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

NCT01687751 | Withdrawn Phase 2

• 1 other identifier: FHREB 2012-057
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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). 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.

Conditions

Pain Intractable; Delirium; Dyspnea; Nausea

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Change in pain (0 to 10 numerical scale)

  Up to 10 days

• Change in dyspnea (0 to 10 numerical scale)

  Up to 10 days

• Change in nausea (0 to 10 numerical scale)

  Up to 10 days

• Change in delirium (16 item clinician rated scale)

  Up to 10 days

• Rousability (10 point scale)

  Up to 10 days

Other Outcomes (2)

• Time to enroll 20 subjects

  One year

• Cost determination for developing a budget for a large multi-center trial

  One year

Study Arms (2)

Dexmedetomidine

EXPERIMENTAL

Dexmedetomidine 0.2 to 1.1 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days

Drug: Dexmedetomidine

Midazolam

ACTIVE COMPARATOR

Midazolam 10 to 100 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days

Drug: Midazolam

Interventions

Dexmedetomidine DRUG

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

Also known as: Precedex, DIN 02339366

Dexmedetomidine

Midazolam DRUG

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

Also known as: DIN 02240286

Midazolam

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Fraser Health: lead

Study Sites (1)

Abbotsford Regional Hospital and Cancer Center

Abbotsford, British Columbia, V2S 0C2, Canada

Location

Related Publications (40)

• 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.

  PMID: 19042839 BACKGROUND

• Anger 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.

  PMID: 21119342 BACKGROUND

• Arain 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.

  PMID: 14693611 BACKGROUND

• Brinkkemper 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.

  PMID: 22045725 BACKGROUND

• Caraceni 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.

  PMID: 19185834 BACKGROUND

• Chang 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.

  PMID: 10813730 BACKGROUND

• Cheung 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.

  PMID: 17924894 BACKGROUND

• Chrysostomou 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.

  PMID: 18484919 BACKGROUND

• Clark, 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

• 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.

  PMID: 15110021 BACKGROUND

• Coyne 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.

  PMID: 21133747 BACKGROUND

• Dere 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.

  PMID: 20531094 BACKGROUND

• Ely 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.

  PMID: 12799407 BACKGROUND

• Gerlach 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.

  PMID: 19934395 BACKGROUND

• Guinter 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.

  PMID: 20651314 BACKGROUND

• Jackson KC 3rd, Wohlt P, Fine PG. Dexmedetomidine: a novel analgesic with palliative medicine potential. J Pain Palliat Care Pharmacother. 2006;20(2):23-7.

  PMID: 16702133 BACKGROUND

• Jones GM, Murphy CV, Gerlach AT, Goodman EM, Pell LJ. High-dose dexmedetomidine for sedation in the intensive care unit: an evaluation of clinical efficacy and safety. Ann Pharmacother. 2011 Jun;45(6):740-7. doi: 10.1345/aph.1P726. Epub 2011 Jun 10.

  PMID: 21666095 BACKGROUND

• Kehl KA. Treatment of terminal restlessness: a review of the evidence. J Pain Palliat Care Pharmacother. 2004;18(1):5-30.

  PMID: 15148006 BACKGROUND

• Kent CD, Kaufman BS, Lowy J. Dexmedetomidine facilitates the withdrawal of ventilatory support in palliative care. Anesthesiology. 2005 Aug;103(2):439-41. doi: 10.1097/00000542-200508000-00028. No abstract available.

  PMID: 16052127 BACKGROUND

• Kunisawa T. Dexmedetomidine hydrochloride as a long-term sedative. Ther Clin Risk Manag. 2011;7:291-9. doi: 10.2147/TCRM.S14581. Epub 2011 Jul 11.

  PMID: 21845052 BACKGROUND

• Lum, K. L., & Sanders, H. G. A comparison of midazolam and flunitrazepam in end-of-life care. Progress in Palliative Care, 19(1), 1-6, 2011.

  BACKGROUND

• Maldonado JR, Wysong A, van der Starre PJ, Block T, Miller C, Reitz BA. Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics. 2009 May-Jun;50(3):206-17. doi: 10.1176/appi.psy.50.3.206.

  PMID: 19567759 BACKGROUND

• Maze M, Angst MS. Dexmedetomidine and opioid interactions: defining the role of dexmedetomidine for intensive care unit sedation. Anesthesiology. 2004 Nov;101(5):1059-61. doi: 10.1097/00000542-200411000-00002. No abstract available.

  PMID: 15505438 BACKGROUND

• Mercadante S, Intravaia G, Villari P, Ferrera P, David F, Casuccio A. Controlled sedation for refractory symptoms in dying patients. J Pain Symptom Manage. 2009 May;37(5):771-9. doi: 10.1016/j.jpainsymman.2008.04.020. Epub 2008 Nov 28.

  PMID: 19041216 BACKGROUND

• Muttu S, Liu EH, Ang SB, Chew PT, Lee TL, Ti LK. Comparison of dexmedetomidine and midazolam sedation for cataract surgery under topical anesthesia. J Cataract Refract Surg. 2005 Sep;31(9):1845-6. doi: 10.1016/j.jcrs.2005.09.019. No abstract available.

  PMID: 16246802 BACKGROUND

• Prommer E. Review article: dexmedetomidine: does it have potential in palliative medicine? Am J Hosp Palliat Care. 2011 Jun;28(4):276-83. doi: 10.1177/1049909110389804. Epub 2010 Dec 3.

  PMID: 21131636 BACKGROUND

• Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009 Feb 4;301(5):489-99. doi: 10.1001/jama.2009.56. Epub 2009 Feb 2.

  PMID: 19188334 BACKGROUND

• Roberts SB, Wozencraft CP, Coyne PJ, Smith TJ. Dexmedetomidine as an adjuvant analgesic for intractable cancer pain. J Palliat Med. 2011 Mar;14(3):371-3. doi: 10.1089/jpm.2010.0235. Epub 2011 Jan 17.

  PMID: 21241196 BACKGROUND

• Ruokonen E, Parviainen I, Jakob SM, Nunes S, Kaukonen M, Shepherd ST, Sarapohja T, Bratty JR, Takala J; "Dexmedetomidine for Continuous Sedation" Investigators. Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med. 2009 Feb;35(2):282-90. doi: 10.1007/s00134-008-1296-0. Epub 2008 Sep 16.

  PMID: 18795253 BACKGROUND

• Shehabi, Y., Botha, J. A., Ernest, D., Freebairn, R. C., Reade, M., Roberts, B. L., et al. Clinical application, the use of dexmedetomidine in intensive care sedation. Critical Care and Shock, 13(2), 40-50, 2010.

  BACKGROUND

• Soares LG, Naylor C, Martins MA, Peixoto G. Dexmedetomidine: a new option for intractable distress in the dying. J Pain Symptom Manage. 2002 Jul;24(1):6-8. doi: 10.1016/s0885-3924(02)00423-2. No abstract available.

  PMID: 12183087 BACKGROUND

• Tan JA, Ho KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis. Intensive Care Med. 2010 Jun;36(6):926-39. doi: 10.1007/s00134-010-1877-6. Epub 2010 Apr 8.

  PMID: 20376429 BACKGROUND

• Tobias JD. Subcutaneous dexmedetomidine infusions to treat or prevent drug withdrawal in infants and children. J Opioid Manag. 2008 Jul-Aug;4(4):187-91. doi: 10.5055/jom.2008.0024.

  PMID: 18837201 BACKGROUND

• Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci. 2001 Spring;13(2):229-42. doi: 10.1176/jnp.13.2.229.

  PMID: 11449030 BACKGROUND

• Ustun Y, Gunduz M, Erdogan O, Benlidayi ME. Dexmedetomidine versus midazolam in outpatient third molar surgery. J Oral Maxillofac Surg. 2006 Sep;64(9):1353-8. doi: 10.1016/j.joms.2006.05.020.

  PMID: 16916668 BACKGROUND

• Wallace S, Mecklenburg B, Hanling S. Profound reduction in sedation and analgesic requirements using extended dexmedetomidine infusions in a patient with an open abdomen. Mil Med. 2009 Nov;174(11):1228-30. doi: 10.7205/milmed-d-00-6009.

  PMID: 19960834 BACKGROUND

• Fraser Health Authority (FHA) Hospice Palliative Care Program Symptom Guideline "Refractory Symptoms and Palliative Sedation Therapy Guideline", May 9, 2011. Retrieved from http://www.fraserhealth.ca/media/RefractorySymptomsandPalliativeSedationTherapyRevised_Sept%2009.pdf )

  BACKGROUND

• Flanagan E, Gentry J. He's taking how much Dilaudid! Dexmedetomidine: a novel approach to refractory symptom management. Presentation of the American Academy of Hospice and Palliative Medicine & Hospice and Palliative Nurses Association Conference 2011 Feb 16-19; Vancouver, British Columbia

  BACKGROUND

• Doyle, D. et al, Oxford Textbook of Palliative Medicine, Third Edition 2004, p. 219.

  BACKGROUND

• Storey P, Knight C. Assessment and Treatment of Pain in the Terminally Ill. UNIPAC Three, Hospice/Palliative Care Training for Physicians, A Self-Study Program, American Academy of Hospice and Palliative Medicine, Second Edition, Mary Ann Liebert, Inc., 2003, p. 62.

  BACKGROUND

MeSH Terms

Conditions

Pain, Intractable; Delirium; Dyspnea; Nausea; Neoplasms; Death

Interventions

Dexmedetomidine; Midazolam

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Confusion; Neurobehavioral Manifestations; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms, Digestive; Pathologic Processes

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Neil K Hilliard, MD

  1. BC Cancer Agency 2. Fraser Health Authority

  PRINCIPAL INVESTIGATOR

• Stuart Brown, MD

  Fraser Health Authority

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 29, 2012
• First Posted: September 19, 2012
• Study Start: November 1, 2012
• Primary Completion: November 1, 2014
• Study Completion: November 1, 2014
• Last Updated: May 25, 2015

Record last verified: 2013-01

Locations

CA (1)