least one dose of study medication. A priori, the protocol identified a key exploratory question: to identify any sub-group who might be more likely to respond, experience harms or experience no response in order to focus future research efforts using baseline clinical and demographic characteristics in a regression model. All estimates are presented with 95% confidence intervals (CI). All statistical tests were twosided tests at the 5% level of significance. Secondary endpoints were exploratory and pvalues were not adjusted for multiple comparisons. All secondary analyses (excluding the breathlessness sensitivity analyses) were conducted on the data as observed, with no imputation for missing values. Analyses were performed with SAS version 9.4. (SAS Corporation, Carey, NC, USA). This study is reported using the CONSORT statement. [26] Results Between February 2010 and July 2014, 157 participants were randomised to oxycodone (n=74) or placebo (n=83; Figure 1). Two participants in the placebo arm withdrew from the study before completing any baseline assessment and were excluded from the ITT analysis (n=155). Participants had a mean age of 75 years (SD, 8.63); 48 (65%) were male; 93 (60%) had COPD; 108 (72%) were ex-smokers; and 95 (68%) had a baseline mMRC breathlessness 8

score of 3-4 (Table 1). More participants completed treatment when on placebo (n=69, 85%) than oxycodone (n=54, 73%). Breathlessness endpoints The proportion of people who achieved a >15% reduction in breathlessness now did not differ between arms (CR oxycodone 45.6%; placebo 50.7%; p=0.489). The proportion who achieved an 8.9 mm reduction did not differ (CR oxycodone 50.9%; placebo 53.5%; p=0.693). The reduction in breathlessness now was greater in the placebo arm (mean difference 5.33; 95% CI, ─1.22 to 11.88; p=0.109; Table 2) and the odds of ≥15% improvement in baseline breathlessness scores in the oxycodone group were 0.78 times the odds of response in the placebo group (95% CI for odds ratio 0.38 to 1.59, p-value = 0.489). No statistically significant differences were seen for any of the secondary breathlessness outcomes (Table 2). All sensitivity analyses were consistent with the main analysis in direction and magnitude, and were non-significant. Function, quality of life and blinded participants’ preference Functional status and global quality of life were not significantly different between arms (Table 3). Emotional functioning (EORTC-QLQ-15) improved significantly more from baseline to the end of treatment in the placebo arm (mean difference -6.76; 95% CI -13.36 to -0.15; p=0.045). Conversely, nausea or vomiting (EORTC-QLQ-15) increased significantly more from baseline to the end of treatment in the oxycodone arm (mean difference 7.04; 95% CI 0.19 to 13.89; p=0.044), as did anorexia (EORTC-QLQ-C15, mean difference 17.56; 95% CI 7.54, 27.59). Blinded participants’ preferences differed between study arms: although nearly half of the participants believed they were less breathless after starting the study medication whether they were on oxycodone (44.9%) or placebo (51.3%; p-value=0.436), a higher percentage of participants in the placebo arm considered that the study medication would benefit them enough to take it long term (50.6% vs. 27.3%, p-value=0.006). Use of rescue medication The average total number of doses of rescue medication taken in the study was higher in the placebo arm (7.0 doses) compared with the oxycodone arm (4.2 doses; adjusted ratio 0.61; 95% CI of adjusted ratio, 0.52 to 0.70; p≤ 0.001). Similarly, the average number of daily doses taken was lower in the oxycodone arm (mean difference -0.61; 95% CI, ─1.02 to ─0.20; p<0.001), and this difference was consistent across all study days (non-significant interaction between study day and rescue treatment; p=0.688). Safety The profile of TEAEs was similar between oxycodone and placebo. Most participants in both treatment arms experienced at least one TEAE of interest (90.3% oxycodone, 94.9% placebo; p=0.276) but less than 25% of participants experienced a serious TEAE (20.8% oxycodone, 9

24.1% placebo). A higher proportion of grade 3-5 adverse events led to withdrawal from the study medication in the oxycodone arm (26.1%) compared with the placebo arm (6.3%). For the oxycodone arm, all of these adverse events either resolved or were resolving by the end of the study. For the placebo arm, most adverse events were still unresolved by the end of the study. Significantly more participants in the placebo group experienced bronchospasm (29.2% oxycodone, 50.6% placebo; p=0.008). Conversely, participants taking oxycodone experienced significantly more nausea than participants taking placebo (43.1%. 1.3%; p<0.001). Vomiting was higher in the placebo arm (5.6%, 22.8%; p=0.003; Table 4). ETCO2 increased more from baseline to the end of treatment in the oxycodone arm than in the placebo arm (mean difference 3.39; 95% CI, 1.52 to 5.26; p<0.001). Oxyhemoglobin saturation decreased more from baseline to the end of treatment in the oxycodone arm than in the placebo arm (mean difference -2.65; 95% CI, -4.09 to -1.21; p<0.001). There was no significant between-group difference in change from baseline to the end of treatment for respiratory rate (mean difference -0.81; 95% CI, -2.71 to 1.10; p=0.404) and no difference in mortality. Sub-group analyses Hypothesis-generating sub-group analyses were conducted for the purpose of identifying any sub-groups who were more likely to respond, have more harms or no benefit with the intervention. The treatment difference in each of the sub-groups was consistent with the overall result. There were no sub-groups from baseline characteristics who had a statistically significant interaction with treatment (all sub-group by interaction p-values > 0.05). Discussion This is the largest RCT evaluating oxycodone for symptomatic chronic breathlessness. People with a range of aetiologies were included. Immediate and short term signal of benefits and harms were measured. Due to delays in recruitment and constraints in funding, the oxycodone arm was ceased early. [17] Thus, this analysis is underpowered to demonstrate differences between arms and the results must be interpreted in this context. This study failed to demonstrate any signal of differences between oxycodone and placebo on intensity of breathlessness now or the secondary measures of breathlessness. Those in the placebo arm had a greater reduction in breathlessness now but this group used slightly more breakthrough morphine (a between group difference of less than three doses of 2.5 mg of morphine over the week) which may have slightly reduced differences between arms. A sub-group analysis of the morphine/placebo analysis [17] indicated that participants with mMRC 3 and 4 at baseline (the population in the present study and the original population in the morphine/placebo study) could potentially derive more benefit from therapy than patients with mMRC 2. Previous pooled data demonstrated that people with more severe 10

breathlessness derive more benefit from opioid therapy. [27] Results from this study suggest oxycodone may be ineffective in reducing the sensation of chronic breathlessness. Both oxycodone and morphine are pure opioid agonists [28] with a particularly high affinity for µ-opioid receptors which are found in respiratory centres and in other central structures involved in the perception of breathlessness. [29] However, previous research has demonstrated the anti-nociceptive effects of oxycodone are also strongly mediated by its action on κ-opioid receptors. [30] Further work needs to be done to understand the relative contribution and interactions between µ and κ opioid receptors, and their modulation of the sensation of chronic breathlessness. Such work will help to understand whether there is a class effect of opioids, or a more receptor-specific effect. Oxycodone caused more nausea than placebo. Emotional function (EORTC-QLQ-15) worsened significantly more on the placebo arm. Anorexia increased significantly more in the oxycodone arm. Persistence of these side effects after seven days of therapy does not reflect previous trials of morphine for chronic breathlessness. [10, 31] Interestingly, vomiting was higher in the placebo arm which can be a result of chance or a consequence of the higher number of rescue doses of immediate-release morphine taken by people in that arm. The absence of clinical benefit together with the adverse event profile in steady state is similar to the findings in a recent study of SR morphine for people with breathlessness associated with pulmonary arterial hypertension. [32] This absence of net benefit and continuing nausea may occur when opioids saturate receptors while leaving excess circulating opioid to trigger harms. [28] The absence of net benefit is further suggested by the higher number of participants who have a blinded preference for placebo over oxycodone. Strengths and limitations This was the first multi-centre, parallel-arm, randomised, placebo-controlled trial conducted to evaluate oxycodone for chronic breathlessness across a range of aetiologies. It was conducted in concordance with good clinical practices, it followed a rigorous methodology and included relevant and validated outcomes. It is an important study given the widespread use of oxycodone in clinical practice. This study did not recruit to target. Low sample sizes increase chances of type 2 errors. In addition, all participants had access to up to six daily doses of immediate-release oral morphine for breathlessness, lessening differences between arms. Implications for future research This study showed no signal in direction nor magnitude for CR oxycodone over placebo for the reduction of symptomatic chronic breathlessness. Whether this exploratory study justifies a larger phase III study is a challenging question. Oxycodone is widely used in clinical practice for pain, so its impact on the reduction of chronic breathlessness is of clinical 11

interest. Whether there is an opioid class effect on the reduction of the sensation of chronic breathlessness is an important scientific and clinical question to resolve. Conclusions This trial showed no signal of differences between CR oxycodone and placebo for reducing chronic breathlessness associated with different aetiologies but the study was underpowered. Differences between arms in use of rescue medication were statistically significant but clinically small. It is unlikely that an adequately powered study would have found clinically significant differences between arms for the relief of chronic breathlessness. Disclosures and Acknowledgement Conflicts of Interest DF, SL, PM, BF, CMcD, MA, KC, NM, and ME report no conflicts of interest. DCC is an unpaid advisory board member for Helsinn Pharmaceuticals. He is a paid consultant and receives payment for intellectual property with Mayne Pharma and is a consultant with Specialised Therapeutics Australia Pty. Ltd. Acknowledgements Thanks go to every participant in this study at a very difficult time of their life, and to the families and friends who supported them. Thanks go to the staff at each site also for their enduring efforts in working with participants recruited for the study. The author Diana H. Ferreira would like to thank Fundação para a Ciência e Tecnologia (FCT), from the Portuguese Government, for funding her PhD grant (SFRH/BD/109920/2015). The authors thank Ms. Debbie Marriott for her ready assistance and for her expertise in article formatting and submission. Funding Funding was provided for the study by the Australian Government Department of Health through the National Palliative Care Program. The funder had no control over study design, conduct, analysis nor dissemination of results. Data Sharing The dataset analysed during the current study is available from the corresponding author on reasonable request.

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References 1. Johnson MJ, Yorke J, Hansen-Flaschen J, et al. Towards an expert consensus to delineate a clinical syndrome of chronic breathlessness. Eur Respir J 2017;49(5):1602277. 2. Currow DC, Plummer JL, Crockett A, et al. A community population survey of prevalence and severity of dyspnea in adults. J Pain Symptom Manage 2009;38(4):533-545. 3. Moens K, Higginson IJ, Harding R, EURO IMPACT. Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review. J Pain Symptom Manage 2014;48(4):660677. 4. Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage 2006;31(1):58-69. 5. Rocker G, Horton R, Currow D, et al. Palliation of dyspnoea in advanced COPD: revisiting a role for opioids. Thorax 2009;64(10):910-915. 6. Currow DC, Smith JM, Chansriwong P, et al. Missed opportunity? Worsening breathlessness as a harbinger of death. A cohort study. Eur Respir J 2018;52(3):1800684. 7. O'Driscoll M, Corner J, Bailey C. The experience of breathlessness in lung cancer. Eur J Cancer Care (Engl) 1999;8(1):37-43. 8. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012;185(4):435-452. 9. Global Strategy for the Diagnosis, Management and Prevention of COPD: Global Initiative for Chronic Obstructive Lung Disease; 2017 Available from: http://goldcopd.org/ Accessed 06 February 2019. 10. Abernethy AP, Currow DC, Frith P, et al. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ 2003;327(7414):523-528. 11. Currow DC, McDonald C, Oaten S, et al. Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study. J Pain Symptom Manage 2011;42(3):388-399. 12. Ekstrom M, Nilsson F, Abernethy AA, Currow DC. Effects of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease. A systematic review. Ann Am Thorac Soc 2015;12(7):1079-1092. 13

13. Bajwah S, Davies JM, Tanash H, et al. Safety of benzodiazepines and opioids in interstitial lung disease: A national prospective study. Eur Respir J 2018;DOI: 10.1183/13993003.01278-2018 14. Ekström M, Bajwah S, Bland JM, et al. One evidence base; three stories: do opioids relieve chronic breathlessness? Thorax 2018;73(1):88-90. 15. García-Toyos N E-CM, Sanz-Amores R, Guerra-De Hoyos JA, et al. Preferences of Caregivers and Patients Regarding Opioid Analgesic Use in Terminal Care. Pain Med 2014;15:577-587. 16. Oxberry SG, Torgerson DJ, Bland JM, et al. Short-term opioids for breathlessness in stable chronic heart failure: a randomized controlled trial. Eur J Heart Fail 2011;13(9):10061012. 17. Currow D, Louw S, Mccloud P, et al. Regular extended release morphine for chronic breathlessness: a multi-centre double-blind RCT. Eur Respir J 2018;52 Suppl. 62:OA1624. 18. Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest 1988;93(3):580-586. 19. Abernethy AP, Shelby-James T, Fazekas BS, et al. The Australia-modified Karnofsky Performance Status (AKPS) scale: a revised scale for contemporary palliative care clinical practice [ISRCTN81117481]. BMC Palliat Care 2005;4(1):7. 20. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-376. 21. Weitzner MA, Jacobsen PB, Wagner H Jr, et al. The caregiver Quality of Life IndexCancer (CQOLC) scale: development and validation of an instrumentto measure quality of life of the family caregiver of patients with cancer. Qual Life Res 1999;8(1-2):55-63. 22. Farrar JT, Young JP, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94(2):149-158. 23. Institute NC. Common Terminology Criteria for adverse events (CTCAE) Version v4.0 NCI, NIH, DHHS. NIH publication # 09-7473, 2009. accessed 30 Jan 2019. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50 24. Johnson MJ, Bland JM, Oxberry SG, et al. Clinically important differences in the intensity of chronic refractory breathlessness. J Pain Symptom Manage 2013;46(6):957-963. 14

25. Statistical Computing Seminars Missing Data in SAS Part 1: UCLA: Statistical Consulting Group; [Available from: http://www.ats.ucla.edu/stat/sas/seminars/missing_data/mi_new_1.htm. 26. Schulz KF, Altman DG, Moher D and the CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMC Med 2010;8(1):18. 27. Johnson MJ, Bland JM, Oxberry SG, et al. Opioids for chronic refractory breathlessness: patient predictors of beneficial response. Eur Respir J 2013;42(3):758-766. 28. Fallon MT, Cherny NI. Opioid therapy: optimizing analgesic outcomes. In: Oxford textbook of palliative medicine. Fifth edition. Oxford: Oxford University Press, 2015. Chapter 9.4. p.525-559. 29.

Kalso E. How different is oxycodone from morphine? Pain. 2007;132(3):227-228.

30. Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone appear to be κ-opioid receptor mediated. Pain 1997;73(2):151-157. 31. Johnson MJ, McDonagh TA, Harkness A, et al. Morphine for the relief of breathlessness in patients with chronic heart failure--a pilot study. Eur J Heart Fail 2002;4(6):753-756.

32. Ferreira DH, Ekström M, Sajkov D, et al. Extended-Release Morphine for Chronic Breathlessness in Pulmonary Arterial Hypertension—A Randomized, Double-Blind, PlaceboControlled, Crossover Study. J Pain Symptom Manage 2018;56(4):483-492.

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Table 1 - Baseline characteristics of the intention-to-treat population Intention-to-treat – population

Age

Oxycodone

Placebo

n=74

n=81

74

80

Mean (SD)

74.49 (8.35)

74.83 (8.92)

Min, max

55.3, 89.2

52.2, 89.4

26 (35.1%)

28 (34.6%)

69

77

Mean (SD)

24.79 (5.25)

26.16 (7.77)

Min, max

13.7, 34.8

12.3, 47.8

74

79

Mean (SD)

3.2 (2.3)

3.1 (2.1)

Min, max

1, 13

1, 8

74

81

Mean (SD)

62.4 (8.2)

60.6 (9.3)

Min, max

40, 80

40, 80

n

Gender n (%)

Female

BMI (kg/m2)

n

Charlson Co-morbidity Index

Performance status (AKPS)

n

n

Smoking status

Never smoked

14 (18.9%)

15 (18.5%)

n (%)

Ex-smoker

51 (68.9%)

57 (70.4%)

Current smoker

6 (8.1%)

7 (8.6%)

Missing

3 (4.1%)

2 (2.5%)

74

80

34.88 (23.68)

40.87 (23.25)

0-100mm visual analogue scale

n

(VAS) for breathlessness now at

Mean (SD)

baseline - mm (SD)

Min, max

2, 82

mMRC breathlessness score at

1

8 (11.4%)

5 (7.1%)

baseline *

2

15 (21.4%)

17 (24.3%)

n (%)

3

13 (18.6%)

17 (24.3%)

4

34 (48.6%)

31 (44.3%)

Primary cause for breathlessness

COPD

44 (59.5%)

49 (60.5%)

n (%)

Cancer

10 (13.5%)

11 (13.6%)

2 (2.7%)

1 (1.2%)

Cardiac failure

3, 94

End-tidal CO2

Pulse oximetry

Oxygen use

Mixed

11 (14.9%)

12 (14.8%)

Other

7 (9.5%)

8 (9.9%)

70

70

Mean (SD)

24.25 (6.93)

25.47 (6.81)

Min, max

10.6, 47.0

10.4, 42.9

74

80

Mean (SD)

93.42 (3.53)

92.37 (4.81)

Min, max

80.0, 98.0

72.0, 98.0

Yes n (%)

42 (56.8%)

50 (61.7%)

n

n

BMI - body mass index; AKPS – Australian-modified Karnofsky Performance Status; mMRC modified Medical Research Council (breathlessness score); COPD – chronic obstructive pulmonary disease; CO2 carbon dioxide. *The inclusion criteria of mMRC of 3 or higher was measured at Screening. This table presents mMRC at Baseline.

Table 1 - Treatment effects on breathlessness of oxycodone 15 mg/day vs. placebo from baseline to day 5 to 7 or end of treatment in the intention-to-treat population (n=155) Oxycodone 15

Placebo arm

Oxycodone vs. placebo

mg/day arm n=74

n=81

Mean change from baseline

Mean difference (95%

(SE)

CI)

p value

Primary outcome Breathlessness now (VAS)

-3.69 (2.90)

-9.02 (2.67)

5.33 (-1.22, 11.88)

0.109

Worst breathlessness (VAS)

-8.34 (3.39)

-5.83 (3.19)

-2.51 (-10.33, 5.31)

0.525

Best breathlessness (VAS)

2.36 (2.91)

-3.02 (2.79)

-5.39 (-1.30, 12.08)

0.113

Average breathlessness

-2.17 (2.59)

-5.11 (2.49)

2.93 (-3.08, 8.95)

0.335

-0.22 (3.10)

-1.64 (2.90)

1.42 (-5.67, 8.50)

0.692

Secondary outcomes

(VAS) Breathlessness now unpleasantness (VAS) Response was defined as a difference of ≥ 8.9 mm or <-8.9 mm from baseline to days 5 to 7. VAS – 100mm visual analogue scale.

Table 1 - Treatment effects of oxycodone 15 mg/day vs. placebo from baseline to day 5 to 7 or end of treatment in the intention-to-treat population (n=155) Oxycodone

Placebo arm

Oxycodone vs. placebo

15 mg/day arm

n=81

n=74

Change in participant functional

Mean change from baseline

Mean difference (95%

(SE)

CI)

P-value

-2.09 (1.16)

-0.45 (1.14)

-1.65 (-4.23, 0.94)

0.210

mMRC breathlessness score

-0.19 (0.14)

-0.30 (0.14)

0.11 (-0.21, 0.44)

0.493

Life-space score

-2.68 (1.90)

-4.22 (1.83)

1.54 (-2.70, 5.77)

0.474

NRS Global Quality of Life Score

-0.46 (0.25)

-0.26 (0.24)

-0.21 (-0.77, 0.35)

0.464

Participant quality of life

-1.66 (3.15)

2.82 (3.11)

-4.48 (-11.69, 2.73)

0.221

Appetite loss (EORTC-QLQ-15)

7.92 (4.32)

-9.65 (4.37)

17.56 (7.54, 27.59)

<.001*

Constipation (EORTC-QLQ-15)

11.89 (4.47)

-4.44 (4.41)

16.33 (6.07, 26.60)

0.002

Dyspnoea (EORTC-QLQ-15)

-8.70 (3.52)

-8.24 (3.54)

-0.46 (-8.60, 7.67)

0.911

Emotional Functioning (EORTC-

-0.02 (2.86)

6.74 (2.91)

-6.76 (-13.36, -0.15)

0.045*

Fatigue (EORTC-QLQ-15)

0.28 (3.71)

-7.48 (3.73)

7.75 (-0.83, 16.34)

0.076

Nausea/Vomiting (EORTC-QLQ-

4.06 (2.97)

-2.98 (2.98)

7.04 (0.19, 13.89)

0.044*

Pain (EORTC-QLQ-15)

4.35 (3.74)

0.55 (3.87)

3.80 (-5.05, 12.65)

0.396

Physical Functioning (EORTC-

-0.81 (3.00)

5.42 (3.04)

-6.23 (-13.15, 0.69)

0.077

Insomnia (EORTC-QLQ-15)

-4.13 (4.37)

-13.30 (4.45)

9.17 (-1.19, 19.53)

0.082

Carers quality of life (CQOLC)

-11.04 (4.81)

-0.80 (7.81)

-10.24 (-37.79, 17.32)

0.383

31/69 (44.9%)

40/78 (51.3%)

N/A

0.436

status (AKPS)

(EORTC-QLQ-15)

QLQ-15)

15)

QLQ-15)

Blinded treatment preference I have been less breathless during

the past week This medication would benefit

18/66 (27.3%)

39/77 (50.6%)

N/A

0.006

me enough to be on it long term *Statistically significant; AKPS – Australian-modified Karnofsky Performance Status; mMRC – Modified Medical Research Council Scale; NRS – Numerical Rating Scale.

Table 1 - Treatment emergent adverse events of special interest Safety analysis ITT population Oxycodone

Placebo

p-value for

n=72

n=79

treatment

Participants (%)

Participants

difference

(%) Subjects with at least one special interest TEAE

65 (90.3%)

75 (94.9%)

0.276

Respiratory disorders

21 (29.2%)

40 (50.6%)

0.008*

21 (29.2%)

40 (50.6%)

0.008*

2 (2.8%)

2 (2.5%)

0.931

58 (80.6%)

52 (65.8%)

0.045*

Constipation

37 (51.4%)

39 (49.4%)

0.807

Dry mouth

22 (30.6%)

19 (24.1%)

0.374

Nausea

31 (43.1%)

1 (1.3%)

<0.001*

Vomiting

4 (5.6%)

18 (22.8%)

0.003*

Abdominal discomfort

1 (1.4%)

0 (0.0%)

0.303

Abdominal pain

0 (0.0%)

1 (1.3%)

0.348

7 (9.7%)

9 (11.4%)

0.743

Arrhythmia

6 (8.3%)

9 (11.4%)

0.535

Tachycardia

2 (2.8%)

0 (0.0%)

0.142

52 (72.2%)

62 (78.5%)

0.376

Somnolence

37 (51.4%)

45 (57.0%)

0.496

Dizziness

20 (27.8%)

26 (32.9%)

0.498

Tremor

18 (25.0%)

16 (20.3%)

0.490

Headache

17 (23.6%)

14 (17.7%)

0.375

22 (30.6%)

34 (43.0%)

0.117

Agitation

17 (23.6%)

24 (30.4%)

0.355

Mood altered

9 (12.5%)

12 (15.2%)

0.637

Delirium

2 (2.8%)

8 (10.1%)

0.073

14 (19.4%)

14 (17.7%)

0.789

14 (19.4%)

14 (17.7%)

0.789

Bronchospasm Wheezing Gastrointestinal disorders

Cardiac disorders

Nervous system disorders

Psychiatric disorder

Skin disorders Urticaria

Renal and urinary disorders

5 (6.9%)

4 (5.1%)

0.631

5 (6.9%)

4 (5.1%)

0.631

10 (13.9%)

9 (11.4%)

0.648

Hypertension

7 (9.7%)

5 (6.3%)

0.446

Flushing

5 (6.9%)

5 (6.3%)

0.883

Urinary retention Vascular disorders

Data presented as frequency (percentage). *Statistically significant; TEAE - treatment emergent adverse event.

Figure 1 – Consort Diagram