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Long-term Pain Modulation by Intravenous Esketamine in CRPS (KetCRPS-2)

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ClinicalTrials.gov Identifier: NCT05212571
Recruitment Status : Recruiting
First Posted : January 28, 2022
Last Update Posted : May 20, 2022
Sponsor:
Information provided by (Responsible Party):
Thomas J. P. Mangnus, MD, Erasmus Medical Center

Tracking Information
First Submitted Date  ICMJE December 13, 2021
First Posted Date  ICMJE January 28, 2022
Last Update Posted Date May 20, 2022
Actual Study Start Date  ICMJE April 19, 2022
Estimated Primary Completion Date February 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 16, 2022)
Change from baseline pain scores [ Time Frame: Baseline (week 0), During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11), Follow-up (3 months), End of study (6 months) ]
Pain intensity measured by Numerical Rating Scale (NRS). Minimum value=0 and maximum value is 10. Higher scores mean a worse outcome.
Original Primary Outcome Measures  ICMJE
 (submitted: January 14, 2022)
Change from baseline pain scores [ Time Frame: Baseline (week 0), During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11), End of study (week 12) ]
Pain intensity measured by Numerical Rating Scale (NRS). Minimum value=0 and maximum value is 10. Higher scores mean a worse outcome.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2022)
  • Change from baseline Quantitative Sensory Testing [ Time Frame: Baseline (week 0) and follow-up visit (week 12) ]
    To assess the sensory-discriminative dimensions of pain before and after ketamine treatment
  • Change from baseline Thermography [ Time Frame: Baseline (week 0) and follow-up visit (week 12) ]
    Objectively measured effects on the extremity temperature by each of the administration regimens on symptoms vasomotor disturbances. The investigators use an infrared camera.
  • Adverse events due to S-ketamine infusion [ Time Frame: During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11) ]
    Assessed by physical examination and vital parameters (blood pressure, heart rate, saturation and temperature)
  • Change from baseline pain medication dose [ Time Frame: Baseline (week 0), follow-up visit (3 months) and end of study (6 months) ]
  • Change from baseline Complex Regional Pain Syndrome severity score [ Time Frame: Baseline (week 0) and follow-up visit (3 months) ]
    according to Harden et al. (2010). All symptoms and signs are scored as Yes = 1 and No = 0. Sum up the total score (i.e., number of "Yes" responses) to derive the total CSS score. The Complex Severity Score can range from 0-16. Higher scores mean a worse outcome.
  • Global Perceived Effect [ Time Frame: During telephone consultation (week 1, 3, 5, 7, 9, 11), follow-up visit (3 months) and end of study (6 months) ]
    The Global Perceived Effect asks the patient to rate, on a numerical scale 0-7, how much their condition has improved or deteriorated since some predefined time point. Higher scores mean a worse outcome. According to Hudak et al. 2000.
  • Patient-Reported Outcomes Measurement Information System (PROMIS) -29 Profile [ Time Frame: Baseline (week 0) and follow-up visit (3 months) ]
    Assesses 7 domains, each with 4 questions (ranging from 1-5, ranging from no/never/not at all to yes/always/continuously): depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities. According to Terwee et al. 2014
  • Short-form McGill Pain Questionnaire-2 [ Time Frame: Baseline (week 0) and follow-up visit (3 months) ]
    Neuropathic pain items capturing the quality of pain. Scale ranging from 0-10. Higher scores mean a worse outcome. According to Dworkin et al., 2009
  • Pain Catastrophizing Scale [ Time Frame: Baseline (week 0) and follow-up visit (3 months) ]
    The respondent considers how confident they are performing each activity, while taking their pain into account. Scale from 0-4. Higher scores mean a worse outcome. According to Sullivan et al., 2011
  • EQ-5D-5L. [ Time Frame: Baseline (week 0) and follow-up visit (3 months) ]
    To measure health state, comprising mobility, self-care, usual activities, pain/discomfort, anxiety/depression. The 5 questions about health status are scored on a 5-point scale (1-5) Placing these numbers one after the other creates a 5-digit index that represents a health profile (eg 12323). According to Herdman et al., 2011
  • Pain Self-Efficacy Questionnaire [ Time Frame: Baseline (week 0) and follow-up visit (3 months) ]
    The respondent considers how confident they are performing each activity, while taking their pain into account. The scale ranges from 0-6. Higher scores mean a better outcome. According to Nicholas et al., 2007
Original Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2022)
  • Change from baseline Quantitative Sensory Testing [ Time Frame: Baseline (week 0) and end of study (week 12) ]
    To assess the sensory-discriminative dimensions of pain before and after ketamine treatment
  • Change from baseline Thermography [ Time Frame: Baseline (week 0) and end of study (week 12) ]
    Objectively measured effects on the extremity temperature by each of the administration regimens on symptoms vasomotor disturbances. The investigators use an infrared camera.
  • Adverse events due to S-ketamine infusion [ Time Frame: During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11) ]
    Assessed by physical examination and vital parameters (blood pressure, heart rate, saturation and temperature)
  • Change from baseline pain medication dose [ Time Frame: Baseline (week 0) and end of study (week 12) ]
  • Change from baseline Complex Regional Pain Syndrome severity score [ Time Frame: Baseline (week 0) and end of study (week 12) ]
    according to Harden et al. (2010). All symptoms and signs are scored as Yes = 1 and No = 0. Sum up the total score (i.e., number of "Yes" responses) to derive the total CSS score. The Complex Severity Score can range from 0-16. Higher scores mean a worse outcome.
  • Global Perceived Effect [ Time Frame: During telephone consultation (week 1, 3, 5, 7, 9, 11), End of study (week 12) ]
    The Global Perceived Effect asks the patient to rate, on a numerical scale 0-7, how much their condition has improved or deteriorated since some predefined time point. Higher scores mean a worse outcome. According to Hudak et al. 2000.
  • Patient-Reported Outcomes Measurement Information System (PROMIS) -29 Profile [ Time Frame: Baseline (week 0) and end of study (week 12) ]
    Assesses 7 domains, each with 4 questions (ranging from 1-5, ranging from no/never/not at all to yes/always/continuously): depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities. According to Terwee et al. 2014
  • Short-form McGill Pain Questionnaire-2 [ Time Frame: Baseline (week 0) and end of study (week 12) ]
    Neuropathic pain items capturing the quality of pain. Scale ranging from 0-10. Higher scores mean a worse outcome. According to Dworkin et al., 2009
  • Pain Catastrophizing Scale [ Time Frame: Baseline (week 0) and end of study (week 12) ]
    The respondent considers how confident they are performing each activity, while taking their pain into account. Scale from 0-4. Higher scores mean a worse outcome. According to Sullivan et al., 2011
  • EQ-5D-5L. [ Time Frame: Baseline (week 0) and end of study (week 12) ]
    To measure health state, comprising mobility, self-care, usual activities, pain/discomfort, anxiety/depression. The 5 questions about health status are scored on a 5-point scale (1-5) Placing these numbers one after the other creates a 5-digit index that represents a health profile (eg 12323). According to Herdman et al., 2011
  • Pain Self-Efficacy Questionnaire [ Time Frame: Baseline (week 0) and end of study (week 12) ]
    The respondent considers how confident they are performing each activity, while taking their pain into account. The scale ranges from 0-6. Higher scores mean a better outcome. According to Nicholas et al., 2007
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Long-term Pain Modulation by Intravenous Esketamine in CRPS
Official Title  ICMJE Long-term Pain Modulation by Intravenous Esketamine in Complex Regional Pain Syndrome: a Non-inferiority Study
Brief Summary

Intravenous administration of esketamine is an effective recognized therapeutic option in refractory pain in CRPS, which sometimes in at least a part of the patients has a prolonged therapeutic effect. Unfortunately, CRPS literature contains a wide range of ketamine dosing regimens with the result that clinical protocols on dosage and administration are very heterogeneous. The current esketamine regimen in Erasmus MC consists of a 6-day hospital admission for continuous administration. In the Netherlands, both inpatient and outpatient esketamine treatments are offered. Inpatient and outpatient ketamine treatments have never been compared in randomized controlled trials and it is therefore unknown whether these two dosing regimens are equally effective.

The primary objective is to demonstrate non-inferiority of experimental esketamine administration of 6x 1 day per 2 weeks (in total 3 months) as compared with standard esketamine administration of 1x 6 consecutive days. The end of study is at 6 months after the start of the study/treatment.

Detailed Description

Rationale: Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition of one or more limbs. Its diagnosis is based on (combinations of) underlying pathophysiological mechanisms. Achieving relevant pain relief fails in a significant proportion of CRPS patients. Intravenous administration of esketamine is an effective therapeutic option in refractory pain in CRPS, which in at least a part of the patients has a prolonged therapeutic effect. Unfortunately, CRPS literature contains a wide range of ketamine dosing regimens with the result that clinical protocols on dosage and administration are very heterogeneous. In the Netherlands, both inpatient and outpatient esketamine treatments are offered. The current esketamine regimen in Erasmus MC consists of a 6-day hospital admission for continuous administration; however, logistical boundaries limit this therapy. Esketamine infusions in an outpatient setting might increase flexibility and availability of esketamine treatment. However, inpatient and outpatient ketamine treatments have never been compared in randomized controlled trials and it is therefore unknown whether these two dosing regimens are equally effective.

Objective: The primary objective is to demonstrate non-inferiority of experimental esketamine administration of 6x 1 day per 2 weeks (in total 3 months) as compared with standard esketamine administration of 1x 6 consecutive days at 3 months after the start of the study/treatment. The secondary objective is to assess pain scores till 6 months follow-up, logistical problems, adverse effects, questionnaires, thermography and quantitative sensory testing in both treatment groups.

Study design: Prospective, randomized, non-inferiority study in 60 patients

Study population: Sixty adult patients with chronic pain due to CRPS

Intervention: All patients will receive intravenous esketamine. The standard treatment group receives intravenous esketamine for 6 consecutive days (in hospital). The experimental intervention group visits the outpatient clinic to receive intravenous esketamine in day-care setting every 2 weeks for 3 months.

Main study parameters/endpoints: The main study parameter is pain intensity, measured by means of Numerical Rating Scale (NRS), to demonstrate non-inferiority of the experimental treatment after three months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
prospective, randomized non-inferiority study
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Complex Regional Pain Syndromes
  • CRPS (Complex Regional Pain Syndromes)
Intervention  ICMJE
  • Drug: S-ketamine infusion inpatient setting
    S-ketamine is administered intravenously for six consecutive days. The administered dose of S-ketamine is 50 mcg/kg/h and can be increased to a maximum of 200 mcg/kg/h.
    Other Names:
    • ketamine
    • esketamine
  • Drug: S-ketamine infusion outpatient setting
    S-ketamine is administered intravenously for six hours. The administered dose of S-ketamine is 50 mcg/kg/h and can be increased to a maximum of 200 mcg/kg/h.
    Other Names:
    • ketamine
    • esketamine
Study Arms  ICMJE
  • Experimental: Outpatient
    The experimental intervention group visits the outpatient clinic to receive intravenous esketamine in day-care setting every 2 weeks for 3 months.
    Intervention: Drug: S-ketamine infusion outpatient setting
  • Active Comparator: Inpatient
    The standard treatment group receives intravenous esketamine for 6 consecutive days in hospital.
    Intervention: Drug: S-ketamine infusion inpatient setting
Publications *

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 14, 2022)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2025
Estimated Primary Completion Date February 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Meeting the new International Association for the Study of Pain (IASP) diagnostic criteria for CRPS ("the Budapest Criteria) (Harden et al., 2010) or having met the new IASP diagnostic criteria of CRPS ("CRPS with Remission of Some features") (Goebel et al., 2021).
  • Willing and capable to participate in the study.
  • CRPS in one upper extremity and/or CRPS in one lower extremity
  • Treatment in an elective setting.
  • Adequate comprehension of the Dutch language
  • Age ≥ 18 years

Exclusion Criteria:

  • Severe liver disease
  • Psychiatric (schizophrenia, psychosis, delirium, manic depression)
  • Active substance abuse
  • Intoxication with alcohol or other substances
  • Poorly controlled hypertension
  • Unstable angina
  • High-risk coronary vascular disease
  • Heart failure
  • Elevated intracranial pressure
  • Elevated intraocular pressure
  • Thyrotoxicosis
  • Pregnancy
  • Combination with derivates of xanthines (theophylline) or ergometrine
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: Thomas JP Mangnus, MD +31610746907 ext +31 t.mangnus@erasmusmc.nl
Contact: Maaike Dirckx, MD, PhD +31107040140 ext +31 m.dirckx@erasmusmc.nl
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05212571
Other Study ID Numbers  ICMJE NL77785.078.21
2021-000640-21 ( EudraCT Number )
MEC-2021-0426 ( Other Identifier: Medical Ethics Committee of Erasmus MC )
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: Undecided
Current Responsible Party Thomas J. P. Mangnus, MD, Erasmus Medical Center
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Erasmus Medical Center
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Frank JP Huygen, MD, PhD Erasmus MC, Center for Pain Medicine
PRS Account Erasmus Medical Center
Verification Date May 2022

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