FULL PROTOCOL TITLE
FULL PROTOCOL TITLEA Pilot Study: Early Integration of Palliative Care in End-Stage Liver Disease: Impact on quality of life, hospitalization rate, cost of care, and survival Principal Investigator:Blaire E Burman, MD, MASDepartment and Gastroenterology and Hepatology 1100 Ninth Ave, C3-GAS Seattle WA 98111Work phone: 206-341-0685Blaire.burman@ Supported by:Digestive Disease Institute at Virginia Mason Medical CenterTABLE OF CONTENTSCLINICAL SITES PARTICIPATING IN THE STUDYPROTOCOL SYNOPSISSTUDY OBJECTIVESPrimary ObjectivesSecondary ObjectivesPrimary EndpointSecondary EndpointsBACKGROUND Rationale Supporting DataSTUDY DESIGN3.1 Retrospective Study3.2 Prospective Study TARGET STUDY POPULATION SPECIFICS Inclusion Criteria Exclusion Criteria Data Collection ProceduresSTATISTICAL CONSIDERATIONSHypothesisData AnalysisDATA COLLECTIONRecords to be keptSecure storage of dataQuality AssuranceHUMAN SUBJECTSInstitutional Review Board (IRB) Review and Informed ConsentPotential RisksSubject ConfidentialityStudy Modification/DiscontinuationPUBLICATION OF RESEARCH FINDINGSREFERENCES CLINICAL SITES PARTICIPATING IN THE STUDYVirginia Mason Medical Center Principal Investigator: Blaire E Burman, MD, MASSub-Investigators:Alex Kuo, MD Asma Siddique, MDChristina Pham, ARNP Protocol SynopsisTITLEA Pilot Study: Early Integration of Palliative Care in End-Stage Liver Disease: Impact on quality of life, hospitalization rate, cost of care, and survivalNUMBER OF SITES1RATIONALEPatients with End Stage Liver Disease (ESLD) have a high symptom burden and high cost of care, escalating at end-of-life. Historically, palliative care (PC) services have been underutilized in this population. This is a prospective study of the effect of early integration of PC services for non-transplant patients with ESLD on symptom burden and Quality of Life (QOL), in addition to cost of care and survival.STUDY DESIGNThis is a pilot prospective study with no randomization nor blinding component. This study will also utilize a retrospective chart review for a comparison cohort to the prospective population enrolled in this trial. PRIMARY OBJECTIVETo identify whether early integration of PC services for non-transplant eligible patients with ESLD improves health related quality of life.SECONDARY OBJECTIVESTo identify whether early integration of PC services for patients with ESLD can reduce hospitalization rates, Intensive Care Unit (ICU) admission rates, and/or cost of care, without impacting survival.NUMBER OF SUBJECTSThe goal will be to enroll 50 subjects in the prospective cohort. The retrospective chart review will include all ESLD patients treated at Virginia Mason (VM) from 2010-2015.SELECT SUBJECT ENTRANCECRITERIAInclusion Criteria:Diagnosis of End Stage Liver Disease, with or without Hepatocellular Carcinoma (HCC), meeting at least one of the following criteria:Child Class of B or C (composite score based on presence of ascites, encephalopathy, and level of bilirubin, INR, and albumin) orModel for End Stage Liver Disease (MELD) score > 20 (composite score based on bilirubin, INR, creatinine, and sodium). Is planning to continue care with Virginia Mason Hepatology as well as VM Palliative Care services if applicable.Exclusion Criteria:Currently listed for liver transplant or transplant eligible in the short term.Presence of any of the clinical contraindications to participation listed below:Predicted < 1 month survivalCritical illness requiring ongoing ICU carePresence of grade II or higher hepatic encephalopathyClinical circumstances precluding participation in a questionnaire based study such as inability to participate in meaningful discussions. dURATION OF SUBJECT PARTICIPATION AND DURATION OF STUDYSubjects will participate in the study until consent is withdrawn, continuing care at Virginia Mason is terminated, until deceased, or at Investigator Discretion, whichever is shortest. The study is expected to last approximately 2 years.ECONCOMMITANT MEDICATIONSAll concomitant medications are allowed.Primary endpointChronic Liver Disease Questionnaire (CLDQ)Secondary endpointsHospitalization rates, ICU admission rates, cost of care, survival, code status, place of death.Safety EvaluationsAll subjects will be closely monitored per standard of care by their hepatology provider as well as palliative care provider as applicable. Planned Interim Analyses None.STATISTICSPrimary Analysis PlanDescriptive statistics will be performed for the retrospective and prospective portions of the study. Multivariate regression analysis will be used to identify factors associated with PC. Cost analysis: Generalized linear models (GLMs) with a γ distribution and log link will be used to calculate the average incremental effect of PC on total direct hospital. Additional analyses may be performed as appropriate. All analyses will be performed using Stata (version 12; StataCorp, College Station, TX). STUDY OBJECTIVESPrimary ObjectivesTo identify whether the utilization of early integration of palliative care (PC) services for non-transplant eligible patients with End Stage Liver Disease (ESLD) improves health related quality of life (QOL). Secondary ObjectivesTo identify whether early integration of PC services for patients with ESLD can reduce hospitalization rates, Intensive Care Unit (ICU) admission rates, and/or cost of care, without impacting survival. Primary EndpointChronic Liver Disease Questionnaire (CLDQ)Secondary EndpointsHospitalization rates, ICU admission rates, length of hospital stay(s), code status during stay, place of death, survival, cost of care.BACKGROUNDRationaleEnd-stage liver disease is a term synonymous with decompensated cirrhosis. This is a progressive and terminal illness with a median 2 year survival [1], a high symptom burden, and is associated with psychosocial distress and marked impact on quality of life (QOL). The only existing cure is liver transplantation which is an option available to a small minority of patients; remaining therapies are palliative in nature. Decompensated cirrhosis is associated with portal hypertension and characterized by ascites, hepatic encephalopathy, and gastrointestinal bleeding, with high risk for infections, coagulopathy, and renal failure. In addition to these medical complications, patients frequently experience debilitating physical symptoms including fatigue, pain, confusion, depression, muscle wasting, cramping, and sleep disturbance. Quality of life in this population is significantly impacted [1-3], and studies have also shown that patients with ESLD approaching end of life experience more suffering in comparison to those dying of other chronic diseases [4]. Further, with cirrhosis, the trajectory of functional decline is less predictable, and many patients are in a constant state of poor or declining health interspersed by intermittent exacerbations and hospitalizations. Despite poor prognosis and impact on physical and psychosocial wellbeing, palliative care services are grossly underutilized in ESLD. Palliative care is defined as “patient and family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering.” It is considered standard of care for any patient with a terminal illness that has less than 1-2 years life expectancy and should be considered for all patients with advanced chronic disease at any point in the disease trajectory, including early in the course of the illness in conjunction with other therapies that are intended to prolong life (National Consensus Project for Quality Palliative Care Guidelines). Addressing end-of-life issues through PC is known to improve communication between providers, patients, and their caregivers as well as reduce symptom burden, enhance QOL, and for certain conditions, prolong life as well [5-7]. Limited studies also suggest PC is associated with decreased health care utilization and expenditures [8]. Despite this, PC is often not utilized until the last few weeks of life in this ‘end stage’ population. As such, the value with regard to improving patient care in ESLD while controlling cost of care has not been evaluated. Supporting DataTo date there are a paucity of studies investigating access and barriers to PC among patients with ESLD. Limited data from single center retrospective studies identify that ESLD patients, even at terminal hospitalizations, rarely receive palliative services. Further, such consultations occur very late in the disease course, often in the setting of transition to comfort care, rather than in proactive symptom management and facilitating goals of care. Poonja et al reported their experience in the liver transplant population at University of Alberta and found that of 102 patients declined or removed from the wait list over a 5 year periods, only 10% were referred for palliative care despite high burden of symptoms including pain [9]. Kathpalia et al found that among patients with ESLD without access to liver transplant, only 17% received palliative care services, and half of all consults occurred within 3 days of death, and 20% on the same day as death [10]. In another retrospective review of non-transplant ESLD patients, median survival after PC consult was 15 days, and without consultation, aggressive intervention continued until hours before death [11]. More recently, a larger retrospective nationwide cohort analysis using the National Inpatient Sample (NIS) revealed PC consultation was performed rarely on average (4.5% of ESLD patients), however during the study period (2006-12) there was a significant increase in referral rates suggesting improved acceptance and utilization of services. Nevertheless, there were persistent glaring disparities to access based on socioeconomic status and race [12]. Further, no studies have highlighted use of PC in the outpatient setting of ESLD patients seen in hepatology clinics.There has been increased attention on ways to improve quality of end-of-life care for patients with ESLD, and curb frequent hospitalizations and associated costs. However there are no prospective studies of the value of PC in this setting to date. In a small single center study, Baumann et al showed that early PC utilization in patients listed for liver transplant led to improved symptom management and well-being [13]. This has not been evaluated among non-transplant ESLD patients. In addition, a recent retrospective analysis of adults with decompensated cirrhosis, also using the NIS from 2009 to 2013, showed PC was associated with lower procedure burden after adjusting for other factors, and was associated with a cost reduction of $8,892 per hospitalization [8]. The impact of early PC on hospitalizations and cost of care has not been evaluated prospectively.Patients with ESLD have a high symptom burden and high cost of care, which escalates at end-of-life. This is the first prospective study to evaluate the effect of early integration of PC services for non-transplant patients with ESLD. This study will evaluate impact on symptom burden and QOL, in addition to complexity and cost of care, and survival. If positive results are seen in this study, the goal is to perform future studies with multiple sites in order to include a broader population of end-stage liver patients and attempt to demonstrate a universal benefit of early integration of PC services in other populations, including liver transplant centers.STUDY DESIGNRetrospective StudyA retrospective cohort study of adult patients seen at Virginia Mason with ESLD between 2010 and 2015 (5 years) will be performed to establish a historical control for the prospective portion of the trial. ESLD will be defined as diagnosis of Child B or C cirrhosis and/or Model for End Stage Liver Disease (MELD) score > 20). The retrospective study will provide background and context for baseline rates of referral to and receipt of palliative care services in this population, timing and predictors of such services, and to investigate the difference in hospitalization rates, complexity and cost of care, and survival between those who did and did not receive palliative care prior to death. The primary objective will be to determine rate of referral and receipt of PC services for these subjects. Additionally, the impact of demographics or disease related factors (Child Pugh score, MELD score, etiology of liver disease, presence of Hepatocellular Carcinoma (HCC)) will be analyzed to ascertain if there are any predictors of PC service receipt. Rates of PC receipt for ESLD patients at Virginia Mason between 2010-2015 will be compared to those published in the literature Secondary outcomes will include 90-day re-hospitalization rate, ICU admission rate, cost and complexity of care, survival, code status, and place of death (home vs hospital or long-term care facility). Prospective StudyA prospective study of the effect of PC intervention for ESLD patients seen at Virginia Mason will be performed. Patients with ESLD who are not likely to become transplant eligible will be offered PC services as part of standard of care. The decision to accept or decline these services will not impact enrollment into this trial. Given that a randomized controlled trial of PC was not deemed feasible or ethical, enrolled subjects will be compared to historical controls, as well as to the enrolled subjects who opted not to utilize PC. Once the decision about the utilization of PC has been made, patients will be asked to participate in this trial. After informed consent is obtained, enrolled subjects will complete a baseline QOL assessment using the standardized and validated CLDQ. Caregivers, if present, may assist in filling out the questionnaire.CLDQ is the most widely used and well validated disease-specific tool for assessment of QOL in patients with liver disease. It is a standardized questionnaire with a simple format and consists of 29 questions split into six domains; higher scores represent better HR-QOL PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Zb3Vub3NzaTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA [14, 15]. If the subject has opted for PC services and the initial consultation has not yet been completed, a PC provider will consult with the subject (and caregiver if present) and develop a PC action plan. This consultation and all follow up visits are considered standard of care. Subjects will have follow up visits with their hepatology provider at approximately 3 month intervals (± 1 month), as per standard practice. Subjects who did not opt for PC services before the study will be asked to confirm that decision at each visit and may enter PC services at any point during the study. For subjects utilizing PC, either the hepatology provider or a PC provider will revisit the PC action plan and goals of care with the subject at each follow up visit. Subjects will complete the CLDQ questionnaire at each follow up visit. Subjects may opt to start or stop PC services at any time during the study; they will continue to be followed at 3 month intervals and asked to complete the CLDQ at each visit regardless of their decision to utilize PC services.Diagnosis date of ESLD, start and stop date(s) of PC services (as applicable), demographic and disease related variables (Child Pugh score, MELD score, etiology of liver disease, presence of HCC), 90-day re-hospitalization rate, ICU admission rate, length of any hospital stay, cost of care, survival, code status, and place of death (home vs hospital or long-term care facility) will be collected for each subject via the electronic medical record. All data will be entered into a secure password-protected clinical research database maintained on a Virginia Mason computer. The goal is to enroll 50 patients based on an estimation of eligible subjects seen within the Virginia Mason hepatology clinic and inpatient service. Currently, every week 2-3 new patients with ESLD who are unlikely to be eligible for liver transplant are seen. The rate of enrollment is expected to be 1-2 patients per week. While enrolled patients will have their primary hepatologist and PC provider within the VMMC system, we anticipate some degree of loss-to-follow up, and the potential need to collect hospitalization data from outside systems.We will be evaluating the impact of PC intervention compared to historical controls and current prospective patients who opted out of PC. Each subject will receive baseline questionnaire and be followed at 3 month intervals until withdrawal of consent, transfer of care outside the Virginia Mason system, death or at Investigator Discretion. Given the median survival is between 6-24 months for this population in lieu of liver transplant, we expect the intervention period will be less than 2 years. TARGET STUDY POPULATION SPECIFICSInclusion CriteriaAge 18 or aboveDiagnosis of End Stage Liver Disease, with or without Hepatocellular Carcinoma (HCC), meeting at least one of the following criteria:Child Class of B or C (composite score based on presence of ascites, encephalopathy, and level of bilirubin, INR, and albumin) orModel for End Stage Liver Disease (MELD) score > 20 (composite score based on bilirubin, INR, creatinine, and sodium). Is planning to continue care with Virginia Mason Hepatology as well as VM Palliative Care Services if applicable.Exclusion CriteriaCurrently listed for liver transplant or transplant eligible in the short-term.Presence of any of the clinical contraindications to participation listed below:Predicted < 1 month survivalCritical illness requiring ongoing ICU carePresence of grade II or higher hepatic encephalopathyClinical circumstances precluding participation in a questionnaire based study such as inability to participate in meaningful discussions. Inability of unwillingness of subject or legal guardian/representative to give informed consent. Data Collection ProceduresVirginia Mason Hepatology providers will identify patients for potential study participation. Informed consent will be obtained for all subjects who wish to participate in this trial. Upon consent, study staff will obtain baseline and demographic data, perform the CLDQ questionnaire, and schedule the palliative care evaluation if applicable. At follow up visits, the CLDQ will be obtained for participating patients and the PC plan and goals reviewed with the patient. Additional data points under study (see section 3.2) will be obtained from the subject’s electronic medical record.STATISTICAL CONSIDERATIONSHypothesesThere is a low rate of palliative care services provided to patients with ESLD who are not transplant candidates. Patients with Child B or C cirrhosis and a MELD of >20 have an expected median six-month prognosis and high burden of morbidity, hospitalizations, and psychosocial distress.Early integration of palliative care can improve HR-QOL (assessed by CLDQ), and may impact hospitalization rates, ICU admission rates, code status clarification rates, place of death, and survival. Plan for future multisite study to include expansion of evaluation of early PC intervention to partner transplant and academic centers based on results of year 1-2 of prospective trial. 5.2 Data AnalysesDescriptive statistics will be performed for the retrospective and prospective portions of the study. Multivariate regression analysis will be used to identify factors associated with PC. Cost analysis: Generalized linear models (GLMs) with a γ distribution and log link will be used to calculate the average incremental effect of PC on total direct hospital. Additional analyses may be performed as appropriate. All analyses will be performed using Stata (version 12; StataCorp, College Station, TX). DATA COLLECTIONRecords to be keptClinical and demographic data is available through electronic medical records and will be entered directly into the study database. Any paper study documents that are generated, such as the CLDQ, will be securely stored and archived for 10 years following study completion. There may be an electronic option for CLDQ completion via REDcap.Secure Storage of DataAll study data will be entered into a secure password-protected clinical research database maintained on a Virginia Mason computer. No PHI will be transferred outside of Virginia Mason.Quality AssuranceThe Clinical Research Program will assess the risk of this trial and will devise and implement an internal monitoring and/or auditing plan for this trial. This plan will be revised as necessary during the life of the trial based upon a variety of factors, including but not limited to: protocol amendments, staff turnover, enrollment metrics, and compliance issues noted. HUMAN SUBJECTSInstitutional Review Board (IRB) Review and Informed ConsentThis protocol and informed consent document/study information sheet and any subsequent modifications will be reviewed and approved by the IRB at Benaroya Research Institute at Virginia Mason prior to implementation. Informed consent will be obtained from all subjects prior to study entry following Good Clinical Practice and FDA guidelines.Potential RisksThe risks associated with the completion of quality of life questionnaires is minimal.Subject ConfidentialityAll paper records will be kept in a file cabinet within secure Virginia Mason offices during the trial. The database will be maintained on a Virginia Mason computer located on the secure Virginia Mason maintained network, which requires user login for access. Clinical information will not be released without written permission of the subject, except as necessary for monitoring by the IRB, FDA, OHRP, or CRP. All paper study records will be securely archived by CRP for 10 years following completion of the study.Study Modification/DiscontinuationThe study may be modified or discontinued at any time by the IRB, Investigator, OHRP, FDA or other Government agencies as part of their duties to ensure that research subjects are protected.PUBLICATION OF RESEARCH FINDINGSPublication of the results of this trial will be governed by the policies and procedures of the journal for which it is submitted. Any presentation, abstract, or manuscript will be made available for review by the Benaroya Research Institute IRB.REFERENCES ADDIN EN.REFLIST 1.D'Amico, G., G. Garcia-Tsao, and L. Pagliaro, Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol, 2006. 44(1): p. 217-31.2.Marchesini, G., et al., Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology, 2001. 120(1): p. 170-8.3.Martin, L.M., M.J. Sheridan, and Z.M. Younossi, The impact of liver disease on health-related quality of life: a review of the literature. Curr Gastroenterol Rep, 2002. 4(1): p. 79-83.4.Roth, K., et al., Dying with end stage liver disease with cirrhosis: insights from SUPPORT. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. J Am Geriatr Soc, 2000. 48(5 Suppl): p. S122-30.5.Manfredi, P.L., et al., Palliative care consultations: how do they impact the care of hospitalized patients? J Pain Symptom Manage, 2000. 20(3): p. 166-73.6.Temel, J.S., et al., Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med, 2010. 363(8): p. 733-42.7.Connor, S.R., et al., Comparing hospice and nonhospice patient survival among patients who die within a three-year window. J Pain Symptom Manage, 2007. 33(3): p. 238-46.8.Patel, A.A., et al., Palliative Care and Health Care Utilization for Patients With End-Stage Liver Disease at the End of Life. Clin Gastroenterol Hepatol, 2017.9.Poonja, Z., et al., Patients with cirrhosis and denied liver transplants rarely receive adequate palliative care or appropriate management. Clin Gastroenterol Hepatol, 2014. 12(4): p. 692-8.10.Kathpalia, P., A. Smith, and J.C. Lai, Underutilization of palliative care services in the liver transplant population. World J Transplant, 2016. 6(3): p. 594-8.11.Kelly, S.G., et al., The Utilization of Palliative Care Services in Patients with Cirrhosis who have been Denied Liver Transplantation: A Single Center Retrospective Review. Ann Hepatol, 2017. 16(3): p. 395-401.12.Rush, B., et al., Palliative Care Access for Hospitalized Patients with End Stage Liver Disease Across the United States. Hepatology, 2017.13.Baumann, A.J., et al., Benefit of Early Palliative Care Intervention in End-Stage Liver Disease Patients Awaiting Liver Transplantation. J Pain Symptom Manage, 2015. 50(6): p. 882-6 e2.14.Younossi, Z.M., et al., Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut, 1999. 45(2): p. 295-300.15.Bhanji, R.A., E.J. Carey, and K.D. Watt, Review article: maximising quality of life while aspiring for quantity of life in end-stage liver disease. Aliment Pharmacol Ther, 2017. 46(1): p. 16-25. ................
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