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

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ClinicalTrials.gov Identifier: NCT03513822
Recruitment Status : Unknown
Verified April 2018 by Redar.
Recruitment status was:  Recruiting
First Posted : May 2, 2018
Last Update Posted : May 2, 2018
Sponsor:
Collaborators:
Hôpital Raymond Poincaré
Hopital Lariboisière
Institut National de la Santé Et de la Recherche Médicale, France
Fondation Apicil
Hospital Ambroise Paré Paris
Recherche Clinique Paris Descartes Necker Cochin Sainte Anne
Information provided by (Responsible Party):
Redar

Tracking Information
First Submitted Date  ICMJE March 23, 2018
First Posted Date  ICMJE May 2, 2018
Last Update Posted Date May 2, 2018
Actual Study Start Date  ICMJE February 16, 2018
Estimated Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 19, 2018)
Numeric pain rating scale decrease between H0 and H4. [ Time Frame: 4 hours after the end of infusion ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2018)
  • Paraclinical: Kynurenine pathway levels : SEROTONIN [ Time Frame: Hour 0 and Hour 6 (4 hours after the ending of infusion) ]
    Levels of SEROTONIN (millimoles/liter)
  • Paraclinical: Kynurenine pathway levels : KYNURENINE [ Time Frame: Hour 0 and Hour 6 (4 hours after the ending of infusion) ]
    Levels of KYNURENINE (millimoles/liter)
  • Paraclinical: Kynurenine pathway levels : IDO ACTIVITY [ Time Frame: Hour 0 and Hour 6 (4 hours after the ending of infusion) ]
    Levels of INDOLEAMINE DIOXYGENASE ACTIVITY (division Kynurenine/Tryptophane quote)
  • Paraclinical: Kynurenine pathway levels : KYNURENIC ACID [ Time Frame: Hour 0 and Hour 6 (4 hours after the ending of infusion) ]
    Levels of Kynurenic acid (millimoles/liter)
  • Paraclinical: Kynurenine pathway levels : QUINOLINIC ACID [ Time Frame: Hour 0 and Hour 6 (4 hours after the ending of infusion) ]
    Levels of Quinolinic acid (millimoles/liter)
  • Paraclinical: Kynurenine pathway levels : IL1 [ Time Frame: Hour 0 and Hour 6 (4 hours after the ending of infusion) ]
    Levels of Interleukin 1 (picograms/milliliter)
  • Paraclinical: Kynurenine pathway levels : IL6 [ Time Frame: Hour 0 and Hour 6 (4 hours after the ending of infusion) ]
    Levels of Interleukin 6 (picograms/milliliter)
  • Paraclinical: Kynurenine pathway levels: TNF alpha [ Time Frame: Hour 0 and Hour 6 (4 hours after the ending of infusion) ]
    Levels of TNF alpha (picograms/milliliter)
  • Clinical: Neuropathic pain symptom inventory [ Time Frame: Hour 0, Day 1, Day 4, Day 7 ]
    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.
  • Clinical: Pain timeline [ Time Frame: Seven days ]
    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.
  • Percentage overall improvement in pain over a week with self assessment [ Time Frame: Between Hour 0 and Day 7 ]
    Self assessment of the global improvement in pain over the week after infusion
  • Clinical: Subscore of Neuropathic pain symptom inventory [ Time Frame: Hour 0, Day 1, Day 4, Day 7 ]
    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).
  • Clinical: Hospital anxiety and depression scale [ Time Frame: Hour 0, Day 7. ]
    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.
  • Percentage overall improvement in mood over a week with self assessment [ Time Frame: Between Hour 0 and day 7 ]
    Self assessment of the global improvement of the mood over the week after infusion
  • Clinical: Pain area on a body cartography [ Time Frame: Hour 0, Day 1, Day 7. ]
    Evaluation of pain area on a body surface cartography
  • Clinical: Ketamine adverse effects [ Time Frame: Hour 0 to hour 4 ]
    Recording ketamine adverse effects during and right after the infusion
  • Paraclinical: Kynurenine pathway activation with ulcer pressure [ Time Frame: Hour 0 ]
    Studying the levels of the kynurenine pathway elements between patients with inflammatory component (ulcer pressure) and without inflammatory component (without ulcer pressure)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine's Efficiency in the Treatment of Chronic Pain: Kynurenin Pathway
Official Title  ICMJE 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
Brief Summary

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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Interventional randomized placebo-controlled clinical trial. 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 Ketamine infusion 1 mg / kg IVSE over two hours versus Nacl perfusion 0.9%
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:

The randomisation is done with R software. Each randomisation card is put in a sealed opaque envelope. The two products being transparent, it's impossible to differentiate the two products with identical packaging is a syringe of 50 cc Luer Lock Plastipack BD with a standard extension for syringe Luer Lock.

Both products will be prepared by an SSPI nurse who opens the envelope, the nurse does not participate in the study, the patient assessment investigator as well as the patient will remain blind about the administration of the product. Each syringe will be labeled for each patient with a special label without indication of the product The outcomes assessor, investigator and participant are blinded.

Primary Purpose: Treatment
Condition  ICMJE
  • Neuralgia
  • Chronic Pain
  • Inflammation
Intervention  ICMJE
  • Drug: Ketamine 10 MG/ML
    Ketamine infusion 1mg/kg with electric syringe during 2 hours.
  • Drug: Placebos
    Sodium chloride infusion with the same rate, electric syringe during 2 hours.
    Other Name: Sodium chloride infusion
  • Drug: Midazolam 1 MG/ML
    Bolus of Midazolam 1mg before each perfusion.
Study Arms  ICMJE
  • 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.

    Interventions:
    • Drug: Ketamine 10 MG/ML
    • Drug: Midazolam 1 MG/ML
  • 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.

    Interventions:
    • Drug: Placebos
    • Drug: Midazolam 1 MG/ML
  • 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.

    Interventions:
    • Drug: Ketamine 10 MG/ML
    • Drug: Midazolam 1 MG/ML
  • 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.

    Interventions:
    • Drug: Placebos
    • Drug: Midazolam 1 MG/ML
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: April 19, 2018)
48
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2018
Estimated Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03513822
Other Study ID Numbers  ICMJE REDAR
2017-003930-10 ( EudraCT Number )
protocole ph-03-2018 ( Registry Identifier: CPP ILE DE FRANCE X )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Redar
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Redar
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Hôpital Raymond Poincaré
  • Hopital Lariboisière
  • Institut National de la Santé Et de la Recherche Médicale, France
  • Fondation Apicil
  • Hospital Ambroise Paré Paris
  • Recherche Clinique Paris Descartes Necker Cochin Sainte Anne
Investigators  ICMJE
Study Chair: Didier Bouhassira, Md, PhD INSERM U987
PRS Account Redar
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP