Esketamine as Treatment for Chronic Pain Due to Endometriosis: a RCT Study

Endometriosis Clinical Trial

— EASYlight  

Official title:

Esketamine as Treatment for Chronic Pain Due to Endometriosis: a RCT Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06161805
• Other study ID #: EASYlight-NEK
• Status: Recruiting
• Phase: Phase 3
• Start date: March 1, 2024
• Est. completion date: June 6, 2025

Study information

• Verified date: February 2024
• Source: Reinier de Graaf Groep
• Contact: Mathijs Blikkendaal, MD, PhD
• Phone: 070 340 1222
• Email: M.Blikkendaal[@]rdgg.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this randomized controlled trial is to investigate the effect of esketamine versus placebo on the NRS score for chronic pelvic pain. Secondary endpoints are to assess pain scores, side-effects, quality of life, depressive symptoms and pain coping.

Description:

Endometriosis is a chronic inflammatory disease affecting approximately 10% of reproductive-aged women. Severe pain symptoms and subfertility result in a lower quality of life, higher prevalence of depression and loss of productivity. Consequently, the economic impact of endometriosis is high. Treatment options to suppress chronic pain symptoms in patients with (deep) endometriosis are inadequate, resulting in increased opioid consumption. Ketamine (in our study we will use the S-enantiomer, esketamine), is a versatile drug with analgesic, anti-inflammatory and antidepressant effects and is commonly used in the treatment of chronic pain patients and has shown promising outcomes. However, whilst esketamine targets multiple aspects of endometriosis simultaneously (pain, inflammation, depression), studies on esketamine as treatment for chronic pain due to endometriosis have never been reported. Therefore we aim to conduct a randomized controlled trial to assess the efficacy of esketamine infusion versus placebo in the treatment of chronic endometriosis-induced pain.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 56
• Est. completion date: June 6, 2025
• Est. primary completion date: January 6, 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• Women

• All pre-menopausal women aged above 18 years

• Diagnosed with endometriosis (ultrasound, MRI or previous laparoscopic and/or diagnostic surgery) according to the #Enzian classification [52]. This means that endometriosis is present in the following compartments:

• Rectovaginal space (minimal A1) and/or

• Sacrouterine ligaments, cardinal ligaments, pelvic sidewall (minimal B1) and/or

• Rectum (minimal C1) and/or

• Endometriosis of the intestines, diaphragm and/or

• Adenomyosis (according to the morphological uterus sonographic assessment (MUSA) or evident adenomyosis on the MRI) [53, 54] and/or

• Peritoneal / superficial endometriosis (diagnosed laparoscopically and not treated during surgery).

• Mild to severe chronic pelvic pain (NRS scale >= 6). The 11-point NRS scale ranges from '0' representing no pain to '10' representing the worst pain imaginable.

• Resistant to current recommended lines of analgesics (paracetamol, NSAIDs)

• Usage of strong opioids must not have been prescribed or otherwise have been discontinued for more than 1 week.

• An indication for endometriosis resection surgery or on the waiting list for surgical treatment

• Ability to understand the patient information letter and to give oral and written informed consent

• No alteration in the utilization of hormonal therapy =1 months prior to inclusion.

Exclusion Criteria:

• Pain score <6 out of 10 (NRS) for chronic pelvic pain

• Endometriosis affecting the bladder and ureter

• Increased intracranial pressure

• Poorly regulated hypertension, >180/100mmHg at rest

• Patients with thyroid disease

• Patients with cancer

• History of psychiatric illness (schizophrenia, psychosis, delirium, manic depression)

• Serious medical disease (e.g., cardiovascular, renal , pulmonary or liver disease)

• Severe liver disease

• Patients with glaucoma

• Usage of strong opioid medication

• Usage of xanthine derivatives or ergometrine

• Unstable angina, heart failure, history of cerebral vascular accident (CVA)

• Patients suffering from an active infection

• Patients with epilepsy

• Patients trying to achieve pregnancy and or patients who are breastfeeding

• Not being able to answer questionnaires (in Dutch)

• Mentally incompetent (patients not able to make decisions that are in their best interests, this will be evaluated by their treating physician (e.g. patients with an intellectual disability or mental retardation))

• Alcohol or drug abuse

• Patient with a known (es)ketamine allergy

• Abnormal liver enzyme levels at baseline (ASAT, ALAT, GGT, AF, Bilirubin total)

Patients are allowed to continue the following pain medications: paracetamol, non-steroidal anti-inflammatory drugs as described previously by Sigtermans et al. (Trial NL466 (NTR507))* according to their stable use in dose and frequency.

*in case of tramadol, amitriptylin, selective serotonin reuptake-inhibitors, gabapentin and pregabalin, the usage may also be continued during this study.

Related Conditions & MeSH terms

• Chronic Pain
• Chronic Pelvic Pain Syndrome
• Endometriosis
• Pelvic Pain

Intervention

Drug:
• Esketamine hydrochloride
Esketamine dosing regimen is set at 0.1 mg/kg/h as starting dosage. Dosage will be gradually increased based on heart rate, oxygen saturation, blood pressure and side effects (e.g. nausea and dissociative effects) during a period of 8 hours to a maximum of 0.5 mg/kg/h (in steps of 0.1-0.3-0.5 mg/kg/hour). This dosage regimen is similar to that used earlier by Sigtermans et al. [1].
• Placebo
8 hour infusion with saline (NaCl 0.9%)

Locations

Country	Name	City	State
Netherlands	Nederlandse Endometriose Kliniek, Reinier de Graaf Gasthuis	Delft

Sponsors (1)

Lead Sponsor	Collaborator
Reinier de Graaf Groep

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Chronic pelvic pain	The effect of treatment allocation on the NRS score for chronic pelvic pain. The NRS scale ranges from 0 (no pain) to 10 (worst pain imaginable).	4 weeks after the 8 hour infusion treatment.
Secondary	Dysmenorrhea	NRS score for dysmenorrhea. The NRS scale ranges from 0 (no pain) to 10 (worst pain imaginable).	Baseline and week 4, 8, 12 after the 8 hour infusion treatment
Secondary	Dyschezia	NRS scores for dyschezia.The NRS scale ranges from 0 (no pain) to 10 (worst pain imaginable).	Baseline and week 4, 8, 12 after the 8 hour infusion treatment
Secondary	Dysuria	NRS scores for dysuria. The NRS scale ranges from 0 (no pain) to 10 (worst pain imaginable).	Baseline and week 4, 8, 12 after the 8 hour infusion treatment
Secondary	Dyspareunia	NRS score for dyspareunia. The NRS scale ranges from 0 (no pain) to 10 (worst pain imaginable).	Baseline and week 4, 8, 12 after the 8 hour infusion treatment
Secondary	Chronic pelvic pain	NRS score for chronic pelvic pain. The NRS scale ranges from 0 (no pain) to 10 (worst pain imaginable).	Baseline and week 4, 8, 12 after the 8 hour infusion treatment
Secondary	Depressive symptoms	Hospital Anxiety and Depression scale, 14 questions, scale from 0-3, higher scores mean worse outcome.	Baseline, 4 weeks after infusion treatment
Secondary	Endometriosis associated Quality of Life	Endometriosis Health Profile-30 (EHP-30). The overall EHP-30 score ranges from 0 to 100, with a high score indicating poorer health-related quality of life.	Baseline and week 4, 8, 12 after the 8 hour infusion treatment
Secondary	Quality of life in general	EuroQql five-dimensional 5 levels (EQ-5D-5L). According to the Dutch scoring algorithm, the EQ-5D-5L score index value ranges from -0.446 (55555 worst health state) to 1 (11111, best health state).	Baseline and week 4, 8, 12 after the 8 hour infusion treatment
Secondary	Quality of life in general	EuroQql Visual Analog Scale (EQ-VAS). Overall health will be represented by the EQ-VAS, ranging from 0 to 100, with higher scores indicating better health.	Baseline and week 4, 8, 12 after the 8 hour infusion treatment
Secondary	Productivity costs	Adjusted productivity costs questionnaire (iPCQ): institute for Medical Technology Assessment (iMTA). Adjusted medical consumption questionnaire: iMTA. Productivity costs will be measured by calculating absence from paid work (absenteeism), reduced productivity at paid work (presenteeism), and productivity loss in unpaid work. Hours of productivity loss will be translated by a standard cost price of productivity per hour.	12 weeks post-infusion treatment
Secondary	Medical costs	Medical consumption costs will be calculated based upon the iMCQ.	Baseline, 12 weeks post-infusion treatment
Secondary	Pain coping and cognition	Pain Coping and Cognition list (PCCL), consists of 42 items divided in four scales: pain catastrophising (higher scores mean a higher degree of catastrophising), pain coping (lower scores mean a lower degree of pain coping), internal pain control (lower scores mean less internal pain control) and external pain control (higher scores mean less external pain control.	Baseline, 12 weeks post-infusion treatment
Secondary	The effect infusion treatment psychedelic effects	Bowdle questionnaire, scale from 0-100, higher scores mean worse outcome.	On the day of infusion (prior to infusion and during infusion)
Secondary	Treatment experience	1 question, treatment rating on a scale from 0 (worst experience possible) -10 (excellent experience)	Directly after infusion