Pilot Study Comparing Treatment With Dexmedetomidine to Midazolam for Symptom Control in Advanced Cancer Patients

Study Overview
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Brief Summary
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Cancer patients with very difficult to control symptoms at the Abbotsford (AC) and Fraser Valley (FVC) Cancer Centers are referred and admitted to the Tertiary Palliative Care Units at the Abbotsford Regional Hospital and Cancer Center(ARHCC). For symptom management, patients are sometimes given midazolam continuously through a needle placed underneath the skin. While effective in symptom management, midazolam can be sedating, leaving patients unable to interact with loved ones in their last days. This study is a pilot project. Before proceeding to a full-scale study, a pilot study or feasibility study is often carried out first to test the design of a study, the likelihood of successful recruitment or the acceptability of the intervention to potential subjects. The basic idea is to find out whether it will be practical to proceed to a larger study that will include more subjects. This type of study involves only a small number of subjects and therefore the results can only be used as a guide for further larger studies. The investigators also will determine whether palliative care cancer patients taking a medication called dexmedetomidine would have improved rousability (more easily and fully awakened) and symptom control (pain, shortness of breath, nausea or confusion) compared with those taking standard of care which is receiving the medication midazolam. The use of dexmedetomidine in other clinical situations (in the Operating Room or Intensive Care Unit where the patient can still respond to the doctor) has been shown to be effective in symptom control and to provide a better degree of rousability to patients but has not been well studied in the palliative care environment.

Detailed Description
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INTRODUCTION AND BACKGROUND Advanced cancer patients nearing the end of life suffer from pain, anxiety and other symptoms that can be very difficult to control. The current practice within Fraser Health Authority is to admit these patients to one of three tertiary palliative care units (TPCUs) for pain and symptom management. Once admitted, if pain and symptom relieving measures are insufficient, patients are given a continuous subcutaneous infusion (CSCI) of the drug midazolam for symptom management. While effective, sedation with midazolam often leaves patients unable to eat or drink or interact with their environment. Dexmedetomidine is a unique and promising agent for managing intractable symptoms in palliative patients at the end of life . In addition to providing proportional sedation for symptom control, compared to midazolam, dexmedetomidine has the additional attributes of providing improved management of pain, dyspnea and delirium. Of special interest to patients who would like to continue to be involved in decision making and to be able to communicate with loved ones at the end of life is the quality of rousability possible when dexmedetomidine is used for sedation instead of midazolam. These features have been well studied in the ICU and anaesthesia literature but not in the palliative care environment. PURPOSE AND JUSTIFICATION Currently, standard care for patients with difficult or intractable symptoms for patients admitted to the tertiary palliative care units in Fraser Health is the administration of midazolam by CSCI as recommended in the evidence based Fraser Health Authority (FHA) Hospice Palliative Care Program Symptom Guideline Refractory Symptoms and Palliative Sedation Therapy Guideline. The same guideline states that among the criteria for implementation of palliative sedation therapy is that in all but the most unusual circumstances, death is anticipated within hours to days. However, many other patients with difficult or intractable symptoms have a natural course of their illness that is longer than 'hours to days'. These patients would benefit from a degree of sedation that is proportional to the severity of their symptoms. Therefore, particularly in these circumstances, an option other than deep palliative sedation with midazolam is necessary where the patient would very often like to be aware of those around them and still not be confused or in pain. Despite many studies among ICU and anaesthesia patients, only two reports with four patients have evaluated use of dexmedetomidine in the palliative care environment. The first case was a 45 year old man with cervical paraganglioma, palliative performance scale (PPS) 10% with uncontrolled pain, insomnia, anxiety and severe psychological distress. Combined with morphine, a continuous intravenous infusion (CIVI) of dexmedetomidine provided relief of pain and anxiety within 30 minutes. The patient was sleeping without sign of pain, but prompt communication with his sister was possible. The infusion continued 24 hrs with good physical and psychological symptom control. The second case was 54 year old woman with breast cancer, PPS 20%, delirium and hypercalcemia. Treatment also included CIVI morphine, haloperidol 10 mg/day. Dexmedetomidine CIVI for 48 hr infusion improved agitation and the patient was able to transfer out of the bed, sit in a chair and communicate when necessary. When intravenous access was lost, the patient was sedated with midazolam CSCI 5 mg/hr and died 72 hours hours later. The third case was a 40 year old woman with advanced cervical cancer, PPS 10%, renal failure, hypercalcemia, intractable agitated delirium and pain with movement. Treatment included CSCI morphine, hydration and haloperidol 8 mg/day. Dexmedetomidine infusion temporarily improved delirium for 5 hours, but not pain with movement. When restlessness returned, dexmedetomidine was changed to midazolam 12 mg/hr for the 4 days until the patient died. The fourth case was a 46 year old woman with intractable back and left abdominopelvic pain radiating into her left leg. She was diagnosed with adenocarcinoma of unknown primary with a progressively expanding left retroperitoneal mass involving the psoas muscle and adjacent vertebral bodies. After the titration phase of dexmedetomidine, pain decreased to 6/10 as measured by a numerical pain scale which was considered tolerable by the patient. There was no significant sedation. By the third day, the pain increased to 9/10. As it was the patient's wish to go home, instead of up titrating the dexmedetomidine, a continuous epidural was started with bupivicaine and clonidine. Current ongoing studies of dexmedetomidine use in the palliative care environment is limited to a Phase II study of dexmedetomidine in treating symptoms of distress in advanced cancer patients. The objective of this nine patient cohort study at Duke University Medical Center is to assess the effectiveness of 3 separate doses of dexmedetomidine (0.7, 1.5, 2.5 mg/kg/hr by continuous intravenous infusion) as add-on treatment for intractable pain, agitation and or delirium in terminally ill cancer patients in their last week of life until death. Overall, there is limited evidence in the literature to guide practice of using dexmedetomidine in the palliative care environment. Given this gap in knowledge, the investigators propose to conduct a pilot randomized controlled trial (RCT) of dexmedetomidine CSCI compared to midazolam CSCI in advanced cancer patients in the palliative care setting. The subcutaneous route is chosen for this pilot study as the preferred route of drug delivery as this conforms to the current standard of care according the FHA Hospice Palliative Care symptom guideline Refractory Symptoms and Palliative Sedation Therapy Guideline: Where feasible, the use of midazolam by CSCI is preferred to permit responsive titration. In general, subcutaneous administration is preferred to intravenous administration because of the practical advantage of subcutaneous infusion and the greater risk of apnea when bolus injections are administered intravenously. The subcutaneous route is the most commonly used parenteral route in palliative care, Drugs given via the subcutaneous route tend to have a high bioavailability (generally near 100 %) Subcutaneous infusion provides blood levels comparable to those from intravenous administration, Perfusion of subcutaneous tissue is similar to that of muscle, but rate of absorption is slower. Dexmedetomidine has been successfully administered by CSCI in the pediatric population, but so far has not been used by CSCI in palliative care patients. Neither midazolam or dexmedetomidine are currently approved for use by the subcutaneous route, but Health Canada approval will be obtained for the subcutaneous (SC) route for both dexmedetomidine and midazolam before starting the study to provide for use of the preferred subcutaneous route (over intravenous) in the palliative care environment. The goal of this trial is to assess the feasibility and methodological issues before enrolling subjects in a larger, multi-centre RCT to assess the effectiveness of dexmedetomidine in controlling pain, dyspnea, nausea and/or delirium compared to midazolam. Altogether, findings from this research program (pilot RCT and multi-centre RCT) will provide critical information for both clinicians and health policy makers on the use of dexmedetomidine in patients with advanced cancer with difficult to control or intractable symptoms. RESEARCH QUESTION: The overall goal of the investigators is to answer the following question: Does dexmedetomidine enhance control of pain, dyspnea, nausea and/or delirium, but with improved rousability, compared to midazolam in patients with advanced cancer? However, for the purposes of this pilot study, the investigators will address the following question: What is the feasibility of a multicentre RCT comparing dexmedetomidine with midazolam in enhancing control of pain, dyspnea, nausea and/or delirium in advanced cancer patients? RESEARCH OBJECTIVE(S): The objectives of this pilot study are: To identify facilitators and barriers to recruiting and consenting palliative care advanced cancer patients To assess site irritation when administering dexmedetomidine by continuous subcutaneous infusion as an alternate route to continuous intravenous infusion in advanced cancer patients To assess feasibility of collecting study measures To assess utility of a new study measurement of acceptable improvement of symptoms as assessed by patient, family, and staff Other objectives of interest are: To compare arousability of palliative care advanced cancer patients when symptoms are controlled with dexmedetomidine as compared to midazolam To compare pain, dyspnea, nausea, delirium symptoms of palliative care advanced cancer patients sedated with dexmedetomidine as compared to midazolam

Official Title
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Dexmedetomidine Compared to Midazolam for Symptom Control in Advanced Cancer Patients: A Pilot Randomized Controlled Trial (RCT)

Conditions
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Pain Intractable, Delirium, Dyspnea, Nausea

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater or equal to 19 years of age Advanced cancer patient admitted to the Abbotsford Tertiary Palliative Care Unit Difficult to control or intractable symptom (REF 38, page 3) Midazolam CSCI would normally be considered for symptom management Informed consent is able to be provided in the English language Goals of care include do not resuscitate (DNR) For intractable symptoms, patient would prefer proportional sedation rather than no sedation or total sedation. Exclusion Criteria: Second or third degree heart block (without pacemaker) Uncompensated congestive heart failure Heart rate less than 50 beats per minute Mean arterial blood pressure (MAP) < 60 Weight below 35 kg. or above 85 kg. Prior use within the preceding 14 days of high dose benzodiazepines equivalent to the use of 30 mg or more of midazolam or 6 mg or more of lorazepam per 24 hours. Currently enrolled in any other research study involving drugs or devices

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine<br>Dexmedetomidine 0.2 to 1.1 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days | Drug: Dexmedetomidine<br>* Study drugs will be administered by continuous subcutaneous infusion using a weight based protocol at a rate between 1.0 to 5.5 mL/hr. The study drug will be started at a rate of 1.0 mL/hr. The infusion rate is incremented by 0.5 ml/hr every 30 minutes until acceptable symptom control, bradycardia (heart rate < 40) or hypotension (systolic blood pressure < 80) prevent further increase or maximum infusion rate of 5.5 ml/hr, whichever comes first. Achievement of acceptable symptom control will be defined, for purposes of this trial, as a consensus between reports from patient, family care giver and attending registered nurse<br>* Other names: DIN 02339366;|
| Active Comparator: Midazolam<br>Midazolam 10 to 100 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days | Drug: Midazolam<br>* Study drugs will be administered by continuous subcutaneous infusion using a weight based protocol at a rate between 1.0 to 5.5 mL/hr. The study drug will be started at a rate of 1.0 mL/hr. The infusion rate is incremented by 0.5 ml/hr every 30 minutes until acceptable symptom control, bradycardia (heart rate < 40) or hypotension (systolic blood pressure < 80) prevent further increase or maximum infusion rate of 5.5 ml/hr, whichever comes first. Achievement of acceptable symptom control will be defined, for purposes of this trial, as a consensus between reports from patient, family care giver and attending registered nurse<br>* Other names: DIN 02240286;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects needed to recruit for a multicenter double blind randomized controlled phase III trial comparing dexmedetomidine to midazolam for symptom control in advanced cancer patients | Sample size determination for significant improvement in: Pain Dyspnea Nausea Delirium Rousability | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain (0 to 10 numerical scale) | Pain will be evaluated using the Edmonton Symptom Assessment Scale (ESASr) | Up to 10 days | 
| Change in dyspnea (0 to 10 numerical scale) | Dyspnea will be evaluated using the Edmonton Symptom Assessment Scale (ESASr) | Up to 10 days | 
| Change in nausea (0 to 10 numerical scale) | Nausea will be evaluated using the Edmonton Symptom Assessment Scale (ESASr) | Up to 10 days | 
| Change in delirium (16 item clinician rated scale) | Delirium will be assessed using the Delirium Rating Scale-Revised-98 (DRS-R-98) | Up to 10 days | 
| Rousability (10 point scale) | Rousability will be measured using the Richmond Agitation and Sedation Scale (RASS) | Up to 10 days | 
| Acceptable symptom control (yes/no) | Acceptable symptom control of the difficult to control or intractable symptoms of pain, dyspnea, nausea or delirium will be assessed by a two part question addressed to each of subject, family member and assigned palliative care nurse. Subjective responses will be collected from each as binary variables (0/1) with two positive responses indicating acceptable symptom control overall. | Up to 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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feasibility studies, conscious sedation/, dexmedetomidine/, midazolam/, infusions, subcutaneous/, palliative care/, terminal care/, terminally ill/, neoplasms/, treatment outcome, Precedex, end of life, Dying, Advanced cancer, mood/delirium/delirious