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

September 7, 2023 updated by: Thomas J. P. Mangnus, MD, Erasmus Medical Center

Long-term Pain Modulation by Intravenous Esketamine in Complex Regional Pain Syndrome: a Non-inferiority Study

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.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / 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

Enrollment (Estimated)

60

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Zuid Holland
      • Rotterdam, Zuid Holland, Netherlands, 3000 CA
        • Erasmus MC

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Outpatient
The experimental intervention group visits the outpatient clinic to receive intravenous esketamine in day-care setting every 2 weeks for 3 months.
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
Active Comparator: Inpatient
The standard treatment group receives intravenous esketamine for 6 consecutive days in hospital.
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline (week 0) and follow-up visit (week 12)
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.
Baseline (week 0) and follow-up visit (week 12)
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)
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)
Change from baseline pain medication dose
Time Frame: Baseline (week 0), follow-up visit (3 months) and end of study (6 months)
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.
Baseline (week 0) and follow-up visit (3 months)
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.
During telephone consultation (week 1, 3, 5, 7, 9, 11), follow-up visit (3 months) and end of study (6 months)
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
Baseline (week 0) and follow-up visit (3 months)
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
Baseline (week 0) and follow-up visit (3 months)
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
Baseline (week 0) and follow-up visit (3 months)
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
Baseline (week 0) and follow-up visit (3 months)
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
Baseline (week 0) and follow-up visit (3 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Erasmus Medical Center

Investigators

  • Principal Investigator: Frank JP Huygen, MD, PhD, Erasmus MC, Center for Pain Medicine
  • Study Director: Thomas Mangnus, MD, Erasmus MC, Center for Pain Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 19, 2022

Primary Completion (Estimated)

October 1, 2026

Study Completion (Estimated)

October 1, 2027

Study Registration Dates

First Submitted

December 13, 2021

First Submitted That Met QC Criteria

January 14, 2022

First Posted (Actual)

January 28, 2022

Study Record Updates

Last Update Posted (Actual)

September 11, 2023

Last Update Submitted That Met QC Criteria

September 7, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL77785.078.21
  • 2021-000640-21 (EudraCT Number)
  • MEC-2021-0426 (Other Identifier: Medical Ethics Committee of Erasmus MC)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Complex Regional Pain Syndromes

Clinical Trials on S-ketamine infusion outpatient setting

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Ireland

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe