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

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

Tracking Information

• First Submitted Date: December 13, 2021
• First Posted Date: January 28, 2022
• Last Update Posted Date: May 20, 2022
• Actual Study Start Date: April 19, 2022
• Estimated Primary Completion Date: February 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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.

Current Secondary Outcome Measures (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 (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: Long-term Pain Modulation by Intravenous Esketamine in CRPS
• Official Title: 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: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

prospective, randomized non-inferiority study

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Complex Regional Pain Syndromes
• CRPS (Complex Regional Pain Syndromes)

Intervention

• 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

• 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 *

• 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.
• Mangnus TJP, Bharwani KD, Stronks DL, Dirckx M, Huygen FJPM. Ketamine therapy for chronic pain in The Netherlands: a nationwide survey. Scand J Pain. 2021 Aug 24;22(1):97-105. doi: 10.1515/sjpain-2021-0079. Print 2022 Jan 27.
• Mangnus TJP, Dirckx M, Bharwani KD, de Vos CC, Frankema SPG, Stronks DL, Huygen FJPM. Effect of intravenous low-dose S-ketamine on pain in patients with Complex Regional Pain Syndrome: A retrospective cohort study. Pain Pract. 2021 Nov;21(8):890-897. doi: 10.1111/papr.13056. Epub 2021 Jul 24.
• Harden NR, Bruehl S, Perez RSGM, Birklein F, Marinus J, Maihofner C, Lubenow T, Buvanendran A, Mackey S, Graciosa J, Mogilevski M, Ramsden C, Chont M, Vatine JJ. Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain Syndrome. Pain. 2010 Aug;150(2):268-274. doi: 10.1016/j.pain.2010.04.030. Epub 2010 May 20.
• Grieve S, Perez RSGM, Birklein F, Brunner F, Bruehl S, Harden RN, Packham T, Gobeil F, Haigh R, Holly J, Terkelsen A, Davies L, Lewis J, Thomassen I, Connett R, Worth T, Vatine JJ, McCabe CS. Recommendations for a first Core Outcome Measurement set for complex regional PAin syndrome Clinical sTudies (COMPACT). Pain. 2017 Jun;158(6):1083-1090. doi: 10.1097/j.pain.0000000000000866.
• Goebel A, Birklein F, Brunner F, Clark JD, Gierthmühlen J, Harden N, Huygen F, Knudsen L, McCabe C, Lewis J, Maihöfner C, Magerl W, Moseley GL, Terkelsen A, Thomassen I, Bruehl S. The Valencia consensus-based adaptation of the IASP complex regional pain syndrome diagnostic criteria. Pain. 2021 Sep 1;162(9):2346-2348. doi: 10.1097/j.pain.0000000000002245.
• Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):521-546. doi: 10.1097/AAP.0000000000000808. Review.
• Zhao J, Wang Y, Wang D. The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis. Curr Pain Headache Rep. 2018 Feb 5;22(2):12. doi: 10.1007/s11916-018-0664-x. Review.
• Harden NR, Bruehl S, Perez RSGM, Birklein F, Marinus J, Maihofner C, Lubenow T, Buvanendran A, Mackey S, Graciosa J, Mogilevski M, Ramsden C, Schlereth T, Chont M, Vatine JJ. Development of a severity score for CRPS. Pain. 2010 Dec;151(3):870-876. doi: 10.1016/j.pain.2010.09.031. Epub 2010 Oct 20.
• Hudak PL, Wright JG. The characteristics of patient satisfaction measures. Spine (Phila Pa 1976). 2000 Dec 15;25(24):3167-77. Review.
• Terwee CB, Roorda LD, de Vet HC, Dekker J, Westhovens R, van Leeuwen J, Cella D, Correia H, Arnold B, Perez B, Boers M. Dutch-Flemish translation of 17 item banks from the patient-reported outcomes measurement information system (PROMIS). Qual Life Res. 2014 Aug;23(6):1733-41. doi: 10.1007/s11136-013-0611-6. Epub 2014 Jan 9.
• Dworkin RH, Turk DC, Revicki DA, Harding G, Coyne KS, Peirce-Sandner S, Bhagwat D, Everton D, Burke LB, Cowan P, Farrar JT, Hertz S, Max MB, Rappaport BA, Melzack R. Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2). Pain. 2009 Jul;144(1-2):35-42. doi: 10.1016/j.pain.2009.02.007. Epub 2009 Apr 7.
• Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 Dec;20(10):1727-36. doi: 10.1007/s11136-011-9903-x. Epub 2011 Apr 9.
• Nicholas MK. The pain self-efficacy questionnaire: Taking pain into account. Eur J Pain. 2007 Feb;11(2):153-63. Epub 2006 Jan 30.
• Mangnus TJP, Bharwani KD, Dirckx M, Huygen FJPM. From a Symptom-Based to a Mechanism-Based Pharmacotherapeutic Treatment in Complex Regional Pain Syndrome. Drugs. 2022 Apr;82(5):511-531. doi: 10.1007/s40265-022-01685-4. Epub 2022 Mar 5. Review.

Recruitment Information

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

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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: Netherlands

Administrative Information

• NCT Number: NCT05212571
• Other Study ID Numbers: 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

• 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: Erasmus Medical Center
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Frank JP Huygen, MD, PhD; Erasmus MC, Center for Pain Medicine

• PRS Account: Erasmus Medical Center
• Verification Date: May 2022