Chronic knee pain remains a disabling disease despite current treatment strategies. There is an increase in the prevalence of osteoarthritis (OA) of the knee in the general population, presently affecting approximately 450,000 individuals in Belgium. A total knee replacement is a viable alternative for severe knee OA that does not respond to conservative therapy. Unfortunately, up to 53% of patients who undergo a total knee replacement develop persistent post-surgical pain (PPSP). There is currently no effective therapy for PPSP.

A radiofrequency (RF) treatment applies high frequency current on the nerve responsible for pain conduction, resulting in an interruption of the transmission of pain. This can be applied to the nerves innervating the knee joint - the superolateral, superomedial and inferomedial genicular nerves - and could be an alternative, minimally invasive treatment for patients with knee OA who fail conservative treatments and for patients with PPSP. Data from the recent literature indicates that this treatment leads to a reduction of pain intensity and could result in an improvement of knee function, of the psychological state of the individual, and finally in an increase in health-related quality of life. Furthermore, RF of the genicular nerves could help avoid or delay a total knee replacement therefore potentially contributing to cost reduction. Both cooled and conventional RF treatments are reported in the literature to improve pain. The use of water to cool the RF electrodes results in an increased lesion size by removing heat from adjacent tissue, allowing power delivery to be increased. As a consequence, cooled RF could result in a higher chance of success and longer duration of effect. Until now, the studies performed on cooled RF are industry initiated and a direct comparison between conventional, cooled and a sham procedure is lacking.

The aim of the COGENIUS trial is to investigate the effect of the two types of RF treatment on individuals experiencing chronic knee pain that is resistant to conservative treatments. For this purpose, the efficacy and cost-effectiveness of cooled and conventional RF will be compared to a sham procedure in patients suffering from knee OA and PPSP after total knee replacement.

In this three-arm, pragmatic, prospective, multicentre, double blind, randomised sham-controlled trial of approximately 4 years duration, 400 patients with chronic moderate to severe anterior knee pain (>12 months) refractory to conventional treatments will be included. Two groups of chronic knee pain patients will be enrolled depending on the aetiology of knee pain: OA and PPSP. Each patient will undergo a run-in period of 1 to 3 months depending on the previous treatments of the patient. A run-in period is added to the trial to guarantee that conservative treatment is performed in an optimal way before randomisation. In each group (osteoarthritis and persistent post-surgical pain), non-responders to the run-in period will be randomly allocated to a conventional RF intervention of the genicular nerves, a cooled RF intervention of the genicular nerves or a sham procedure in a 2:2:1 ratio. The patients will be followed up for a period of 2 years.

Inclusion Criteria:

• Signed written informed consent must be obtained before any study assessment is performed.
• Adult patients (Age ≥ 18 years old).
• Chronic anterior knee pain (> 12 months) that is moderate to severe (defined as NRS > 4 on most or all days for the index knee either constantly or with motion at time of screening and, an average NRS score reported in the patient diary >4 at the end of the run-in period).
• Unresponsive (meaning insufficient pain reduction or intolerance) to conventional treatments ongoing for at least 12 months prior to inclusion. Conventional treatments must include all of the following: active physiotherapy, pharmacological treatment of pain and intra-articular corticosteroid infiltration.
• Only for patients with Osteoarthritis (OA): Radiologic confirmation of knee osteoarthritis of grade 2 (mild), 3 (moderate) or 4 (severe) noted within 12 months prior to the screening for the index knee according the Kellgren Lawrence criteria diagnosed by an independent radiologist with experience in musculoskeletal imaging on radiography (Rx) or magnetic resonance imaging (MRI). If imaging will need to be performed at screening it is recommended to perform an MRI instead of Rx. Imaging with MRI will enable the independent radiologist to perform a better estimation of the grade of OA.
• Only for patients with Persistent Post-Surgical Pain (PPSP) after Total Knee Arthroplasty (TKA): Patients with PPSP* after TKA need to have had a negative orthopaedic work-up

Exclusion Criteria:

• Local or systemic infection (bacteraemia).
• Evidence of inflammatory arthritis or an inflammatory systemic disease responsible for knee pain.
• Intra-articular injections (steroids, hyaluronic acid, platelet enriched plasma, ...) in the index knee during the 3 months prior to procedure.
• Pregnant, nursing or planning to become pregnant before the study intervention. Participants who become pregnant after the study intervention during the follow-up period will not be excluded.
• Chronic widespread pain.
• Patients with unstable psychosocial disorder.
• Allergies to products used during the procedure (lidocaine, propofol, chlorhexidine).
• Uncontrolled coagulopathy defined as supratherapeutic dose of anticoagulation medication.
• Uncontrolled immune suppression.
• Participating in another clinical trial/investigation within 30 days prior to signing informed consent.
• Patient is currently implanted with a neurostimulator.
• Current radicular pain in index leg.
• Previous conventional or cooled radiofrequency of the index knee.
• Patients with bilateral knee pain defined as chronic knee pain (> 12 months) in both knees that is moderate to severe (defined as a numeric rating scale (NRS) > 4 on most or all days either constantly or with motion) and that is unresponsive (meaning insufficient pain reduction or intolerance) to conventional treatments ongoing for at least 12 months prior to inclusion. Conventional treatments must include all of the following: active physiotherapy, pharmacological treatment of pain and intra-articular corticosteroid infiltration.
• Patients who have a planned TKA in the near future defined as patients who already have agreed on a date for the TKA procedure.
• Patients who are unwilling or mentally incapable to complete the study questionnaires.

Researcher will need to contact ctu@zol.be in order to request the 'Data Sharing Application' form. Users will need to complete an application form, 'Request for Data Sharing'. The application will be reviewed by the Trial Steering Committee with regard to feasibility and confidentiality. When the application is approved by the Trial Steering Committee, the applicant will be requested to sign a 'Data Use Agreement'. This Data Use Agreement shall be countersigned by ZOL as Sponsor and the CI of the COGENIUS study.

Considering that ongoing research contributing to the completion of datasets must not be compromised by premature or opportunistic sharing and analysis of data, ZOL will not release the data of its studies until the primary study results have been published, unless authorized for release has been granted.

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