Ketamine's Efficiency in the Treatment of Chronic Pain: Kynurenin Pathway (KEKU1)

Ketamine's Efficiency in the Treatment of Chronic Pain With an Added Inflammatory Component Exploring the Kynurenin Pathway. A Randomized, Double Blind, Placebo-controlled Trial

The kynurenine pathway is involved in hyperalgesia. This pathway is activated by inflammation. Ketamine would interact with the kynurenine pathway and inflammation. Our working hypotheses are: the clinical effects of ketamine on neuropathic pain are greater in the presence of systemic inflammation and the mechanism of action involves an interaction on the kynurenine pathway.

Study design: Interventional randomized placebo-controlled clinical trial.

Main goals:

1. To show a better clinical efficacy of ketamine in chronic pain in patients with an inflammatory component.
2. Explore the anti-inflammatory activity of ketamine through the Kynurenine pathway.

Study Overview

• Status: Unknown
• Conditions: Inflammation; Chronic Pain; Neuralgia
• Intervention / Treatment: Drug: Ketamine 10 MG/ML; Drug: Midazolam 1 MG/ML; Drug: Placebos

Detailed Description

The kynurenine pathway is involved in hyperalgesia. This pathway is activated by inflammation. Ketamine would interact with the kynurenine pathway and inflammation. Our working hypotheses are: the clinical effects of ketamine on neuropathic pain are greater in the presence of systemic inflammation and the mechanism of action involves an interaction on the kynurenine pathway.

Study design: Interventional randomized placebo-controlled clinical trial.

Main goals:

1. To show a better clinical efficacy of ketamine in chronic pain in patients with an inflammatory component.
2. Explore the anti-inflammatory activity of ketamine through the Kynurenine pathway.

Population Adult, medullary injured (BM), with chronic neuropathic pain (DN). 4 groups: BM with DN with bedsore Ketamine Group versus Placebo Group BM with DN without bedsore group Ketamine versus Placebo Group

Intervention Ketamine infusion 1 mg / kg IVSE over two hours versus Nacl perfusion 0.9%

 Primary judgment criterion Decrease by more than 30% the intensity of neuropathic pain evaluated at the moment on a numerical scale of 10 points between H0 and H4. Comparison of groups two by two.

Secondary judgment criterions:

NPSI score (Neuropathic pain symptom inventory) at H1, H4, D1, D4, J7 Sub score of NPSI; H1, H4, J1, J4, J7 Depression Scale HADS (Hospital Anxiety Depression Scale) J0, J1, J7 Plasma serotonin (5-HT) kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (KYN / TRP ratio), kynurenic acid ( KA) and quinolinic acid (QA), as well as 3 proinflammatory cytokines IL-1β, IL-6, and TNF-α before perfusion and H4 perfusion.

In parallel blood samples will be collected to study the activation of the kynurenine pathway in response to inflammation due to a pressure ulcer.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Cyril QUEMENEUR, Resident; Phone Number: 0033681193981; Email: c.quemeneur@gmx.com
• Study Contact Backup: Name: Valeria Martinez, Md, Ph d; Phone Number: 0033601819222; Email: valeria.martinez@aphp.fr

Study Locations

• France
  • Hauts De Seine
    • Garches, Hauts De Seine, France, 92380
      • Recruiting
      • Raymond Poincaré Hospital
      • Contact: Cyril QUEMENEUR, Resident; Phone Number: 0033681193981; Email: c.quemeneur@gmx.com
      • Contact: Valeria Martinez, MD, PhD; Phone Number: 0033601819222; Email: valeria.martinez@aphp.fr

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:

• Adults speaking and understanding French
• presenting chronic neuropathic pain as defined by IASP
• Painful intensity> or = to 6/10 during the week preceding the inclusion - Medullary lesion, whatever the origin (traumatic, degenerative, tumoral, postoperative), responsible for paraplegia in a chronic state.
• Able to give informed consent, after clear, fair and appropriate information
• Having given their consent by a written consent signature.

Exclusion Criteria:

• Hypersensitivity to ketamine or any of its components
• Participation in another interventional trial, or participation in another trial.
• Patient unable to give consent.
• Pregnancy or breastfeeding
• Refusal to sign the consent
• Cardiovascular diseases associated in particular with disorders of rhythm and severe cardiac insufficiency, coronary insufficiency, discovered on examination, on ECG or by biological balance or known. - unstabilized HTA> 180/100 mmHg
• Severe hepatic and / or renal hepatic insufficiency.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Chronic neuropathic pain and bedsore Ketamine group; Spinal cord injury population with central neuropathic pain at the lesional or sub-lesion level, chronically (for more than three months). Patients medullary wounded with chronic pain and ulcer pressure (inflammation factor). Midazolam 1mg before infusion. KETAMINE INFUSION IVSE 1mg/kg during 2 hours (0,5mg/kg/h). Preparation of 100mg in fifty cc, syringe with 2mg/ml. Rate of administration: Speed = Patient weight divided by four. Maximum 100mg. One and only perfusion.	Drug: Ketamine 10 MG/ML; Ketamine infusion 1mg/kg with electric syringe during 2 hours.; Drug: Midazolam 1 MG/ML; Bolus of Midazolam 1mg before each perfusion.
Placebo Comparator: Chronic neuropathic pain and bedsore Placebo group; Spinal cord injury population with central neuropathic pain at the lesional or sub-lesion level, chronically (for more than three months). Patients medullary wounded with chronic pain and ulcer pressure (inflammation factor). Midazolam 1mg before infusion. Sodium chloride infusion IVSE during 2 hours. Rate of administration : Speed = patient weight divided by four. One and only perfusion.	Drug: Midazolam 1 MG/ML; Bolus of Midazolam 1mg before each perfusion.; Drug: Placebos; Sodium chloride infusion with the same rate, electric syringe during 2 hours.; Other Names: Sodium chloride infusion
Active Comparator: Chronic neuropathic pain without bedsore Ketamine group; Spinal cord injury population with central neuropathic pain at the lesional or sub-lesion level, chronically (for more than three months). Patients medullary wounded with chronic pain and no ulcer pressure (no inflammation factor). Midazolam 1mg before infusion. KETAMINE INFUSION IVSE 1mg/kg during 2 hours (0,5mg/kg/h). Preparation of 100mg in fifty cc, syringe with 2mg/ml. Rate of administration: Speed = Patient weight divided by four. Maximum 100mg. One and only perfusion.	Drug: Ketamine 10 MG/ML; Ketamine infusion 1mg/kg with electric syringe during 2 hours.; Drug: Midazolam 1 MG/ML; Bolus of Midazolam 1mg before each perfusion.
Placebo Comparator: Chronic neuropathic pain without bedsore Placebo group; Spinal cord injury population with central neuropathic pain at the lesional or sub-lesion level, chronically (for more than three months). Patients medullary wounded with chronic pain and no ulcer pressure (no inflammation factor). Midazolam 1mg before infusion. Sodium chloride infusion IVSE during 2 hours. Rate of administration : Speed = patient weight divided by four. One and only perfusion.	Drug: Midazolam 1 MG/ML; Bolus of Midazolam 1mg before each perfusion.; Drug: Placebos; Sodium chloride infusion with the same rate, electric syringe during 2 hours.; Other Names: Sodium chloride infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Numeric pain rating scale decrease between H0 and H4.	Numeric pain rating scale is a scale from 0 to 10. 0 is no pain, 10 is the worst pain we could imagine. The first outcome is decreasing the intensity of neuropathic pain evaluated at the moment on a numerical scale of 10 points at H4. Comparison of groups two by two.	4 hours after the end of infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Paraclinical: Kynurenine pathway levels : SEROTONIN	Levels of SEROTONIN (millimoles/liter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Paraclinical: Kynurenine pathway levels : KYNURENINE	Levels of KYNURENINE (millimoles/liter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Paraclinical: Kynurenine pathway levels : IDO ACTIVITY	Levels of INDOLEAMINE DIOXYGENASE ACTIVITY (division Kynurenine/Tryptophane quote)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Paraclinical: Kynurenine pathway levels : KYNURENIC ACID	Levels of Kynurenic acid (millimoles/liter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Paraclinical: Kynurenine pathway levels : QUINOLINIC ACID	Levels of Quinolinic acid (millimoles/liter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Paraclinical: Kynurenine pathway levels : IL1	Levels of Interleukin 1 (picograms/milliliter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Paraclinical: Kynurenine pathway levels : IL6	Levels of Interleukin 6 (picograms/milliliter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Paraclinical: Kynurenine pathway levels: TNF alpha	Levels of TNF alpha (picograms/milliliter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Clinical: Neuropathic pain symptom inventory	NPSI scoring: Neuropathic pain symptom inventory. A composite score composed by neuropathic pain components: Burning, Pressure, Squeezing, Electric shocks, Stabbing, Evoked by brushing, evoked by pressure, evoked by cold stimuli, pins and needles, tingling. Two questions about the time of pain for twenty four hours, and the numbers of crisis. Score from 0 to 100. 100 is the maximum.	Hour 0, Day 1, Day 4, Day 7
Clinical: Pain timeline	Timeline of self assessment on a simple numeric scale of the pain three times a day during a week. Numeric pain rating scale is a scale from 0 to 10. 0 is no pain, 10 is the worst pain we could imagine.	Seven days
Percentage overall improvement in pain over a week with self assessment	Self assessment of the global improvement in pain over the week after infusion	Between Hour 0 and Day 7
Clinical: Subscore of Neuropathic pain symptom inventory	Subscore on NPSI scoring: NEUROPATHIC PAIN SYMPTOM INVENTORY, subscore are burning from 0 to 10, pressing (deep) spontaneous pain from 0 to 10, paroxysmal pain from 0 to 10, evoked pain from 0 to 10, paresthesia or dysesthesia from 0 to 10 (0 is the minimal, 10 is the maximal value for each of the component).	Hour 0, Day 1, Day 4, Day 7
Clinical: Hospital anxiety and depression scale	Recording scoring on hospital anxiety and depression scale. HADS scale is a tool to detect anxiety and depressive disorders. It includes fourteen questions from 0 to 3 points each. Seven are related to anxiety. Seven are related to depressive mood. It permits to obtain 2 different scales with the maximum of each of 21.	Hour 0, Day 7.
Percentage overall improvement in mood over a week with self assessment	Self assessment of the global improvement of the mood over the week after infusion	Between Hour 0 and day 7
Clinical: Pain area on a body cartography	Evaluation of pain area on a body surface cartography	Hour 0, Day 1, Day 7.
Clinical: Ketamine adverse effects	Recording ketamine adverse effects during and right after the infusion	Hour 0 to hour 4
Paraclinical: Kynurenine pathway activation with ulcer pressure	Studying the levels of the kynurenine pathway elements between patients with inflammatory component (ulcer pressure) and without inflammatory component (without ulcer pressure)	Hour 0

Collaborators and Investigators

• Sponsor: Redar
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; Fondation Apicil; Hopital Lariboisière; Hôpital Raymond Poincaré; Recherche Clinique Paris Descartes Necker Cochin Sainte Anne; Hospital Ambroise Paré Paris
• Investigators: Study Chair: Didier Bouhassira, Md, PhD, Inserm U987

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2018
• Primary Completion (Anticipated): October 1, 2018
• Study Completion (Anticipated): November 1, 2018

Study Registration Dates

• First Submitted: March 23, 2018
• First Submitted That Met QC Criteria: April 19, 2018
• First Posted (Actual): May 2, 2018

Study Record Updates

• Last Update Posted (Actual): May 2, 2018
• Last Update Submitted That Met QC Criteria: April 19, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: KETAMINE; CHRONIC PAIN; NEUROPATHIC PAIN; KYNURENINE; KYNURENINE PATHWAY; BEDSORES; ANTI-INFLAMMATORY; ULCER PRESSURE
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Inflammation; Chronic Pain; Neuralgia; 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; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Ketamine; Midazolam
• Other Study ID Numbers: REDAR; 2017-003930-10 (EudraCT Number); protocole ph-03-2018 (Registry Identifier: CPP ILE DE FRANCE X)

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
• product manufactured in and exported from the U.S.: No