Oral Ketamine for Control of Chronic Pain in Children (KETA-2011)

• ClinicalTrials.gov Identifier: NCT01369680
• Recruitment Status: Completed
• First Posted: June 9, 2011
• Results First Posted: February 11, 2013
• Last Update Posted: February 15, 2013
• Sponsor: University of Rochester
• Information provided by (Responsible Party): David Korones, University of Rochester

Tracking Information

• First Submitted Date: May 23, 2011
• First Posted Date: June 9, 2011
• Results First Submitted Date: October 24, 2012
• Results First Posted Date: February 11, 2013
• Last Update Posted Date: February 15, 2013
• Study Start Date: May 2011
• Actual Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 7, 2013)

Number of Participants Tolerating Dose [ Time Frame: Up to 2 weeks ]

According to CTCae any dose causing grade 2 or worse toxicity will be an untolerated dose. Tolerability is defined as ability to take the medication for 2 weeks without having a grade 2 or worse toxicity.

Original Primary Outcome Measures (submitted: June 7, 2011)

Tolerable dose [ Time Frame: Up to 2 weeks ]

According to CTCae any dose causing grade 2 or worse toxicity will be an untolerated dose. Tolerability is defined as ability to take the medication for 2 weeks without having a grade 2 or worse toxicity.

Current Secondary Outcome Measures (submitted: February 11, 2013)

• Neurocognitive Effect [ Time Frame: At 14 weeks ]
  Baseline neurocognitive testing will be done before study drug is given. Subjects will be reassessed for any changes in neurocognitive scores at end of dosing (week 2) and at three weeks off study drug (week 14). Significant changes were measured at week 14 compared to baseline. Week 2 was measured to inform future studies. The neurocognitive scores are standardized scores with a mean of 100; low scores correlate with low neurocognitive function, while high scores correlate with high function. A significant change is defined as greater than or equal to 10% decrease in scores.
• Norketamine Cmax (Measured in ng/mL). [ Time Frame: At week 1 ]
  Pharmacokinetic testing will be done during chronic ketamine administration on subjects consenting to additional testing one week into study drug administration. This is to further describe the activity of ketamine in the blood of children when administered chronically and to enable comparison of any clinical effect or toxicity with steady state levels of ketamine in children.
• Pain Control [ Time Frame: Week 2 ]
  Subjects will be assessed for clinically significant change in pain scores during and after study drug administration. Significant change in pain scores were determined at week 2, though week 14 scores were collected as well. Participants with a 2 point (or greater) decrease in pain scores compared to baseline were considered to have responded. The NRS scale was used, the scale ranges from 0-10, with 10 being the most pain.

Original Secondary Outcome Measures (submitted: June 7, 2011)

• Neurocognitive effect [ Time Frame: At 2 and 14 weeks ]
  Baseline neurocognitive testing will be done before study drug is given. Subjects will be reassessed for any changes in neurocognitive scores at end of dosing (week 2) and at three weeks off study drug (week 14).
• Steady state blood ketamine level (measured in ng/mL). [ Time Frame: At week 1 ]
  Pharmacokinetic testing will be done during chronic ketamine administration on subjects consenting to additional testing one week into study drug administration. This is to further describe the activity of ketamine in the blood of children when administered chronically and to enable comparison of any clinical effect or toxicity with steady state levels of ketamine in children.
• Pain control [ Time Frame: Up to 4 months ]
  Subjects will be assessed for change in pain scores during and after study drug administration.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Oral Ketamine for Control of Chronic Pain in Children
• Official Title: Oral Ketamine for Control of Chronic Pain in Children
• Brief Summary: The study is a maximum tolerated dose finding study for oral, chronic, daily administration of oral ketamine (by mouth) in children with long-term daily pain.

Detailed Description

Pain control in children is a major concern when children have chronic diseases, such as cancer and sickle cell disease with frequent pain crises. Additionally, though the traditional pain medications of morphine and acetaminophen are regarded as safe and effective for pain control in children, there are few alternative therapies available when these medications are insufficient. Chronic pain (whether cancer or non-cancer pain) in children has few approved and well tolerated therapeutic options with proven efficacy.

Ketamine is a medication that was first described in 1962[1]. It is an NMDA-R (N-methyl-D-aspartate-receptor) antagonist with dissociative amnestic and analgesic effects[1-2]. Ketamine is particularly successful as a dissociative amnestic for children in the emergent setting as it has little respiratory or cardiac impact, has a short half-life, and has fewer psychomimetic effects in the pediatric population than in adults[1]. Its function is via antagonism and reduction of NMDA-receptors in the afferent pain pathway. In effect, this decreases pain receptors and can dramatically reduce the need for narcotic pain medications for patients with chronic pain.

Unfortunately, with such dissociative effects, ketamine has been a drug of abuse for decades[1,3]. Additionally, there is concern that ketamine may have long-term deleterious effects on cognition for those subjects chronically exposed to IV ketamine[4], especially children whose neural pathways may still be developing[1,5]. These effects may include difficulty with attention and working memory, though the effects appear to be short-term and reversible in adults. However, much of this data is derived from rodent or primate studies, and there is little evidence that there are long-term cognitive effects on humans chronically exposed to ketamine[1]. This lack of data is particularly impactful in the pediatric group.

Ketamine has been evaluated as an analgesic medication for patients with chronic pain that is not resolved with narcotics and gabapentin. There are a number of case reports and small case series that suggest ketamine is a useful medication for control of chronic pain in adults[2,4,6-8]. Additionally, there are case studies that describe lasting (12 week) pain control in adults after 4-10 days of ketamine therapy[7-8]. However, there are, to date, little data that aid a pediatrician in determining if ketamine is a safe and effective option as a chronic, oral therapy for children with chronic pain.

Overall, there are few proven safe and effective medications for use in chronic pain management for children. Ketamine is a well known medication with a well elaborated safety profile, when given intravenously and for short periods of time. There is, as above, emerging data that ketamine is useful for chronic pain control in adults. The question that remains to be answered is whether ketamine is a safe option for chronic use in children, whose brains are significantly more plastic and whose metabolism is different compared with those of adults.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Pain

Intervention

Drug: Ketamine

Drug will be given orally three times a day at doses escalating from 0.25mg/kg/dose to 1.5mg/kg/dose in cohorts of 3. Each subject will be administered study drug for 2 weeks.

Other Names:

• Ketalar
• Ketamine hydrochloride

Study Arms

• Experimental: Ketamine 0.25 mg/kg/dose
  The first three subjects were administered 0.25 mg/kg/dose oral ketamine.
  Intervention: Drug: Ketamine
• Experimental: Ketamine 0.5 mg/kg/dose
  The second group of three subjects were administered 0.5 mg/kg/dose oral ketamine.
  Intervention: Drug: Ketamine
• Experimental: Ketamine 1 mg/kg/dose
  The third group of three subjects were administered 1 mg/kg/dose oral ketamine.
  Intervention: Drug: Ketamine
• Experimental: Ketamine 1.5 mg/kg/dose
  The fourth group of three subjects were administered 1.5 mg/kg/dose oral ketamine.
  Intervention: Drug: Ketamine

Publications *

• Green SM, Coté CJ. Ketamine and neurotoxicity: clinical perspectives and implications for emergency medicine. Ann Emerg Med. 2009 Aug;54(2):181-90. doi: 10.1016/j.annemergmed.2008.10.003. Epub 2008 Nov 6. Review.
• Okon T. Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician. 2007 May;10(3):493-500. Review.
• Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliat Care Pharmacother. 2002;16(3):27-35. Review.
• Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006 Aug;60(7):341-8. Epub 2006 Jul 5. Review.
• Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009 Apr;110(4):796-804. doi: 10.1097/01.anes.0000344728.34332.5d.
• Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009 Dec 15;147(1-3):107-15. doi: 10.1016/j.pain.2009.08.015. Epub 2009 Sep 23.
• Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous SM, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009 Oct;145(3):304-311. doi: 10.1016/j.pain.2009.06.023. Epub 2009 Jul 14.
• Bell RF. Ketamine for chronic non-cancer pain. Pain. 2009 Feb;141(3):210-214. doi: 10.1016/j.pain.2008.12.003. Epub 2009 Jan 6. Review.
• Bredlau AL, McDermott MP, Adams HR, Dworkin RH, Venuto C, Fisher SG, Dolan JG, Korones DN. Oral ketamine for children with chronic pain: a pilot phase 1 study. J Pediatr. 2013 Jul;163(1):194-200.e1. doi: 10.1016/j.jpeds.2012.12.077. Epub 2013 Feb 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 7, 2011): 12
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: October 2012
• Actual Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subject, parent, or guardian willing and able to give informed consent
• NRS for pain >4
• Chronic pain, which has been present for >3 months, or persisting longer than is normal for the underlying diagnosis
• Chronic pain related to diagnoses including but not limited to: cancer, rheumatologic disease, sickle cell anemia, cystic fibrosis, pancreatitis, and neuromuscular disease (e.g. Duchenne muscular dystrophy)
• Able to tolerate and cooperate with neurocognitive assessment
• Age 8-22 years old

Exclusion Criteria:

• If they are known or suspected to have drug dependence or addiction
• History of psychiatric disorder such as depression, schizophrenia, or bipolar disorder
• History of hypertension
• Unable to cooperate with neurocognitive assessment
• Chronic pain related to chronic abdominal pain syndrome
• Known liver disease or elevation of AST or ALT greater than 3 times the upper limit of normal.
• Previous intolerance or allergic reaction to ketamine
• Pregnancy
• Use of CYP3A4 inhibitors or inducers within the 2 week period prior the study drug administration or within 5 half-lives of the respective medication, whichever is longer, until study conclusion.
• Consumption of grapefruit or grapefruit products from at least 2 weeks prior to study drug administration until study conclusion.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 8 Years to 22 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01369680
• Other Study ID Numbers: KETA-2011
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: David Korones, University of Rochester
• Study Sponsor: University of Rochester
• Collaborators: Not Provided

Investigators

• Principal Investigator: David Korones, MD; University of Rochester

• PRS Account: University of Rochester
• Verification Date: February 2013