Continuous IntraVenous Infusion of Ketamine in Terminally Ill Cancer Patients

Study Overview
=================
Brief Summary
-----------------
To establish the role of ketamine in hospitalized terminally ill cancer patients with refractory cancer pain, using continuous intravenous infusion of 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.

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

Conditions
-----------------
Refractory Cancer Pain, Ketamine

Intervention / Treatment
-----------------
* Drug: Ketamine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. 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 Hospitalized patients with intravascular access during at least 5 days Age 18 or older 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: Patients who were treated with ketamine for pain control within 6 months Patients who have been treated with radiotherapy within 4 weeks or plan to intervention for pain control during study period Cancer pain cannot be excluded the Opioid induced hyperalgesia 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective, Single institution, Open-label, Phase 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>continuous intravenous infusion of ketamine | Drug: Ketamine<br>* 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)<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ketamine, Refractory cancer pain, Terminally ill cancer patients, Palliative care