Intranasal (NAS) Ketamine for Cancer Pain

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to determine the safety, feasibility, and utility of intranasal (NAS) ketamine in persistent uncontrolled cancer related pain. In this prospective clinical trial the researchers will investigate the use of NAS ketamine in patients with pain related to cancer or cancer treatment. The researchers plan to enroll at least 25 patients meeting inclusion/exclusion criteria, to achieve a minimum of 10 patients who complete the study. Participants will be recruited from the supportive oncology clinic, oncology clinics, the pain clinic and Acute Pain Service at Emory. Participants will be asked to return to the Phase I unit of the Winship Cancer Building C for a total of 5 study visits, each two to five days apart. During these visits participants will complete questionnaires, have blood samples drawn and will have study medication administered to them in escalating doses. For safety monitoring participants will be contacted by telephone 14 days after the last dose of medication administered.

Detailed Description
-----------------
There are about 11.9 million Americans affected with cancer. 53% of patients with cancer experience pain at all stages of cancer. These patients often require high doses of opioids with uncontrolled pain that makes them too sedated to effectively participate in day-to-day activities and have a good quality of life. Depression often co-exists with cancer pain due to the nature of the disease. The researchers are searching for improved therapies for chronic cancer pain and ketamine with its novel mechanism of action may be a promising solution. Ketamine is an FDA approved anesthetic with the ability to effect memory loss, pain relief and sedation. Safety and efficacy of ketamine as an anesthetic and analgesic agent is well documented. Low doses of ketamine have minimal adverse impact on circulatory or breathing functions but can reduce pain. Research has shown that ketamine is effective in controlling breakthrough pain and reducing depression in a randomized double blind controlled trial. There is limited data regarding the use of ketamine for pain management in cancer. One of the challenges with ketamine is the route of administration, most commonly given intravenously (IV) or intramuscularly (IM). It has also been given by mouth and rectally, but absorption is very poor. Intranasal (NAS) administration may be a promising method of delivery and can be ordered by a physician from a compounding pharmacy. From other research the investigators expect absorption to be higher than oral or rectal administration and this method of delivery as needle-free is a patient-friendly route of administration. The main purpose of this study is to determine the safety, feasibility, and utility of intranasal (NAS) ketamine in persistent uncontrolled cancer related pain. In this prospective clinical trial the researchers will investigate the use of NAS ketamine in patients with pain related to cancer or cancer treatment. The researchers plan to enroll at least 15 patients meeting inclusion/exclusion criteria, to achieve a minimum of 10 patients who complete the study. Participants will be recruited from the oncology clinic, pain clinic and Acute Pain Service at Emory. Participants will be asked to return to the Phase I unit of the Winship Cancer Building C for a total of 5 study visits, each two to five days apart. During these visits participants will complete questionnaires, have blood samples drawn and will have study medication administered to them in escalating doses. For safety monitoring participants will be contacted by telephone 14 days after the last dose of medication administered. Data obtained from this study will help determine if ketamine provides a reduction of pain using the Numeric Pain Rating Scale and a reduction in the use of opioid consumption and other rescue medications. Additionally the researchers will study the bioavailability, pharmacodynamics and pharmacokinetics of ketamine and the safety profile of NAS ketamine.

Official Title
-----------------
Safety of Intranasal Ketamine for Reducing Uncontrolled Cancer Related Pain

Conditions
-----------------
Cancer, Pain

Intervention / Treatment
-----------------
* Drug: Intranasal ketamine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with uncontrolled pain related to cancer or cancer treatment. Uncontrolled pain will be defined as: Pain which persists for more than 7 days and is rated >/=4 on Numerical Pain Rating Score (NPRS) Use of breakthrough medication more than 4 times in 24 hours or being treated with oral morphine equivalent of 50 mg/d or more Patients who are able to follow-up in person during the trial Patient on stable analgesic regimen for >7 days without escalation during study period with rescue or immediate release medication every 3 hours or longer Patients who are willing and able to maintain a daily pain diary Patients who are able to understand written and verbal English Patient weight >/= 50 kg Exclusion Criteria: Transportation issues interfering with return study visits Patients with high disposition of laryngospasm or apnea Presence of severe cardiac disease Presence of conditions where significant elevations in blood pressure would be a serious hazard. Stage 2 hypertension or greater (systolic blood pressure > 160 and/or diastolic blood pressure >100) Baseline tachycardia, heart rate (HR) >100 History of seizures, elevated intracranial pressure (ICP) or cerebrospinal fluid (CSF) obstructive states (e.g. severe head injury, central congenital or mass lesions) Conditions that may increase intraocular pressure (e.g. glaucoma, acute globe injury) History of uncontrolled depression or other psychiatric comorbidity with psychosis History of liver disease History of interstitial cystitis History of nasal or sinus anomalies or dysfunction e.g. allergic or infectious rhinitis. Patients with lesions to the nasal mucosa Pregnant women, nursing mothers and women of childbearing potential not using contraception known to be highly effective. Highly effective contraception methods include combination of any two of the following: Use of oral, injected or implanted hormonal methods of contraception or; Placement of an intrauterine device (IUD) or intrauterine system (IUS); Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; Total abstinence or; Male/female sterilization. Illicit substance abuse within the past 6 months Documented history of medication abuse/misuse (e.g. Unsanctioned dose escalation, broken opioid agreement etc.) Clinical requirement for medications that are concurrent inducers or inhibitors of CYP3A4. CYP3A4 substrates are allowed. Porphyria (possibility of triggering a porphyric reaction) Severe active anemia ( a hemoglobin< 8 documented by labs drawn within 3 months of first study treatment) History of difficult intravenous access Intractable vomiting

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: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intranasal ketamine treatment<br>Study participants who are receiving intranasal ketamine treatments. | Drug: Intranasal ketamine<br>* 10mg of intranasal ketamine will be given to make sure that the study patients are able to tolerate a small dose of NAS ketamine. On the second visit, 10 mg of IV ketamine will be given to help establish bioavailability of NAS ketamine, with patients serving as their own controls. On the third and fourth visit, higher doses of ketamine, 30 mg and 50 mg respectively, will be given. All doses of ketamine will be administered by an anesthesia research nurse.<br>* Other names: Ketamine hydrochloride (HCl) intranasal;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bioavailability of Ketamine | Blood samples were obtained at the study visits where ketamine was administered to measure the bioavailability (a pharmacokinetic characteristic) of intranasal and intravenous ketamine. Bioavailability is assessed as nanograms per milliliter (ng/mL) of ketamine circulating in blood. Each study participant received each dose of ketamine during separate study visits. Samples were obtained prior to ketamine administration, and at 2, 30, 60 and 240 minutes after medication administration, during study visits 1 through 4. The baseline sample was not collected at the first study visit as assessing prior intake of ketamine was not necessary. | Baseline, Minutes 2, 30, 60, and 240 during Study Visits 1 through 4, up to 4 weeks | 
| Peak Concentration (Cmax) of Ketamine | Blood samples were obtained at the study visits where ketamine was administered to measure the peak concentration (Cmax) of intranasal and intravenous ketamine. Peak concentration is assessed as the maximum ng/mL of ketamine circulating in blood. Each study participant received each dose of ketamine during separate study visits. Samples were obtained at 2, 30, 60 and 240 minutes after medication administration. | Minute 2 through Minute 240 during Study Visits 1 through 4, up to 4 weeks | 
| Area Under the Curve of Ketamine | Blood samples were obtained at the study visits where ketamine was administered to measure the elimination (a pharmacokinetic characteristic) of intranasal and intravenous ketamine. Elimination of the drug disappearing from the body is assessed as the area under the curve (AUC). Each study participant received each dose of ketamine during separate study visits. Samples were obtained at 2, 30, 60 and 240 minutes after medication administration. Each subject did not have quantitative levels at all time points. There were not enough data to construct a curve for each participant and therefore calculate an AUC. Data from all participants were naively pooled to calculate one AUC for the entire population (i.e., across all participants' data). | Minute 2 through Minute 240 during Study Visits 1 through 4, up to 4 Weeks | 
| Time to Peak Concentration (Tmax) of Ketamine | Blood samples were obtained at the study visits where ketamine was administered to measure the time to peak concentration (Tmax) of intranasal and intravenous ketamine. Time is measured as minutes after administration when the maximum concentration of ketamine in blood is reached. | Minute 2 through Minute 240 during Study Visits 1 through 4, up to 4 weeks | 
| Numerical Pain Rating Scale (NPRS) Score | The Numerical Pain Rating Scale (NPRS) was used to evaluate patient reported pain. Pain scores were recorded prior to and at 5,10,15, 30, 45, 60, 120, 180 and 240 minutes after administration of ketamine. The NPRS asks participants rate their current level of pain intensity on a scale from 0 (no pain) to 10 (worst possible pain). In general, improvements of pain severity of 1.5 points or less on NPRS could be seen as clinically irrelevant. Above that value, the cutoff point for clinical relevance depends on patients' baseline pain severity, and ranges from 2.4 to 5.3. Higher baseline scores require larger raw changes to represent clinically important differences. | Baseline, Minutes 5, 10, 15, 30, 45, 60, 120, 180, and 240 during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Fatigue Score | To evaluate self-reported fatigue, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Dizziness Score | To evaluate self-reported dizziness, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Nausea Score | To evaluate self-reported nausea, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Headache Score | To evaluate self-reported headache, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Feeling of Unreality Score | To evaluate self-reported feeling of unreality, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Change in Hearing Score | To evaluate self-reported change in hearing, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Change in Vision Score | To evaluate self-reported change in vision, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Mood Change Score | To evaluate self-reported mood change, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) General Discomfort Score | To evaluate self-reported general discomfort, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Side Effect Rating Scale for Dissociative Anesthetics (SERSDA) Hallucinations Score | To evaluate self-reported hallucinations, participants completed the Side Effect Rating Scale for Dissociative Anesthetics (SERSDA). During visits 1 through 4, side effects were documented by SERSDA prior to administration of medication and 30, 60 and 240 minutes after ketamine administration. Participants indicated the severity of this side effect by selecting 0 (side effect is absent), 1 (weak side effect), 2 (modest side effect), 3 (bothersome side effect), or 4 (side effect is very bothersome). | Baseline, Minutes 30, 60, and 240, during Study Visits 1 through 4, up to 4 weeks | 
| Montgomery Asberg Depression Rating Scale (MADRS) Score | Depression was assessed on the Montgomery Asberg Depression Rating Scale (MADRS) during each study visit, before medication administration and 180 minutes after medication administration. The MADRS is designed to be particularly sensitive to treatment effects. The MADRS is a 10-item scale where the survey administrator rates the participant on a variety of aspects related to depression (such as apparent sadness, tension, and pessimistic thoughts) based on a clinical interview. Responses are provided on a scale of 0 to 6 where 0 signifies no difficulties in this area and 6 signifies severe difficulty. Total scores range from 0 to 60 with higher scores indicating greater severity of depression. | Baseline and Minute 180, during Study Visits 1 through 5, up to 6 weeks | 
| Edmonton Symptom Assessment System (ESAS) Score | The Edmonton Symptom Assessment System (ESAS) assesses nine symptoms that are common in cancer patients: pain, tiredness, drowsiness, nausea, lack of appetite, shortness of breath, depression, anxiety, and well-being. Each symptom is rated on a scale ranging from 0 (absence of symptom) to 10 (worst possible degree of symptom). The ESAS was administered at the baseline time point at each study visit. | Baseline during Study Visits 1 through 5, up to 6 weeks | 
| Eastern Cooperative Oncology Group (ECOG) Score | The Eastern Cooperative Oncology Group (ECOG) score evaluates performance status of the participants by rating their ability to perform physical tasks and self care. Responses are 0 (fully active), 1 (restricted in physical strenuous activity but ambulatory), 2 (ambulatory and capable of all self-care but unable to carry out work activities), 3 (capable of only limited self-care), 4 (completely disabled), or 5 (dead). The ECOG score will be obtained at the baseline time point at each study visit where medication is administered. | Baseline during Visits 1 through 4, up to 4 weeks | 
| Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Score | The PROMIS Global Health questionnaire, version 1.1, consists of 10 items assessing general domains of health and functioning. Items are scored on a 5-point scale where 1 = poor and 5 = excellent. Total scores are standardized to a T-score with a mean of 50 and a standard deviation of 10. Scores above 50 indicate better health and functioning, while scores below 50 indicate physical, mental and social health that is below average. | Baseline during Visit 1 and Visit 5, up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Rescue Medication Use | The opioid sparing effect of NAS ketamine will be determined by evaluating frequency of rescue medications use prior to and during the study. | Visit 1 through Visit 5, up to 6 weeks | 
| Total Opioid Consumption | The opioid sparing effect of NAS ketamine will be determined by evaluating total opioid consumption (rescue medication) prior to and during the study. | Visit 1 through Visit 5, up to 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cancer pain, Anesthesiology, Opiates, Intranasal ketamine