Currow, DC, Clark, K, Louw, S, Fazekas, B, Greene, A & Sanderson, CR 2020, 'A randomized, double-blind, crossover, dose ranging study to determine the optimal dose of oral opioid to treat breakthrough pain for patients with advanced cancer already established on regular opioids.', European journal of pain (London, England), vol. 24, no. 5, pp. 983-991.View/Download from: Publisher's site
BACKGROUND:Pain in people with advanced cancer is prevalent. When a stable dose of opioids is established, people still experience episodic breakthrough pain for which dosing of an immediate release opioid is usually a proportion of the total daily dose. METHODS:This multi-site, double blind, randomized trial tested three dose proportions (1/6, 1/8, 1/12 of total daily dose) in two blocks, each block with three dose proportions in random order (6 numbered bottles in total). When participants required opioid breakthrough doses and it was their first breakthrough dose for that study day, they took the next numbered bottle rather than their usual breakthrough dose. (Subsequent doses on that day reverted to their usual dose.) RESULTS: Eighty-five people were randomized in this study of whom 81 took at least one dose and 73 (90%) took at least block one (one of each dose proportion). No dose was found to be optimal at 30 min with approximately one-third of participants showing maximal reduction with each dose proportion. Median time to pain relief was 120 min. There were no differences in harms: drowsiness, confusion, nausea or vomiting at 30, 60 or 120 min. CONCLUSIONS:This adequately powered study did not show any difference with three dose proportions for reduction in pain intensity, time to pain relief, pain control on the subsequent day nor any difference in harms. From first principles, this suggests 1/12 the 24 hourly dose should be used as the lowest dose that delivers benefit. Future studies should include a placebo arm. SIGNIFICANCE:Despite the widespread use of immediate release morphine solution for breakthrough cancer pain, the ideal dose derived from background dose has not been determined in an adequately powered randomized, double-blind, crossover, dose ranging study. This study tested three dose levels in people with advanced cancer. Given no differences in time to onset, level of analgesia achieved, nor side effects, the lowest dose tested (1/12th of...
Ferreira, DH, Louw, S, McCloud, P, Fazekas, B, McDonald, CF, Agar, M, Clark, K, McCaffrey, N, Ekstrom, M, Currow, DC & Australian national Palliative Care Clinical Studies Collaborative (PaCCSC) 2020, 'Controlled-release oxycodone versus placebo in the treatment of chronic breathlessness - a multi-site randomised placebo controlled trial.', Journal of Pain and Symptom Management, vol. 59, no. 3, pp. 581-589.View/Download from: Publisher's site
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, fixed-dose 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.
Johnson, MJ, Sbizzera, I, Fairhurst, C, Fazekas, B, Agar, M, Ekstrom, M & Currow, DC 2020, 'No excess harms from sustained-release morphine: a randomised placebo-controlled trial in chronic breathlessness.', BMJ Supportive and Palliative Care.View/Download from: Publisher's site
OBJECTIVES:We aimed to identify and evaluate: (1) treatment-emergent adverse events (TEAE (worse or new since baseline)) and the subgroup of severe TEAEs in a placebo-controlled 7-day randomised trial of regular, low-dose, sustained-release oral morphine for chronic breathlessness and (2) clinical characteristics associated with TEAE. METHODS:Safety analysis of trial data. Adults with chronic breathlessness (modified Medical Research Council breathlessness score ≥2) due to heart or lung disease, or cancer, not on regular opioids were eligible. Symptoms associated with opioids (TEAE of special interest) were systematically sought using Common Terminology Criteria for Adverse Events (CTCAE) grading. Other harms could be reported at any time. The relationship between characteristics and presence of ≥1 TEAE of special interest was explored using univariable logistic regression analyses. RESULTS:1449/5624 (26%) Adverse Events from 279 participants were TEAE of which 150/1449 (10%) were severe (CTCAE grades 3-5). 1086/5624 (75%) were events of special interest of which 41/1086 (4%) were severe. Compared with placebo, morphine was not associated with more TEAE or severe TEAE of special interest (TEAE: OR 0.53, 95% CI 0.21 to 1.38, p=0.20; severe TEAE: OR 0.96, 95% CI 0.27 to 3.41, p=0.95) nor with CTCAE severity grade (χ2=4.39, p=0.50). Among the 26/150 (17%) with severe TEAEs, study withdrawal was more common in the morphine arm (18/26 (69%) morphine arm; 8/26 (30%) placebo arm). None of the severe TEAEs was a respiratory harm. CONCLUSIONS:Severe morphine-associated toxicity was uncommon and not associated with study arm. Clinical consequences were minor and self-limiting. TRIAL REGISTRATION NUMBER:ACTRN126000806268.
King, MT, Agar, M, Currow, DC, Hardy, J, Fazekas, B & McCaffrey, N 2020, 'Assessing quality of life in palliative care settings: head-to-head comparison of four patient-reported outcome measures (EORTC QLQ-C15-PAL, FACT-Pal, FACT-Pal-14, FACT-G7).', Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, vol. 28, no. 1, pp. 141-153.View/Download from: Publisher's site
PURPOSE:Head-to-head comparison of reliability, validity and responsiveness of four patient-reported outcome measures (PROMS) suitable for assessing health-related quality of life (HRQOL) in palliative care settings: EORTC QLQ-C15-PAL, FACT-G7, FACIT-Pal and short-form FACIT-Pal-14. METHODS:Secondary analysis of two phase III randomised trials: ketamine for chronic cancer pain, octreotide for vomiting in inoperable malignant bowel obstruction. Sub-groups were defined by Australia-modified Karnofsky performance status (AKPS) and participants' global impression of change (GIC). Two aspects of reliability were assessed: internal consistency (Cronbach alpha, α); test-retest reliability (intra-class correlation coefficient (ICC)) of patients with stable AKPS and those who self-reported 'no change' on GIC. Construct validity was assessed via pre-determined hypotheses about sensitivity of PROM scores to AKPS groups and responsiveness of PROM change scores to GIC groups using analysis of variance. RESULTS:FACIT-Pal had better internal consistency (α ranged 0.59-0.80, 15/18 ≥ 0.70) than QLQ-C15-PAL (0.51-0.85, 4/8 ≥ 0.70) and FACT-G7 (0.54-0.64, 0/2 ≥ 0.70). FACIT scales had better test-retest reliability (FACIT-Pal 11/27 ICCs ≥ 0.70, FACT-G7 2/3 ICCs ≥ 0.70) than QLQ-C15-PAL (2/30 ICCs ≥ 0.70, 18/30 ≤ 0.5). Four scales demonstrated sensitivity to AKPS: QLQ-PAL-15 Physical Functioning and Global QOL, FACT-G Functional Wellbeing and FACIT-Pal Trial Outcome Index (TOI). Nine scales demonstrated responsiveness: three in the ketamine trial population (QLQ-C15-PAL Pain, FACIT-Pal-14, FACT-G7), six in the octreotide trial population (QLQ-C15-PAL Fatigue; FACIT-Pal PalCare, TOI, Total; FACT-G Physical Wellbeing and Total). CONCLUSIONS:No PROM was clearly superior, confirming that choosing the best PROM requires careful consideration of the research goals, patient population and the domains of HRQOL targeted by the intervention being investigated.
Currow, DC, Ekström, M, Louw, S, Hill, J, Fazekas, B, Clark, K, Davidson, PM, McDonald, C, Sajkov, D, McCaffrey, N, Doogue, M, Abernethy, AP & Agar, M 2019, 'Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial.', European Respiratory Journal, vol. 53, no. 1.View/Download from: Publisher's site
Does sertraline provide symptomatic relief for chronic breathlessness in people with advanced disease whose underlying cause(s) are optimally treated?223 participants with chronic breathlessness (modified Medical Research Council breathlessness scale ≥2) who had optimal treatment of underlying cause(s) were randomised 1:1 to sertraline 25-100 mg (titrated upwards over 9 days) or placebo for 4 weeks. The primary outcome was the proportion who had an improvement in intensity of current breathlessness >15% from baseline on a 100-mm visual analogue scale.The proportion of people responding to sertraline was similar to placebo for current breathlessness on days 26-28 (OR 1.00, 95% CI 0.71-1.40) and for other measures of breathlessness. Quality of life in the sertraline arm had a higher likelihood of improving than in the placebo arm over the 4 weeks (OR 0.21, 95% CI 0.01-0.41; p=0.044). No differences in performance status, anxiety and depression, or survival were observed. Adverse event rates were similar between arms.Sertraline does not appear to provide any benefit over placebo in the symptomatic relief of chronic breathlessness in this patient population.
Currow, DC, Agar, M & Ekstroem, M 2019, 'Sertraline or placebo in chronic breathlessness? Lessons from placebo research', EUROPEAN RESPIRATORY JOURNAL, vol. 53, no. 1.View/Download from: Publisher's site
Currow, DC, Ekstrom, M, Louw, S, Hill, J, Fazekas, B, Clark, K, Davidson, P, McDonald, C, Sajkov, D, McCaffrey, N, Doogue, M, Abernethy, AP & Agar, M 2019, 'Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial', European Respiratory Journal, vol. 53, no. 1.View/Download from: Publisher's site
Eastman, P, Currow, DC, Fazekas, B, Brown, L & Le, B 2019, 'Oral dexamethasone in the management of cancer-related pain: A feasibility study.', Palliative Medicine, vol. 33, no. 4, pp. 477-478.View/Download from: Publisher's site
Ekstrom, M, Chang, S, Johnson, MJ, Fazekas, B, Kochovska, S, Huang, C & Currow, DC 2019, 'Low agreement between mMRC rated by patients and clinicians: implications for practice', EUROPEAN RESPIRATORY JOURNAL, vol. 54, no. 6.View/Download from: Publisher's site
Matsuoka, H, Agar, M, Vandersman, Z, Good, P, Fazekas, B, Brown, L, Hardy, J, Weil, J & Currow, DC 2019, 'Harms From Haloperidol for Symptom Management in Palliative Care-a Post Hoc Pooled Analysis of Three Randomized Controlled Studies and Two Consecutive Cohort Studies.', Journal of Pain and Symptom Management, vol. 58, no. 3, pp. e6-e8.View/Download from: Publisher's site
Matsuoka, H, Allingham, S, Fazekas, B, Brown, L, Vandersman, Z, Clark, K, Agar, MR & Currow, DC 2019, 'Comparability of the Australian National Cancer Symptom Trials (CST) Group's Study Populations to National Referrals to Non-CST Specialist Palliative Care Services Participating in the Palliative Care Outcomes Collaboration.', Journal of Pain and Symptom Management, vol. 57, no. 1, pp. e9-e14.View/Download from: Publisher's site
McCaffrey, N, Flint, T, Kaambwa, B, Fazekas, B, Rowett, D, Currow, DC, Hardy, J, Agar, MR, Quinn, S & Eckermann, S 2019, 'Economic evaluation of the randomised, double-blind, placebo-controlled study of subcutaneous ketamine in the management of chronic cancer pain.', Palliative medicine, vol. 33, no. 1, pp. 74-81.View/Download from: Publisher's site
Hosie, A, Phillips, J, Lam, L, Kochovska, S, Noble, B, Brassil, M, Kurrle, SE, Cumming, A, Caplan, GA, Chye, R, Le, B, Ely, EW, Lawlor, PG, Bush, SH, Davis, JM, Lovell, M, Brown, L, Fazekas, B, Cheah, SL, Edwards, L & Agar, M 2019, 'Multicomponent non-pharmacological intervention to prevent delirium for hospitalised people with advanced cancer: study protocol for a phase II cluster randomised controlled trial.', BMJ open, vol. 9, no. 1, pp. e026177-e026177.View/Download from: Publisher's site
INTRODUCTION:Delirium is a significant medical complication for hospitalised patients. Up to one-third of delirium episodes are preventable in older inpatients through non-pharmacological strategies that support essential human needs, such as physical and cognitive activity, sleep, hydration, vision and hearing. We hypothesised that a multicomponent intervention similarly may decrease delirium incidence, and/or its duration and severity, in inpatients with advanced cancer. Prior to a phase III trial, we aimed to determine if a multicomponent non-pharmacological delirium prevention intervention is feasible and acceptable for this specific inpatient group. METHODS AND ANALYSIS:The study is a phase II cluster randomised wait-listed controlled trial involving inpatients with advanced cancer at four Australian palliative care inpatient units. Intervention sites will introduce delirium screening, diagnostic assessment and a multicomponent delirium prevention intervention with six domains of care: preserving natural sleep; maintaining optimal vision and hearing; optimising hydration; promoting communication, orientation and cognition; optimising mobility; and promoting family partnership. Interdisciplinary teams will tailor intervention delivery to each site and to patient need. Control sites will first introduce only delirium screening and diagnosis, later implementing the intervention, modified according to initial results. The primary outcome is adherence to the intervention during the first seven days of admission, measured for 40 consecutively admitted eligible patients. Secondary outcomes relate to fidelity and feasibility, acceptability and sustainability of the study intervention, processes and measures in this patient population, using quantitative and qualitative measures. Delirium incidence and severity will be measured to inform power calculations for a future phase III trial. ETHICS AND DISSEMINATION:Ethical approval was obtained for all four sites. Trial r...
Agar, M, Lawlor, P, Quinn, S, Draper, B, Caplan, G, Rowett, D, Sanderson, C, Hardy, J, Le, B, Eckermann, S, McCaffrey, N, Devilee, L, Fazekas, B, Hill, M & Currow, D 2017, 'Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care A Randomized Clinical Trial', JAMA Internal Medicine, vol. 177, no. 1, pp. 34-42.View/Download from: Publisher's site
Importance: Antipsychotics are widely used for distressing symptoms of delirium, but efficacy has not been established in placebo-controlled trials in palliative care.
Objective: To determine efficacy of risperidone or haloperidol relative to placebo in relieving target symptoms of delirium associated with distress among patients receiving palliative care.
Design, Setting, and Participants: A double-blind, parallel-arm, dose-titrated randomized clinical trial was conducted at 11 Australian inpatient hospice or hospital palliative care services between August 13, 2008, and April 2, 2014, among participants with life-limiting illness, delirium, and a delirium symptoms score (sum of Nursing Delirium Screening Scale behavioral, communication, and perceptual items) of 1 or more.
Interventions: Age-adjusted titrated doses of oral risperidone, haloperidol, or placebo solution were administered every 12 hours for 72 hours, based on symptoms of delirium. Patients also received supportive care, individualized treatment of delirium precipitants, and subcutaneous midazolam hydrochloride as required for severe distress or safety.
Main Outcome and Measures: Improvement in mean group difference of delirium symptom score (severity range, 0-6) between baseline and day 3. Five a priori secondary outcomes: delirium severity, midazolam use, extrapyramidal effects, sedation, and survival.
Results: Two hundred forty-seven participants (mean [SD] age, 74.9 [9.8] years; 85 women [34.4%]; 218 with cancer [88.3%]) were included in intention-to-treat analysis (82 receiving risperidone, 81 receiving haloperidol, and 84 receiving placebo). In the primary intention-to-treat analysis, participants in the risperidone arm had delirium symptom scores that were significantly higher than those among participants in the placebo arm (on average 0.48 Units higher; 95% CI, 0.09-0.86; P = .02) at study end. Similarly, for those in the haloperidol arm, delirium symptom scores were on average 0.24 Units h...
Currow, D, Watts, GJ, Johnson, M, McDonald, CF, Miners, JO, Somogyi, AA, Denehy, L, McCaffrey, N, Eckert, DJ, McCloud, P, Louw, S, Lam, L, Greene, A, Fazekas, B, Clark, KC, Fong, K, Agar, MR, Joshi, R, Kilbreath, S, Ferreira, D, Ekström, M & Australian national Palliative Care Clinical Studies Collaborative (PaCCSC) 2017, 'A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol.', BMJ Open, vol. 7, no. 7, pp. 1-19.View/Download from: Publisher's site
INTRODUCTION: Chronic 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 ANALYSIS: The 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 DISSEMINATION: Ethics 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 NUMBER: NCT02720822; Pre-results.
Hardy, J, Quinn, S, Fazekas, B, Agar, M & Currow, D 2013, 'Can the LANSS scale be used to classify pain in chronic cancer pain trials?', SUPPORTIVE CARE IN CANCER, vol. 21, no. 12, pp. 3387-3391.View/Download from: Publisher's site
Greene, A, Aranda, S, Tieman, JJ, Fazekas, B & Currow, DC 2012, 'Can assessing caregiver needs and activating community networks improve caregiver-defined outcomes? A single-blind, quasi-experimental pilot study: Community facilitator pilot', PALLIATIVE MEDICINE, vol. 26, no. 7, pp. 917-923.View/Download from: Publisher's site
KEREIAKES, D, FERGUSON, JJ, POPMA, JJ, SHAW, RE, TCHENG, JE, WEISMAN, H, LINCOFF, AM, BREZINA, K & AGUIRRE, F 1994, 'UNTITLED', JOURNAL OF INVASIVE CARDIOLOGY, vol. 6, pp. A43-A56.
Hosie, A, Phillips, J, Lam, L, Kochovska, S, Brassil, M, Noble, B, Kurrle, S, Cumming, A, Caplan, G, Chye, R, Le, B, Ely, EW, Lawlor, P, Bush, S, Davis, JM, Lovell, M, Brown, L, Fazekas, B, Cheah, SL, Edwards, L & Agar, M 2018, 'A phase II cluster randomised controlled trial of a multicomponent non-pharmacological intervention to prevent delirium for in-patients with advanced cancer (The PRESERVE pilot study)', ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, WILEY, pp. 166-166.
Currow, D, Louw, S, Hill, J, Fazekas, B, Clark, K, Davidson, P, Mcdonald, C, Sajkov, D, Mccaffrey, N, Doogue, M, Abernethy, A & Agar, M 2018, 'Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial', EUROPEAN RESPIRATORY JOURNAL, International Congress of the European-Respiratory-Society, EUROPEAN RESPIRATORY SOC JOURNALS LTD, Paris, France.View/Download from: Publisher's site
Currow, DC, Glare, PA, Watts, G, Louw, S, Martin, P, Clark, K, Fazekas, B & Agar, M 2018, 'Treating anorexia in people with advanced cancer. a randomised, double blind, controlled trial of megestrol acetate, dexamethasone or placebo', JOURNAL OF CLINICAL ONCOLOGY, AMER SOC CLINICAL ONCOLOGY.View/Download from: Publisher's site