Long-term Pain Modulation by Intravenous Esketamine in CRPS

Study Overview
=================
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.

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

Conditions
-----------------
Complex Regional Pain Syndromes, CRPS (Complex Regional Pain Syndromes)

Intervention / Treatment
-----------------
* Drug: S-ketamine infusion inpatient setting
* Drug: S-ketamine infusion outpatient setting


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prospective, randomized non-inferiority study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Outpatient<br>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<br>* 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.<br>* Other names: esketamine;|
| Active Comparator: Inpatient<br>The standard treatment group receives intravenous esketamine for 6 consecutive days in hospital. | Drug: S-ketamine infusion inpatient setting<br>* 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.<br>* Other names: esketamine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline pain scores | 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 | 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 | 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 | 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 |  | Baseline (week 0), follow-up visit (3 months) and end of study (6 months) | 
| Change from baseline Complex Regional Pain Syndrome severity score | 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 | 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 | 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 | 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 | 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. | 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 | 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CRPS, Complex Regional Pain Syndrome, ketamine, S-ketamine, esketamine