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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - IMI-PainCare (Improving the care of patients suffering from acute or chronic pain)

Teaser

Summary

There is a high need for improving the management of pain. Acute and persistent pain of different origin represent a common medical, social, and economic burden, and its pharmacotherapy is often inadequate. To advance management of pain patients and support decision making in clinical practice, better prediction of treatment success is needed. The development of analgesics is onerous because promising preclinical data often do not translate into the clinic. Improved pharmacodynamic biomarkers could define whether nociceptive signalling is adequately modulated by a new drug, so increasing the chance of successful translation. Further, the pathophysiology of chronic pelvic pain is poorly understood and no adequate preclinical models are available, precluding focused preclinical and translational research.
IMI-PainCare aims at making advances in three areas of pain management via three subtopics that complement each other in various ways. Subtopic PROMPT aims to identify Patient Reported Outcome Measures (PROMs) as tools to standardise assessment of treatment success of acute and chronic pain in Real World conditions and controlled trials, and so improve its management; subtopic BioPain aims to validate the translatability of pharmacodynamic biomarkers and PK-PD modelling in pain pathways of healthy subjects and preclinical species, thereby offering tools to improve drug development; subtopic TRiPP aims to identify biomarkers and novel therapeutic pathways of clinical phenotypes of patients with chronic pelvic pain, which after back-translation, can improve how preclinical models reflect human diseases. The overall objectives of IMI-PainCare are to improve the care of patients with acute or chronic pain by providing a toolbox to streamline the development process for novel analgesic drugs and to improve treatment quality in clinical practice.

Work performed

In the first project year, subproject PROMPT has identified PROMs by systematic literature researches (SLR) and aligned them by a formal Delphi process on patient-reported outcomes domains relevant for the four surgeries to be included in a non-interventional trial (PROMPT NIT-1). The Delphi consensus comprised ten relevant groups of stakeholders, including patient representatives and regulatory authorities. Another SLR identified PROMs which are able to serve as risk factor for chronic post-surgical pain. In parallel, the study design of PROMPT NIT-1 has been prepared (web-based patient follow-up, translation into eight languages, data capture according to European and national data security and privacy requirements, activity tracker). In addition to the 6 hospitals that belong to the Consortium, 11 hospitals across Europe (France, UK, Spain, Italy, Switzerland, Serbia, Portugal) have been chosen and trained to enrol about 4,000 patients.
PROMPT NIT-2, which will be the data source for outcomes in observational studies, has recruited 934 patients in Germany, Italy and France, and is completed. After finalization of data analysis which is expected for end of 2019 the data will be anonymized and transferred to UKJ for comparative analyses. For PROMPT-RCT2 and RCT-3, the study protocols are in final draft. It is foreseen in the protocol to use PROMs which were identified in the Delphi process and literature research which are described above. A further SLR on chronic non-surgical pain in neuropathic and pelvic pain patients has been started.

In the first project year, subproject BioPain has performed systematic literature searches on peripheral, spinal and brain functional biomarkers of nociceptive processing, on human surrogate models that mimic aspects of central sensitization in patients, on pharmacokinetics of standard-of-care pain medications that are suitable to assess PK-PD relationships and on existing PK-PD models in the field of pain research. The results of the systematic literature searches highlighted the need for the studies on functional biomarkers of pain planned within the BioPain subproject and confirmed the premises of its modelling approach. Consensus was reached among BioPain partners on three medications (lacosamide, pregabalin, tapentadol) and legal agreements were made to be able to use one of them that is still under patent protection (tapentadol). Four clinical trials were designed and submitted to the competent authorities for approval, including statistical analysis plans for primary endpoints and key secondary outcome variables. Alignment was reached for functional biomarkers in rodents that are identical or equivalent to those studied in humans. Alignment between participating academic laboratories was initiated on harmonizing the methods used in the multicentre trials in healthy volunteers.

In the first year of this project, subproject TRiPP has focussed on preparing TRiPP NIT-1. This trial will recruit controls and women with endometriosis associated pain (EAP) from bioresources at UOXF and BCH with consent to recontact participants. Women with Bladder Pain Syndrom (BPS) will be recruited from patient support groups and from clinics at IBMC, UCC and UOXF. All preliminary work for this trial is now complete. The protocol, questionnaires, and all patient documents have been produced by the University of Oxford as sponsors of the study and were approved by the appropriate authorities in Oxford and Boston. Local approval processes are underway in Porto and Cork.
The analysis plan has been produced and detailed subject selection criteria agreed upon allowing us to select from the bioresource appropriate participants to contact and samples to analyse (controls and EAP participants). Samples are being prepared for shipping to the CROs undertaking proteomic and metabolomics analyses. Databases are being prepared for data entry.
The preclinical workpackages of TRiPP have focussed their first year on r

Final results

The interim results after one year have yielded several new findings, particularly from the systematic literature reviews and consensus processes. All activities are on track and hence promise to provide the impact outlined by the objectives above. Early contacts with FDA and EMA were appreciated by both agencies, and we hence anticipate to be able to provide rapid wider society impacts by the end of this project.
Patient representatives took part as one of the stakeholder groups in the Delphi-process to consent on a core set of outcome domains for the questionnaires to be used in PROMPT NIT-1. Advocates of the patient organisations EOL, IPBF, and PPSN advised on the study protocol of the TRiPP-NIT1, which significantly accelerated its ethical approval.