Trial Information

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

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