Pain IntractablePhase 2NCT01687751
Pilot Study Comparing Treatment With Dexmedetomidine to Midazolam for Symptom Control in Advanced Cancer Patients
A Phase 2 study testing Dexmedetomidine and Midazolam in people with Pain Intractable and Delirium, run by Fraser Health at 1 site in Canada.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Pain Intractable, Delirium, Dyspnea
- What is being tested?
- Dexmedetomidine and Midazolam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteCanada
- Study dates
- Nov 2012to Nov 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Canada1 site
Abbotsford Regional Hospital and Cancer Center
Abbotsford British Columbia, British Columbia, V2S 0C2
About this study
Official title: Dexmedetomidine Compared to Midazolam for Symptom Control in Advanced Cancer Patients: A Pilot Randomized Controlled Trial (RCT)
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.
Read the detailed description
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
- Conditions
- Pain Intractable, Delirium, Dyspnea, Nausea
- Being tested
- Dexmedetomidine, Midazolam
- Keywords
- 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
- Medical subject headings
- Pain, Intractable, Delirium, Dyspnea, Nausea, Neoplasms, Death
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DexmedetomidineDrug
Also called Precedex, DIN 02339366
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
MidazolamDrug
Also called DIN 02240286
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
| Study group | Role | What they receive |
|---|---|---|
| Dexmedetomidine | Experimental | Dexmedetomidine 0.2 to 1.1 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days Receives: Drug: Dexmedetomidine |
| Midazolam | Active comparator | Midazolam 10 to 100 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days Receives: Drug: Midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: one year
Secondary outcomes (6)
Change in pain (0 to 10 numerical scale)
Pain will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)
Measured: Up to 10 days
Change in dyspnea (0 to 10 numerical scale)
Dyspnea will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)
Measured: Up to 10 days
Change in nausea (0 to 10 numerical scale)
Nausea will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)
Measured: 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)
Measured: Up to 10 days
Rousability (10 point scale)
Rousability will be measured using the Richmond Agitation and Sedation Scale (RASS)
Measured: 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.
Measured: Up to 10 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Sep 2012 (estimated)
- Study startNov 2012
- Primary completionNov 2014
- Study completionNov 2014
Why it stopped: Study design determined to be not likely feasible
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (40)Papers the sponsor has linked to this study.
- Other trials for Pain IntractableStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fraser Health
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Neil K Hilliard, MD, Principal investigator, 1. BC Cancer Agency 2. Fraser Health AuthorityStuart Brown, MD, Principal investigator, Fraser Health Authority
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01687751
- Sponsor's protocol ID
- FHREB 2012-057
- Status last verified
- Jan 2013
- First submitted
- 29 Aug 2012
- Last updated
- 25 May 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Abernethy AP. Pain and palliative care pharmacotherapy literature summaries and analyses. J Pain Palliat Care Pharmacother. 2008;22(2):145-51. doi: 10.1080/15360280801992140.
PubMed 19042839Anger KE, Szumita PM, Baroletti SA, Labreche MJ, Fanikos J. Evaluation of dexmedetomidine versus propofol-based sedation therapy in mechanically ventilated cardiac surgery patients at a tertiary academic medical center. Crit Pathw Cardiol. 2010 Dec;9(4):221-6. doi: 10.1097/HPC.0b013e3181f4ec4a.
PubMed 21119342Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg. 2004 Jan;98(1):153-158. doi: 10.1213/01.ANE.0000093225.39866.75.
PubMed 14693611Brinkkemper T, van Norel AM, Szadek KM, Loer SA, Zuurmond WW, Perez RS. The use of observational scales to monitor symptom control and depth of sedation in patients requiring palliative sedation: a systematic review. Palliat Med. 2013 Jan;27(1):54-67. doi: 10.1177/0269216311425421. Epub 2011 Nov 1.
PubMed 22045725Caraceni A, Simonetti F. Palliating delirium in patients with cancer. Lancet Oncol. 2009 Feb;10(2):164-72. doi: 10.1016/S1470-2045(09)70018-X.
PubMed 19185834Chang VT, Hwang SS, Feuerman M. Validation of the Edmonton Symptom Assessment Scale. Cancer. 2000 May 1;88(9):2164-71. doi: 10.1002/(sici)1097-0142(20000501)88:93.0.co;2-5.
PubMed 10813730Cheung CW, Ying CL, Chiu WK, Wong GT, Ng KF, Irwin MG. A comparison of dexmedetomidine and midazolam for sedation in third molar surgery. Anaesthesia. 2007 Nov;62(11):1132-8. doi: 10.1111/j.1365-2044.2007.05230.x.
PubMed 17924894Chrysostomou C, Schmitt CG. Dexmedetomidine: sedation, analgesia and beyond. Expert Opin Drug Metab Toxicol. 2008 May;4(5):619-27. doi: 10.1517/17425255.4.5.619.
PubMed 18484919Clark, S., & Ezra, M. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients. Journal of the Intensive Care Society, 12(3), 244-245, 2011.
Coull JT, Jones ME, Egan TD, Frith CD, Maze M. Attentional effects of noradrenaline vary with arousal level: selective activation of thalamic pulvinar in humans. Neuroimage. 2004 May;22(1):315-22. doi: 10.1016/j.neuroimage.2003.12.022.
PubMed 15110021Coyne PJ, Wozencraft CP, Roberts SB, Bobb B, Smith TJ. Dexmedetomidine: exploring its potential role and dosing guideline for its use in intractable pain in the palliative care setting. J Pain Palliat Care Pharmacother. 2010 Dec;24(4):384-6. doi: 10.3109/15360288.2010.518227.
PubMed 21133747Dere K, Sucullu I, Budak ET, Yeyen S, Filiz AI, Ozkan S, Dagli G. A comparison of dexmedetomidine versus midazolam for sedation, pain and hemodynamic control, during colonoscopy under conscious sedation. Eur J Anaesthesiol. 2010 Jul;27(7):648-52. doi: 10.1097/EJA.0b013e3283347bfe.
PubMed 20531094Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, Francis J, Speroff T, Gautam S, Margolin R, Sessler CN, Dittus RS, Bernard GR. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003 Jun 11;289(22):2983-91. doi: 10.1001/jama.289.22.2983.
PubMed 12799407Gerlach AT, Murphy CV, Dasta JF. An updated focused review of dexmedetomidine in adults. Ann Pharmacother. 2009 Dec;43(12):2064-74. doi: 10.1345/aph.1M310.
PubMed 19934395Guinter JR, Kristeller JL. Prolonged infusions of dexmedetomidine in critically ill patients. Am J Health Syst Pharm. 2010 Aug;67(15):1246-53. doi: 10.2146/ajhp090300.
PubMed 20651314
Study at a glance
From the registry record, last updated by the sponsor on 25 May 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dexmedetomidine Compared to Midazolam for Symptom Control in Advanced Cancer Patients: A Pilot Randomized Controlled Trial (RCT)
- ClinicalTrials.gov ID
- NCT01687751
- Acronym / sponsor ID
- FHREB 2012-057
- Conditions
- Pain Intractable, Delirium, Dyspnea, Nausea
- Keywords
- feasibility studies, conscious sedation/, dexmedetomidine/, midazolam/, infusions, subcutaneous/, palliative care/, terminal care/, terminally ill/
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Study design determined to be not likely feasible
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Fraser HealthUniversity, hospital or other
- Study start
- Nov 2012
- Primary completion
- Nov 2014 (actual)
- Study completion
- Nov 2014 (actual)
- First posted
- 19 Sep 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dexmedetomidine | Experimental | Drug: DexmedetomidineDexmedetomidine 0.2 to 1.1 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days |
| Midazolam | Active comparator | Drug: MidazolamMidazolam 10 to 100 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DexmedetomidineAlso: Precedex, DIN 02339366Study 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 | Drug | Dexmedetomidine |
| MidazolamAlso: DIN 02240286Study 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 | Drug | Midazolam |
Primary outcome
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
Time frame: one year
Sample size determination for significant improvement in: * Pain * Dyspnea * Nausea * Delirium * Rousability
6 secondary outcomes
Change in pain (0 to 10 numerical scale)
Time frame: Up to 10 days
Change in dyspnea (0 to 10 numerical scale)
Time frame: Up to 10 days
Change in nausea (0 to 10 numerical scale)
Time frame: Up to 10 days
Change in delirium (16 item clinician rated scale)
Time frame: Up to 10 days
Rousability (10 point scale)
Time frame: Up to 10 days
Acceptable symptom control (yes/no)
Time frame: Up to 10 days
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 May 2015.
- Background: PubMed 19042839Abernethy AP. Pain and palliative care pharmacotherapy literature summaries and analyses. J Pain Palliat Care Pharmacother. 2008;22(2):145-51. doi: 10.1080/15360280801992140.
- Background: PubMed 21119342Anger KE, Szumita PM, Baroletti SA, Labreche MJ, Fanikos J. Evaluation of dexmedetomidine versus propofol-based sedation therapy in mechanically ventilated cardiac surgery patients at a tertiary academic medical center. Crit Pathw Cardiol. 2010 Dec;9(4):221-6. doi: 10.1097/HPC.0b013e3181f4ec4a.
- Background: PubMed 14693611Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg. 2004 Jan;98(1):153-158. doi: 10.1213/01.ANE.0000093225.39866.75.
- Background: PubMed 22045725Brinkkemper T, van Norel AM, Szadek KM, Loer SA, Zuurmond WW, Perez RS. The use of observational scales to monitor symptom control and depth of sedation in patients requiring palliative sedation: a systematic review. Palliat Med. 2013 Jan;27(1):54-67. doi: 10.1177/0269216311425421. Epub 2011 Nov 1.
- Background: PubMed 19185834Caraceni A, Simonetti F. Palliating delirium in patients with cancer. Lancet Oncol. 2009 Feb;10(2):164-72. doi: 10.1016/S1470-2045(09)70018-X.
- Background: PubMed 10813730Chang VT, Hwang SS, Feuerman M. Validation of the Edmonton Symptom Assessment Scale. Cancer. 2000 May 1;88(9):2164-71. doi: 10.1002/(sici)1097-0142(20000501)88:93.0.co;2-5.
- Background: PubMed 17924894Cheung CW, Ying CL, Chiu WK, Wong GT, Ng KF, Irwin MG. A comparison of dexmedetomidine and midazolam for sedation in third molar surgery. Anaesthesia. 2007 Nov;62(11):1132-8. doi: 10.1111/j.1365-2044.2007.05230.x.
- Background: PubMed 18484919Chrysostomou C, Schmitt CG. Dexmedetomidine: sedation, analgesia and beyond. Expert Opin Drug Metab Toxicol. 2008 May;4(5):619-27. doi: 10.1517/17425255.4.5.619.
- BackgroundClark, S., & Ezra, M. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients. Journal of the Intensive Care Society, 12(3), 244-245, 2011.
- Background: PubMed 15110021Coull JT, Jones ME, Egan TD, Frith CD, Maze M. Attentional effects of noradrenaline vary with arousal level: selective activation of thalamic pulvinar in humans. Neuroimage. 2004 May;22(1):315-22. doi: 10.1016/j.neuroimage.2003.12.022.
- Background: PubMed 21133747Coyne PJ, Wozencraft CP, Roberts SB, Bobb B, Smith TJ. Dexmedetomidine: exploring its potential role and dosing guideline for its use in intractable pain in the palliative care setting. J Pain Palliat Care Pharmacother. 2010 Dec;24(4):384-6. doi: 10.3109/15360288.2010.518227.
- Background: PubMed 20531094Dere K, Sucullu I, Budak ET, Yeyen S, Filiz AI, Ozkan S, Dagli G. A comparison of dexmedetomidine versus midazolam for sedation, pain and hemodynamic control, during colonoscopy under conscious sedation. Eur J Anaesthesiol. 2010 Jul;27(7):648-52. doi: 10.1097/EJA.0b013e3283347bfe.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Neil K Hilliard, MD principal investigator
1. BC Cancer Agency 2. Fraser Health Authority
Stuart Brown, MD principal investigator
Fraser Health Authority
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Dexmedetomidine and Midazolam in people with Pain Intractable and Delirium, run by Fraser Health at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 25 May 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: one year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01687751, which also lists 40 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 May 2015.