Clinical trial NCT05212571: 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
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Complex Regional Pain Syndromes
CRPS (Complex Regional Pain Syndromes)
Keywords: CRPS
Complex Regional Pain Syndrome
ketamine
S-ketamine
esketamine
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
First posted: 2022-01-28
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: prospective, randomized non-inferiority study
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change from baseline pain scores
timeFrame: 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 outcomes:
measure: Change from baseline Quantitative Sensory Testing
timeFrame: Baseline (week 0) and follow-up visit (week 12)
measure: Change from baseline Thermography
timeFrame: Baseline (week 0) and follow-up visit (week 12)
measure: Adverse events due to S-ketamine infusion
timeFrame: 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)
measure: Change from baseline pain medication dose
timeFrame: Baseline (week 0), follow-up visit (3 months) and end of study (6 months)
measure: Change from baseline Complex Regional Pain Syndrome severity score
timeFrame: Baseline (week 0) and follow-up visit (3 months)
measure: Global Perceived Effect
timeFrame: During telephone consultation (week 1, 3, 5, 7, 9, 11), follow-up visit (3 months) and end of study (6 months)
measure: Patient-Reported Outcomes Measurement Information System (PROMIS) -29 Profile
timeFrame: Baseline (week 0) and follow-up visit (3 months)
measure: Short-form McGill Pain Questionnaire-2
timeFrame: Baseline (week 0) and follow-up visit (3 months)
measure: Pain Catastrophizing Scale
timeFrame: Baseline (week 0) and follow-up visit (3 months)
measure: EQ-5D-5L.
timeFrame: Baseline (week 0) and follow-up visit (3 months)
measure: Pain Self-Efficacy Questionnaire
timeFrame: Baseline (week 0) and follow-up visit (3 months)
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus MC
state: Zuid Holland
Study officials:
affiliation: Erasmus MC, Center for Pain Medicine
name: Frank JP Huygen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus MC, Center for Pain Medicine
name: Thomas Mangnus, MD
role: STUDY_DIRECTOR
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