Continuous IntraVenous Infusion of Ketamine in Terminally Ill Cancer Patients (CIVIK)

A Phase II Study About Efficacy and Safety of the Continuous IntraVenous Infusion of Ketamine in Terminally Ill Cancer Patients With Refractory Cancer Pain

To establish the role of ketamine in hospitalized terminally ill cancer patients with refractory cancer pain, using continuous intravenous infusion of ketamine

Study Overview

• Status: Recruiting
• Conditions: Ketamine; Refractory Cancer Pain
• Intervention / Treatment: Drug: Ketamine

Detailed Description

• There are approximately 20 percent patients of refractory cancer pain, which is troubled with uncontrolled pain though treatment including opioids.
• Ketamine has been showed the performance of Ketamine, N-methyl-D-aspartate (NMDA) receptor blocker, in refractory cancer pain based on prior studies.
• We cannot yet confirm the role of Ketamine comparing the benefit and risk due to incompatible results of prior studies. Additionally, most of prior studies were studied in heterogenous groups, which are from beginning of palliative chemotherapy to terminal status, so role of ketamine was not assessed in homogeneous terminally ill cancer patients. And they has used mostly 'bolus intravenous infusion' or 'continuous subcutaneous infusion (CSCI)', relatively rare in continuous intravenous infusion (CIVI).
• The bolus intravenous method is convenient but is concerned with leading to relatively severe adverse events due to poor general condition of terminally ill cancer patients, the CSCI method is not recommended because of adverse events (AEs) such as skin irritation. On the contrary, the CIVI method using gradual increasing ketamine minimizes AEs and is free of skin irritation. Most of hospitalized terminally ill cancer patients has proper IV access using intravascular devices (chemoport or PICC). So, CIVI method is suitable to hospitalized terminally ill cancer patients.
• This study assess the efficacy and safety of 5-days CIVI gradual dose titration of Ketamine in terminally ill cancer patients with refractory cancer pain.

• Study Type: Interventional
• Enrollment (Anticipated): 26
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mikyung Kang; Email: tesoon@hanmail.net

Study Locations

• Korea, Republic of
  • Gyeongsangnam-do
    • Yangsan, Gyeongsangnam-do, Korea, Republic of, 50612
      • Recruiting
      • Pusan National University Yangsan Hospital
      • Sub-Investigator: So Yeon Oh
      • Sub-Investigator: Sang-Bo Oh
      • Sub-Investigator: Eun-Ju Park

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Among patients with histologically or cytologically confirmed malignancy, patients with expected survival time of several months or less due to a progressive disease without additional anticancer treatment.
2. Patients with refractory cancer pain, which cases of requesting 4 or more breakthrough analgesics or increase of baseline analgesics (average pain score ≥ 4 or Personalized pain goal) in spite of 120 mg/day or more of intravenous Morphine Equivalent Daily Dose
3. Hospitalized patients with intravascular access during at least 5 days
4. Age 18 or older
5. Signed and dated informed consent of document indicating that the patient (or legally acceptable representative) has been informed about all pertinent aspects of the trial prior to enrollment

Exclusion Criteria:

1. Patients who were treated with ketamine for pain control within 6 months
2. Patients who have been treated with radiotherapy within 4 weeks or plan to intervention for pain control during study period
3. Cancer pain cannot be excluded the Opioid induced hyperalgesia

4. Concomitant severe medical, surgical, or disease or problems which were contraindicated to application of Ketamine or have possibilities of unexpected medical problems caused be the Ketamine

   • confirmed or assumed central nervous system lesion which lead to increased intracranial pressure
   • Arrhythmia (supra-ventricular tachycardia, ventricular arrhythmia (frequent premature ventricular contraction, bigeminy, Ventricular tachycardia)
   • history of hemorrhagic stroke or seizure within 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ketamine; continuous intravenous infusion of ketamine	Drug: Ketamine; Application of ketamine using continuous intravenous infusion method during 5 days; Ketamine 100mg/2ml + 5% Dextrose water or Normal saline 98 ml mixed fluid; Dose schedule: 0.05mg/kg/hr -> 0.10mg/kg/hr -> … -> 0.5mg/kg/hr (increase dose at a rate of 0.05mg/kg/hr every 8 hours)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	complete pain response plus partial pain response; Complete pain response is defined as patient reported pain score using numerical rating scale (range 1-10) ≤ 3 or ≤ personalized pain goal (PPG) and receiving less than four rescue analgesic doses for 24 hours, without unacceptable toxicities; Partial pain response is defined as receiving less than four rescue analgesic doses per day without a patient reported pain score using numerical rating scale (range 1-10) ≤ 3 or ≤ personalized pain goal for 24 hr, without unacceptable toxicities	From date of enrollment until 5 days or drop-out, assess up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of pain intensity	Delineate changes of pain intensity daily, from the time baseline until 5th days after application of ketamine. Pain intensity is defined as the mean of terdiurnal checked patient reported pain score during a day.	From date of enrollment until 5 days or drop-out, assess up to 2 years
Rescue analgesics for breakthrough pain	Dose and number of rescue analgesics for breakthrough pain	From date of enrollment until 5 days or drop-out, assess up to 2 years
Patient's satisfaction about Ketamine by a newly developed question in this study	Satisfaction about pain control and Ketamine-related distress during application of ketamine was evaluated by questions as follows: "How do you feel satisfaction about ketamine?" (at 5th days or drop-out)	at the 5th days or drop-out, assess up to 2 years
Guardian's satisfaction about Ketamine by a newly developed question in this study	Satisfaction about pain control and Ketamine-related distress during application of ketamine was evaluated by questions as follows: "How do you feel satisfaction about ketamine?" (at 5th days or drop-out)	at the 5th days or drop-out, assess up to 2 years
Rate of Ketamine-related adverse events	Rate of Ketamine-related adverse events	From date of enrollment until 5 days or drop-out, assess up to 2 years
Rate of early discontinuation	Rate of discontinuation due to Ketamine related AEs	From date of enrollment until 5 days or drop-out, assess up to 2 years
Overall survival	Time from application of ketamine until death or discharge/transfer	From date of enrollment until death or discharge/transfer, assess up to 2 years

Collaborators and Investigators

• Sponsor: Pusan National University Yangsan Hospital

Publications and helpful links

General Publications

• van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol. 2007 Sep;18(9):1437-49. doi: 10.1093/annonc/mdm056. Epub 2007 Mar 12.
• Zech DFJ, Grond S, Lynch J, Hertel D, Lehmann KA. Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain. 1995 Oct;63(1):65-76. doi: 10.1016/0304-3959(95)00017-M.
• Hanks GW, Justins DM. Cancer pain: management. Lancet. 1992 Apr 25;339(8800):1031-6. doi: 10.1016/0140-6736(92)90546-f. No abstract available.
• Hardy J, Quinn S, Fazekas B, Plummer J, Eckermann S, Agar M, Spruyt O, Rowett D, Currow DC. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol. 2012 Oct 10;30(29):3611-7. doi: 10.1200/JCO.2012.42.1081. Epub 2012 Sep 10.
• Jackson K, Ashby M, Martin P, Pisasale M, Brumley D, Hayes B. "Burst" ketamine for refractory cancer pain: an open-label audit of 39 patients. J Pain Symptom Manage. 2001 Oct;22(4):834-42. doi: 10.1016/s0885-3924(01)00340-2.
• Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage. 2000 Oct;20(4):246-52. doi: 10.1016/s0885-3924(00)00194-9.
• Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2017 Jun 28;6(6):CD003351. doi: 10.1002/14651858.CD003351.pub3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2018
• Primary Completion (ANTICIPATED): December 31, 2021
• Study Completion (ANTICIPATED): December 31, 2021

Study Registration Dates

• First Submitted: November 15, 2017
• First Submitted That Met QC Criteria: November 28, 2017
• First Posted (ACTUAL): December 5, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 28, 2021
• Last Update Submitted That Met QC Criteria: September 27, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Palliative care; Ketamine; Refractory cancer pain; Terminally ill cancer patients
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Cancer Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: CIVIK

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No