Achieving improved care of palliative care patients through clinical studies to inform the quality use of medicines.

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1 Achieving improved care of palliative care patients through clinical studies to inform the quality use of medicines. For further information: Linda Devilee National Manager p (08) e paccsc@flinders.edu.au Flinders University receives funding for PaCCSC from the Australian Government Department of Health under the National Palliative Care Program.

2 What Matters Most

4 Outline 1. Introduction What, Why & Where 2. History of PaCCSC 3. Governance and organisational structure 4. Standard Operating Procedures (SOP s) 5. Areas of research 6. The new study process 7. Collateral benefits from conducting research 8. Why do research

5 1. INTRODUCTION

6 What is PaCCSC? People from multiple disciplines The Palliative Care Clinical Studies Collaborative (PaCCSC) is an international research network

7 Why does PaCCSC exist? Many medications and other interventions that are commonly used at the end of life to assist with managing or alleviating patients symptoms have little or no evidence to support their use. Pharmaceutical companies are generally not attracted to this area of clinical research because there are few, if any, commercial gains given that these medications are mostly off-patent.

Currow DC et al. J Am Geriatr Soc 2007;55(4):590-595.

8 Currow DC et al. J Am Geriatr Soc 2007;55(4): Flinders University receives funding for PaCCSC from the Australian Government Department of Health and Ageing under the National Palliative Care Program.

9 Challenge to providing medicines for palliative care The medicine is registered but not PBS listed new section of the PBS (February 2004) The medicine is not registered for this use in Australia PaCCSC studies

10 Why does PaCCSC exist? High quality research which will provide the evidence base to underpin end-of-life care. National investment has benefits beyond palliative care such as the study of anti-psychotics in the treatment of delirium- the world s largest such study in any population.

11 Strategic Directions Strategic Direction-1 Maintain a network of national and international members who collaborate to conduct high quality clinical research in the end of life setting. Strategic Direction-2 Conduct high quality clinical research to build the evidence base to support the quality use of medicines and positively influence healthcare practice in people nearing the end of life. This work may impact on and/or promote access to registered (AUST-R) medicines for use in palliative care.

12 Strategic Directions Strategic Direction-3 Build national capacity in the palliative care sector to support/facilitate high quality clinical research and its translation into clinical practice.

13 2. HISTORY OF PaCCSC

14 Background 2000 ANZSPM members survey regarding medicines considered essential in palliative care Establishment of a whole of government think tank the Palliative Care Medicines Working Group (PCMWG) 2004 Itemised section on the PBS developed for medicines used specifically in palliative care 2006 PaCCSC commenced with mandate to assist in developing the evidence base for medicines used in palliative care March 2008 opened first Phase III clinical trial

15 Funding Funding for PaCCSC is received from the Australian Government Department of Health through the National Palliative Care Program. PaCCSC had early success and has continued to be successful in winning competitive grant funding (NHMRC) and from a range of other grant and philanthropic sources for the conduct of pilot/feasibility studies and phase III clinical trials.

16 3. GOVERNANCE AND ORGANISATIONAL STRUCTURE

17 Governance Funding Partners Flinders University Chief Investigator PaCCSC Initiating Investigators Management Advisory Board Site Investigators Central Coordinating Office Scientific Committee Data & Safety Monitoring Committee Members Trials Management Committee Publications Subcommittee Pilot Studies Subcommittee Trial Subcommittees

18 4. STANDARD OPERATING PROCEDURES

19 ICH GCP reference code Standard Operating Procedures (SOPs) Current version Glossary Investigator Roles and Responsibilities Conflict of interest Randomisation Unblinding Source Data and Documentation SOP development Electronic Data handling Electronic Data transfer Allocation of Participant ID Numbers Investigational Product Handling Adverse Event Reporting Monitoring Site Closure Study Closure Audit KPI Compliance CRF Completion Protocol Development New Study Ideas/Proposals Study Recruitment Re-screening Version Tracking Ethics Approval and Reporting Authorship Dissemination of Study Results Essential Documents Concurrent Medications Archiving of Research/Project Materials Record Destruction 2.1 Data Ownership 1.0 References

20 5. AREAS OF RESEARCH DRIVEN BY PATIENT SYMPTOMS

21 Phase III clinical trials The PaCCSC suite of Phase III clinical studies focuses on a number of symptom nodes commonly experienced by the palliative population. These include: Pain Nausea Gastrointestinal (bowel obstruction, constipation) Breathlessness Cognitive disorders Appetite/anorexia

22 Average Phase III Clinical Trial Life Cycle Year 1 Year 2 Year 3 Years 4-8 Year 9 Year 10 New idea Trial Governance SOPs Recruitment Reach sample size HREC final reporting Protocol development Agreements Regulatory Data management Data management Clinical study report Sponsor Peer/ scientific review Site selection Investigational Product Ethics/ governance Budget Site start up Protocol amendments Site payments Finalise SAP Undertake analysis Dissemination activities Study closure Funding Data Management Equipment/ licences Dissemination plan Draft publication Pre Study Recruitment Completion

23 PaCCSC Phase III Studies Completed: ketamine (complex pain) octreotide (bowel obstruction) risperidone / haloperidol (delirium) megestrol / dexamthasone (anorexia) morphine/oxycodone (breathlessness) Nausea 1 (nausea) Nausea 2 (nausea) Can Less Be Better (constipation)

24 PaCCSC Phase III Studies Current: Sertraline (breathlessness Recruitment hold) Nausea 3 (nausea) BEAMS (breathlessness) Melatonin (delirium) The PEARL Trial (breathlessness, non pharmacological) PAX-1 (pain)

25 RAPID International pharmacovigilance program

26 Phase IV pharmacovigilance audit/studies - RAPID Phase IV protocol designed to monitor medications as they re being prescribed in the real world and collect information about the symptoms of interest Prospective, point of care data collection Clinical information collected Benefit and Toxicity at defined time-points = net clinical benefit Toxicity at any time-point 100+ sites from 20 countries currently participating with constantly growing membership

28 RAPID - pharmacovigilance 6 medication/indication dyads completed: Metoclopramide for nausea Haloperidol for delirium Pregabalin/gabapentin for neuropathic pain Dexamethasone for appetite/anorexia Current series Amitriptyline for neuropathic pain Program expansion (commenced early 2016) to study a medication series for each symptom node: Lorazepam for breathlessness Movicol for constipation Cyclizine for nausea Midazolam for agitation Mirtazapine for appetite

29 RAPID - pharmacovigilance Program also studying non-pharmacological interventions: RBC Transfusions complete (paper drafted) Hypodermoclysis - currently open to recruitment Ascitic Taps - in start-up

31 Metoclopramide/Nausea (complete) 12 hospice/palliative care sites in 2 countries Timepoints T 0 baseline T 1 2 days clinical benefits T 2 7 days clinical harms (and at anytime) 53 patients, data collected between October 2011 and January 2012 Average dose 32.9mg/24 hrs 43% reported benefit at T 1, with 34% of these still using at T 2, remainder ceased due to harms Harms: akathisia (n=4), headache (n=4), abdo pain (n=4) 17% had no clinical benefit and experienced harms

32 Metoclopramide/Nausea (complete) 32% of people experience harms but no new harms were identified Given wide use, this study suggests careful attention to eliciting symptoms including akathisia and tremor Rates of harm are likely to be higher when used with other dopamine antagonists (ie. Haloperidol) Overall positive response with acceptable harms of 34% is low given prevalent use Data reflect the two most recent systematic reviews moderate evidence for use as first-line therapy for nausea

33 Gabapentin/neuropathic pain (complete) 42 hospice/palliative care sites in 7 countries Timepoints T 0 baseline T 1 7 days clinical benefits T 2 21 days clinical harms (and at anytime) 127 patients, data collected between September 2012 and August 2013 Average dose 653mg/24 hrs at T 2 for those still on study 42% reported benefit at T 2, of whom 6% experienced complete pain resolution Harms were reported in 30% at T 1 and included: cognitive disturbance, somnolence, nausea and dizziness 10 participants had meds ceased due to harms

34 Gabapentin/neuropathic pain (complete) Rates of harm were higher than those reported in the literature, with 30% of participants experiencing one or more harms (of which 7% were rates as severe) Somnolence, cognitive disturbance and fatigue appear to be more frequent than those reported in the literature The presence of significant comorbidities appears to increase the risk that a patient will experience a harm Only 9% of participants benefited without also experiencing a harm Baseline data reveal a pattern of high rates of relevant symptomology Uncertain what extent the speed of titration may also effect participants

35 Dexamethasone/anorexia or appetite (complete) 41 hospice/palliative care sites in 8 countries Timepoints T 0 baseline T 1 7 days clinical benefits and/or harms 114 patients, 6 of whom died by T 1 (n=108 evaluable) data collected between July 2013 to July 2014 Average dose 4.1mg/24 hrs at T 1 68% reported 1 reduction in anorexia scores by T 1, of whom 30 were 0 Harms were reported in 32% at T 1 and included: insomnia (n=10), depression (n=7), euphoria (n=7) and hyperglycaemia (n=7) 24 patients had no benefit, 10 reported 1 harms

36 Dexamethasone/anorexia or appetite (complete) NCI CTCAE likert scales use to assess severity of anorexia Study showed positive and negative effects of 7 days of dex as an appetite stimulant >60% participants showed a symptomatic response to dex and approx one in four had a total resolution of anorexia The results support the evidence for the short term use of dex for anorexia in this population Dex was relatively well tolerated in this population Results are generalizable to all hospice/pall care patients in all clinical settings

37 Haloperidol/nausea (complete) 22 hospice/palliative care sites in 5 countries Timepoints T 0 baseline T 1 2 days clinical benefits T 2 7 days clinical harms (and at anytime) 150 patients, 5 patients died before T 1 (145 evaluable patients) collected between May 2014 to March 2016 Average dose 1.5mg/24 hrs at T 1 39% reported 1 reduction in vomiting scores by T 1, of whom most (86%) vomiting resolved completely Improved nausea was reported in 70% Harms were reported in 37 participants and included: constipation n=25, dry mouth n=13 and somnolence n=12

38 Haloperidol/nausea (complete) The study treated nausea and vomiting as distinct symptoms and collected data for each 67% participants had clinical benefit for either or both nausea and vomiting with no harms Most participants who experienced harms had no change to their medication even where there was a lack of benefit A large number of additional symptoms were reported by participants at baseline: constipation, somnolence, dry mouth 17 participants were already receiving an anti-emetic agent at the time of commencement of haloperidol, therefore reported benefits may not be from haloperidol alone Due to short time frame of data collection no quantification of longer term harms can be quantified

39 Practice points Beware harms Stop medication if no benefit

40 RBC Transfusions (complete) 17 hospice/palliative care sites in 5 countries Timepoints T 0 baseline T 1 2 days clinical harms (and at anytime) T 2 7 days clinical benefit 101 participant transfusions at all time points, collected between January 2014 and September 2015 Average 2.6 units transfused Target symptoms: fatigue (61%), breathlessness (16%), generalized weakness (12%), dizziness (6%), other (5%) 49% of transfusions improved the primary target symptom 78% of transfusions improved at least one of the target symptoms Harms were infrequent and mild, and many of them not likely to be related to the transfusion itself.

41 RBC Transfusions (complete) The first study in the RAPID series to examine a nonpharmacological intervention Largest prospective series of RBC transfusions in palliative care patients to date Clinician reporting of improvement following RBC transfusions is also common (65-89%) High cost commodity: estimated cost for one unit (preparation, storage and administration) between US$522-1,183 Need to acknowledge the placebo effect in palliative care studies can be large, recent fatigue study showing a placebo response rate of 54% However study demonstrates symptomatic benefit, when combined with low rates of harm, supports ongoing use.

42 2016 Expansion to the RAPID program Six separate medication series running concurrently, one for each of the symptom nodes of PaCCSC clinical research focus: Pain; Gastrointestinal (bowel obstruction, constipation etc); Nausea; Breathlessness; Appetite/anorexia; Cognitive disorders The six dyads to be studied in parallel are: - Targin for pain (deprescribing) - Lorazepam for breathlessness - Movicol for constipation - Cyclizine for nausea - Midazolam for agitation - Mirtazapine for appetite

43 RAPID - pharmacovigilance RAPID reporting of outcomes at the conclusion of each medication (approx 12 months from series commencement to completion) Continued efficient building of the evidence base for medicines use in palliative care

44 RAPID Further Reading The rationale for the RAPID study is summarised in the following article: Currow DC, Rowett D, Doogue M, To THM, Abernethy AP. (2012) An international initiative to create a collaborative for pharmacovigilance in hospice and palliative care clinical practice. Journal of Palliative Medicine, 15(3): Completed series papers: Currow DC, Vella-Brincat J, Fazekas B, Clark K, Doogue M, Rowett D. (2012) Pharmacovigilance in hospice/palliative care: Rapid report of net clinical effect of metoclopromide. Journal of Palliative Medicine, 15(10): Crawford GB, Agar M, Quinn SJ, Phillips J, Litster C, Michael N, Doogue M, Rowett D, Currow DC. (2013) Pharmacovigilance in Hospice/Palliative Care: Net Effect of Haloperidol for Delirium. Journal of Palliative Medicine, 16(11):1-7 Sanderson C, Quinn S, Agar M, Chye R, Clark K, Doogue M, Fazekas B, Lee J, Lovell M, Rowett D, Spruyt O, Currow D. (2014) Pharmacovigilance in hospice/palliative care: net effect of gabapentin for neuropathic pain. BMJ Supportive & Palliative Care, 5(3): Clark, K, Quinn SJ, Doogue M, Sanderson C, Lovell M, Currow DC. (2015) Routine prescribing of gabapentin or pregabalin in supportive and palliative care: what are the comparative in a palliative care population? Support Care Cancer,. 23(9):

45 RAPID influence on clinical practice This program: standardises clinical assessment evaluates both benefits and harms from prescribed medications records events in a consistent and systematic way provides feedback on practice in a standardised way compares practices across the world

46 RAPID influence on clinical practice Less tangible influences Participating sites adopt a questioning culture Harms as well as benefits become routine questions Provides an avenue to participate in clinical research without the normal significant resource implications Individual learning Part of an international research network

47 RAPID Interested in getting involved? +61 (0)

48 New studies The importance of pilot/feasibility studies Crucial element of good study design Doesn t guarantee success in the main study, but it does increase the likelihood of success PaCCSC have adopted a pipeline approach so that there are a range of pilot/feasibility studies at different stages being undertaken at any one time. The data that results from a pilot is critical in underpinning future submissions for competitive grant funding for Phase III trials without pilot data larger trial funding support from the NHMRC is rare.

49 Pilot/Feasibility Studies PERT Pancreatic Enzyme Replacement Therapy CADET dexamethasone for pain Pyridostigmine use of laxatives OPRA opioids in pulmonary rehabilitation Lignocaine for pain management Cannabis - appetite Renal supportive care pruritis

50 Symptom Node Cognitive disorders Nausea Pain PaCCSC Symptom nodes & studies matrix (CURRENT program as at August 2016) Hypothesis generating idea (Pharmacovigilance & other) Midazolam for agitation Palliative sedation (audit) Benzodiazepines Haloperidol Cyclizine Phase I/II; pilot; feasibility Palliative sedation Phase III (initiation or open to recruitment) Melatonin for delirium Dissemination & knowledge transfer (post close to recruitment) Risperidone/ haloperidol for delirium dissemination New nausea Nausea 3 Nausea 1 & 2 analysis Amitriptyline; Targin CADET; Lignocaine PAX-1 Gastro intestinal Breathlessness Anorexia/appetite Collateral Studies Macrogol (Movicol) for constipation Ascitic Taps Lorazepam Mirtazapine; Fn14 Cancer Induced Cachexia Missing data Hypodermoclysis Deprescribing Pyridostigmine for constipation; PERT 1 & PERT 2; OPRA Ranitidine/dexamethasone for bowel obstruction PERT 3 (follow on) Sertraline; BEAMS; The PEARL Trial Octreotide survey MOP dissemination; Sertraline protocol publication & survey Cannabis Cannabis (follow on) Megestrol analysis Renal Supportive Care; Blood Transfusions dissemination

51 6. THE NEW STUDY PROCESS

52 6.0.1 New Study Ideas SOP The SOP provides information to researchers regarding: 1. How the assessment of new study ideas that are brought to PaCCSC is undertaken; Stage 1 presentation to key stakeholders (TMC), member evaluation (again with criteria) Stage 2 draft protocol submitted for scientific review (SC) Stage 3 finalised protocol, ethical approval, funding

53 6.0.1 New Study Ideas/Proposals 2. Following acceptance of the new study idea, the clinical research infrastructure and support structures available to researchers through the PaCCSC central coordinating office, including: Sponsorship Legals, CTN, CTRA s Insurance Quality assurance, quality control systems (SOP s in place) Monitoring, agreements regarding randomization, blinding, investigational product manufacture and handling, DSMC or medical monitor. Safety reporting

54 7. COLLATERAL BENEFITS OF CONDUCTING CLINCAL RESEARCH WITH PACCSC

55 Changing Practice Ketamine study paper published Sept 2012 Broad dissemination program undertaken Follow up survey of ANZSPM members conducted Sept members responded out of a possible 392, of which 92% had heard of the study, 65% had changed practice in 2014 Hardy, J. R., O. Spruyt, et al. (2014). "Implementing practice change in chronic cancer pain management: clinician response to a phase III study of ketamine." Intern Med J 44(6):

56 Output 100+ publications in peer reviewed journals associated with the work of PaCCSC in key areas being studied Numerous national and international Scientific Conference Presentations Conduct of the 7 th Annual Scientific Forum in March 2016 Suite of capacity building activities including: Good Clinical Practice (GCP) clinical research training; regular in-service education; workshops; critical appraisal skills training, study design innovation, improving processes for informed consent

57 Why do research? To find truth. To find an approximation as close to the truth as possible with just the right outlay of resources Evidence-based medicine is a term that is less than 20 years old

58 The nature of evidence in palliative care What are the key responsibilities of specialist palliative care services? To provide clinical care for the people with the most complex needs To educate colleagues and the next generation of clinicians To strengthen the evidence base for the care of people at the end of life

59 NHMRC Levels of evidence Intervention studies Level 1 A systematic review of level II studies Level 2 A randomised controlled trial Level 3/1 A pseudorandomised controlled trial (ie. alternate allocation or some other method) Level 3/2 A comparative study with concurrent controls: Non-randomised experimental trial Cohort study Case-control study Interrupted time series with a control group Level 3/3 A comparative study without concurrent controls: Historical control study Two or more single arm study Interrupted time series without a parallel control group Level 4 Case series with either post-test or pre-test/post-test outcomes.

60 Myths about palliative care research A few myths: Patients at the end of life do not want to participate in research total randomisations to PaCCSC Phase III studies as at April participants Funders are not interested in end-of-life research Research Ethics Committees won t allow research for hospice / palliative care patients

61 A few myths It is not ethical to do research on people at the end of life We need to distinguish between studies that are designed to directly improve the quality of care AND studies where the person is a participant only because they are dying and the study has nothing to do with their health or their care.

62 Myths Myth: It is not ethical to use placebos in hospice / palliative care research Placebo response rates even in refractory symptoms can be 30% or higher There is nothing unique about research in hospice / palliative care. In interventional studies, the major challenge is attrition unrelated to the intervention. Currow C et al Palliativemodified Intention To Treat analysis. JPSM 2012

63 Applying the evidence In palliative care, there is the added challenge of whether the person in front of you would 1. be referred to the study 2. be eligible for the clinical study Are the findings robust? What have the researchers done to reduce bias? Has everyone been accounted for? How consistent are the findings with the known literature?

64 Being successful Research is a team sport: reach out to established researchers; join existing programs; and seek formal post-graduate learning opportunities in research design and conduct.

65 What research can best inform practice? Adequately powered Control group Prospective Rigorous able to stand up to peer review

67 Can PaCCSC assist your next study? Membership Quarterly Newsletter Annual Research Forum March 2, 2017 Sydney

68 What Matters Most Love with excellence

IMPACCT: Improving palliative, aged and chronic care through clinical research and translation. Professor Jane Phillips Director IMPACCT

IMPACCT: Improving palliative, aged and chronic care through clinical research and translation. Professor Jane Phillips Director IMPACCT : Improving palliative, aged and chronic care through clinical research and translation Professor Jane Phillips Director IMPACCT 2 Research Collaboration: Lessons from Palliative Care 3 Overview To provide