Nicola McCaffrey

Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial.

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 higher (95% CI, 0.06-0.42; P = .009) than in the placebo arm. Compared with placebo, patients in both active arms had more extrapyramidal effects (risperidone, 0.73; 95% CI, 0.09-1.37; P = .03; and haloperidol, 0.79; 95% CI, 0.17-1.41; P = .01). Participants in the placebo group had better overall survival than those receiving haloperidol (hazard ratio, 1.73; 95% CI, 1.20-2.50; P = .003), but this was not significant for placebo vs risperidone (hazard ratio, 1.29; 95% CI, 0.91-1.84; P = .14). Conclusions and Relevance In patients receiving palliative care, individualized management of delirium precipitants and supportive strategies result in lower scores and shorter duration of target distressing delirium symptoms than when risperidone or haloperidol are added. Trial Registration anzctr.org.au Identifier: ACTRN12607000562471.

Clinical trials of medicinal cannabis for appetite-related symptoms from advanced cancer: a survey of preferences, attitudes and beliefs among patients willing to consider participation

Australian clinical trials are planned to evaluate medicinal cannabis in a range of clinical contexts.

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

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.

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

Introduction Breathlessness 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 analysis A 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 dissemination Ethics 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 number ACTRN12610000464066.

Multiple Effects Cost-Effectiveness Analysis in Cost-Disutility Space

Chapter 10 shows that the net benefit correspondence theorem methods, introduced and shown to have distinct advantages for multiple strategy comparisons in Chap. 8 and for multiple provider efficiency comparison consistent with maximising net benefit in Chap. 9, naturally extend such advantages to robust multiple domain comparisons under uncertainty. In Chap. 4 we highlighted that robust and generalisable methods to enable jointly considering costs and multiple effects under uncertainty are required to better inform funding decisions in complex clinical areas such as palliative care. While quality-adjusted life years (QALYs) enable integration of patient survival with morbidity, they are either unable, or struggle, to incorporate domains such as carer impacts, family distress, finalising personal and financial affairs and being in community of choice for place of palliative care and place of death. Consequently, without robust multiple domain methods of cost-effectiveness analysis, the use of conventional single outcome evaluation (QALY measures or otherwise) can misrepresent key palliative care preferences. Scarce resources and funds can easily end up supporting interventions, strategies or programmes with overall negative impacts and not supporting options that maximise palliative care outcomes from limited resources. In this chapter we show how cost-effectiveness analysis in cost-disutility (CDU) space enables robust joint consideration of costs and multiple effects under uncertainty facilitating improved societal decision making. We outline and illustrate how the net benefit correspondence theorem (NBCT) and comparison on the CDU plane introduced in Chap. 8 also facilitate robust multiple effect comparison under uncertainty with analogous multiple effect summary measures. New summary measures identify across any set of threshold values for multiple domains of effect the strategies with lowest expected net loss (ENL) or highest expected net benefit with ENL planes and the potential value of undertaking further research for the optimal strategy as the ENL contour as well as the probability of strategies having highest expected net benefit (CEA planes).

Beyond the Individual: Evaluating Community-Based Health Promotion and Prevention Strategies and Palliative Care Domains of Effect

In this chapter we consider challenges faced undertaking health economic analysis to evaluate health promotion and palliative care programs and strategies in complex community settings and more importantly highlight principles and some promising methods and approaches to address these challenges.