Clinical trial NCT04742790: QSPainRelief-patientCNS : Clinical Biomarkers of Nociception, Sedation and Cognition
Official title: Clinical Calibration and Evaluation of the QSPainRelief Platform in Patients With Disabling Pain Using Functional Biomarkers of Nociception, Sedation and Cognition
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Post-operative Pain
Keywords: acute pain
persistent pain
sedation
Lead sponsor: Université Catholique de Louvain
Sponsor class: OTHER
Collaborators: name: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
First posted: 2021-02-08
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Monocentric prospective longitudinal study
Primary purpose: DIAGNOSTIC

Brief summary: QSPainRelief-patientCNS is a monocentric prospective longitudinal study conducted in patients suffering from disabling post-surgical pain for which the treating physician is about to prescribe a given drug combination for the treatment of their pain with the aim of identifying measures of drug-induced effects on CNS activity that could be used as biomarkers of real-life clinical outcome, both in terms of desired treatment effects (treatment-induced pain relief) but also in terms of undesired treatment effects (treatment-induced sedation and treatment-induced cognitive dysfunction).

Detailed description: QSPainRelief-patientCNS is one of three clinical studies that will be conducted as part of the QSPainRelief project funded by the European Union's Horizon 2020 research and innovation program (grant agreement 848068; http://qspainrelief.eu).

Chronic pain is a complex disease affecting about 20% of Europeans, and up to 60% of patients with chronic pain do not experience adequate pain relief from currently available analgesic combinational therapies and/or suffer confounding adverse effects. Of the many conceivable combinations, only a few have been studied in formal clinical trials. Thus, physicians have to rely on clinical experience when treating chronic pain patients. The vision of the QSPainRelief project is that alternative novel drug combinations with improved analgesic and reduced adverse effects can be identified and assessed by mechanism-based Quantitative Systems Pharmacology (QSP) in silico modelling. The QSPainRelief consortium will setup, calibrate and validate an in silico QSPainRelief platform which integrates recently developed (1) physiologically based pharmacokinetic models to quantitate and adequately predict drug pharmacokinetics in human CNS, (2) target-binding kinetic models; (3) cellular signaling models and (4) a proprietary neural circuit model to quantitate the drug effects on the activity of relevant brain neuronal networks, that also adequately predicts clinical outcome.

Calibration of the QSPainRelief platform modelling the biological processes and neuronal circuits underlying the pain relief and adverse effects induced by drug combinations requires patient data on how different drug combinations affect the central processing of nociceptive input, the central processes underlying pain modulation, as well as the central nervous system (CNS) networks underlying drug-induced adverse effects. After calibration of the QSPainRelief platform, additional patient data is required to evaluate the ability of the platform to actually predict CNS effects of drug combinations in patients. Finally, real-world evidence is needed to relate the effects of drug combinations on CNS activity with the therapeutic and adverse effects self-reported by the patients.

The aims of the QSPainRelief-patientCNS study are thus two-fold.

The first aim is to obtain data from a first set of 60 patients to calibrate the QSPainRelief platform, and from a second set of 120 patients to evaluate the ability of the QSPainRelief platform to predict therapeutic and adverse effects of drug combinations. It will focus on pain relief and its impact on daily life activities as therapeutic effects, and on drug-induced sedation, drug-induced cognitive dysfunction (memory and attention) and pain medication misuse as adverse effects. These adverse effects have been chosen because (1) CNS biomarkers sensitive to drug-induced sedation and drug-induced cognitive dysfunction can be readily obtained using non-invasive measurements of the electroencephalogram (EEG) and (2) the chosen adverse effects can be assessed in patients after a short treatment period using validated patient-reported outcome measures (PROMs).

The second aim is to identify measures of drug-induced effects on CNS activity that could be used as biomarkers of real-life clinical outcome, both in terms of desired treatment effects (treatment-induced pain relief) but also in terms of undesired treatment effects (treatment-induced sedation and treatment-induced cognitive dysfunction).

Eligibility criteria: Inclusion Criteria:

* Aged 18-75 years.
* Presence of disabling post-operative pain for more than two weeks following thoracotomy, sternotomy or breast cancer surgery.
* Current treatment of their post-operative pain with an opioid analgesic (along with possible other drugs).
* Decision by the treating physician to introduce an additional non-opioid treatment for their post-operative pain such as (but not necessarily) an antiepileptic or an anti-depressant.
* Capacity to understand and voluntarily sign an informed consent form.

Exclusion Criteria:

* Insufficient French language skills.
* Planned chemotherapy, hormonotherapy or radiotherapy during the time interval between Visits 1 and 2.
* Clinically evident psychiatric disease that is likely to interfere with the study, according to judgment by the investigator.
* History of peripheral or central nervous system disease before the surgical intervention.
* Dermatological condition involving the sensory testing areas.
* Severe alcohol use disorder (as defined in DSM-5).
* Severe sedative, hypnotic of anxiolytic-related use disorder (as defined in DSM-5).
* Any other mild, moderate or severe substance use disorder except tobacco and caffeine (as defined in DSM-5).
* Consumption of recreational drugs, including cannabis, in the last 4 weeks prior to the study.
* Signs of polyneuropathy at clinical examination.
* Signs of a neurological deficit due to a CNS lesion or dysfunction at clinical examination.
* Any other reason to exclude the subject because it may interfere with the study, according to judgment by the investigator. The reason will be documented.

Primary outcomes:
measure: Correlation between change in magnitude of laser-evoked brain potentials (LEP) and change in the Brief Pain Inventory (BPI) pain severity score
timeFrame: three months
measure: Correlation between change in the alpha attenuation coefficient (AAC) and change in the Stanford Sleepiness Scale (SSS)
timeFrame: 10 days
measure: Correlation between change in magnitude of cognitive P3b potential and change in the PROMIS Neuro-QOL score for cognitive function
timeFrame: 10 days
Secondary outcomes:
measure: Correlation between change in magnitude of the N13 spinal-cord evoked potential and change in the PQ-NEURO score for neuropathic pain
timeFrame: 10 days
measure: Correlation between change in the variation coefficient of pupillary dilation (VCPD) and change in the Brief Pain Inventory (BPI) score
timeFrame: 10 days
measure: Correlation between change in pupil constriction velocity (PCV) and change in the Brief Pain Inventory (BPI) score
timeFrame: 10 days
measure: Correlation between change in saccadic peak velocity (SPV) and change in the Stanford Sleepiness Scale (SSS)
timeFrame: 10 days
measure: Correlation between change in performance of the 2-back working memory task (2-WM) and change in the PROMIS Neuro-QOL score for cognitive function
timeFrame: 10 days
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc
Study officials:
References:
citation: Gjeilo KH, Stenseth R, Wahba A, Lydersen S, Klepstad P. Validation of the brief pain inventory in patients six months after cardiac surgery. J Pain Symptom Manage. 2007 Dec;34(6):648-56. doi: 10.1016/j.jpainsymman.2007.01.010. Epub 2007 Jul 16.
citation: Kaida K, Takahashi M, Akerstedt T, Nakata A, Otsuka Y, Haratani T, Fukasawa K. Validation of the Karolinska sleepiness scale against performance and EEG variables. Clin Neurophysiol. 2006 Jul;117(7):1574-81. doi: 10.1016/j.clinph.2006.03.011. Epub 2006 May 6.
citation: Comerchero MD, Polich J. P3a and P3b from typical auditory and visual stimuli. Clin Neurophysiol. 1999 Jan;110(1):24-30. doi: 10.1016/s0168-5597(98)00033-1.
citation: Cruccu G, Aminoff MJ, Curio G, Guerit JM, Kakigi R, Mauguiere F, Rossini PM, Treede RD, Garcia-Larrea L. Recommendations for the clinical use of somatosensory-evoked potentials. Clin Neurophysiol. 2008 Aug;119(8):1705-1719. doi: 10.1016/j.clinph.2008.03.016. Epub 2008 May 16.
citation: Askew RL, Cook KF, Keefe FJ, Nowinski CJ, Cella D, Revicki DA, Morgan DeWitt EM, Michaud K, Trence DL, Amtmann D. A PROMIS Measure of Neuropathic Pain Quality. Value Health. 2016 Jul-Aug;19(5):623-30. doi: 10.1016/j.jval.2016.02.009. Epub 2016 Apr 6.
citation: Charier DJ, Zantour D, Pichot V, Chouchou F, Barthelemy JM, Roche F, Molliex SB. Assessing Pain Using the Variation Coefficient of Pupillary Diameter. J Pain. 2017 Nov;18(11):1346-1353. doi: 10.1016/j.jpain.2017.06.006. Epub 2017 Jul 13.
citation: Connelly MA, Brown JT, Kearns GL, Anderson RA, St Peter SD, Neville KA. Pupillometry: a non-invasive technique for pain assessment in paediatric patients. Arch Dis Child. 2014 Dec;99(12):1125-31. doi: 10.1136/archdischild-2014-306286. Epub 2014 Sep 3.
citation: Haatveit BC, Sundet K, Hugdahl K, Ueland T, Melle I, Andreassen OA. The validity of d prime as a working memory index: results from the "Bergen n-back task". J Clin Exp Neuropsychol. 2010 Oct;32(8):871-80. doi: 10.1080/13803391003596421. Epub 2010 Apr 9.