Title: Improving neurological outcome in Cervical Spondylotic Myelopathy
Funder: Department of Health and Social Care

Abstract: This is for internal use only; and is not to be published/shared. Any questions see a member of Information & Evaluation team. Background:Cervical Spondylotic Myelopathy (CSM) is the most common spinal cord disorder in those over 55 and a major disability cause. It's induced by degenerative changes in the cervical spine causing compression of the spinal cord(SC). Up to 26% of adults >50 have asymptomatic compression of the SC in the neck. Once SC compression is detected, within 4 years 23% of individuals develop myelopathy. Approximately 4/100,000 of population undergo surgery for CSM/year. However, the post-operative improvements are often limited, many patients remain severely disabled. Improving neurological recovery following CSM represents an important unmet clinical need. In CSM, ischemia, inflammation, cell death, axonal loss, and demyelination result in increasing disability. Preclinical/post mortem studies, including our own work, demonstrate that functional recovery following decompression is associated with axonal plasticity (formation of new nerve connections), modulation of inflammation, and activation of stem cells capable of forming myelin. This can be synergistically achieved by drugs inhibiting Phosphodiesterase 4 (PDE4). Amongst PDE inhibitors, Ibudilast is particularly attractive, studies in MS indicated that Ibudilast is able to reduce areas of demyelination, inhibit brain atrophy, and improve neurological function. Aims & questions to be addressed: The main aim is to prepare the ground for and initiate a study investigating the ability of Ibudilast to improve neurological recovery after surgical decompression in CSM (RECEDE Myelopathy Study). Research questions Q1.1 Which Core Outcomes should be included in clinical trials investigating CSM? Q1.2 Which Patient reported Outcome measures (PROMs) should be collected as part of the management and treatment of CSM patients? Q2.1 Are CSM patients willing to participate and be randomised in a study investigating Ibudilast? Q2.2 Is the use of Ibudilast for patients suffering from CSM safe? Q2.3 Can surrogate markers demonstrate mechanistic efficacy? Q2.4 How many patients need to be included to sufficiently power a phase 3 trial? Plan of investigation WP1 Definition of Core Outcomes sets for CSM There is a paucity of randomised controlled trials (RCTs) in CSM. The variable use of outcome measures in the literature is associated with high risk of bias and compromises the evidence base for CSM. To establish a useful Core Outcome Set, I propose to conduct WP1.1 a systematic review investigating the range of outcome measures used in the literature and WP1.2 a Delphi Survey involving clinicians, academics, allied healthcare professionals, patients, carers, and public representatives. WP2 A Multi-Centre, Randomised, Placebo-Controlled, Double-blinded Trial investigating Feasibility, Safety, and Preliminary Efficacy of Ibudilast for promoting Regeneration following Surgical Decompression in CSM (RECEDE Myelopathy Trial) Potential benefits to patients and the NHS The present trial addresses an unmet clinical need of alleviating the long-term disability caused by CSM. Although CSM is a frequent disease, it is often overlooked. The program and PPI will help to raise awareness for CSM. CSM causes gait disturbance and imbalance and contributes to reduced mobility and frailty. Reducing premature mortality and enhancing quality of life for people with long-term conditions is an important NHS goal (http://www.england.nhs.uk/wp-content/uploads/2014/02/safe-comp-care.pdf). CSM patients are at risk of recurrent falls, which is a major concern (NICE guideline 161). If successful, the present study will form the basis of a future definitive trial investigating the use of Ibudilast for CSM. The Core Outcome Measures identified in WP1 will instruct future CSM trials; the defined PROMs will be implemented in the local CSM care pathway for immediate patient benefit. The trial will form the core of a wider research programme investigating mechanisms of disease in CSM.

Lay abstract: Background: CSM, or Cervical (concerning the neck) Spondylotic (wear and tear arthritis of the spine) Myelopathy (injury to the spinal cord) is the most common spinal cord disorder in individuals over 55 years of age. It is induced by changes of the spine causing compression of the spinal cord. Studies indicated that up to a quarter of adults over 64 years have spinal cord compression in the neck without having symptoms and that once compression is seen, approximately a quarter of individuals develop CSM within 4 years. The symptoms are often mistaken for natural consequences of ageing. They include numb and clumsy hands, loss of coordination, imbalance, bladder and bowel problems, and weakness that can progress to severe paralysis. The main treatment for CSM is surgery. Every year, approximately 4 individuals in 100,000 undergo surgery for CSM. The aim of surgery is to create space for the spinal cord by removing prolapsed discs or removing the back of the vertebrae. This takes the pressure off the spinal cord to prevent further injury. Unfortunately, the post- operative improvements are often limited and many patients remain severely disabled. So far there is no treatment available that promotes recovery after CSM. Improving coordination, sensation, and strength following CSM surgery therefore represents an important unmet need. Recent laboratory findings suggest that a specific class of drugs can stimulate repair by stem cells and nerve cells in the spinal cord. In particular, a neuroregenerative drug that is in use for in stroke in Japan and which is also currently being investigated for other neurological diseases (multiple sclerosis and amyotrophic lateral sclerosis) seems ideally suited to treat CSM. Prompted by encouraging results this study plans to investigate whether this drug is able to benefit patients with CSM. The hope is that this can improve hand function, strength and balance, and potentially ameliorate urinary problems. Work package 1 (6 months): Because this is the first trial investigating repair treatments in CSM, the first step is to determine how success should be measured when treating CSM. The plan is to summarise how CSM has been studied in the past. Subsequently, patient and public representatives as well as experts of various specialities will define which data should be collected in clinical studies for CSM. This will also help to ensure that the planned study collects all relevant data. Work package 2 (4.5 years): Here I propose to conduct a preliminary study of a neuroregenerative drug in patients who undergo surgery for CSM. Treatment with oral tablets will be started the day after surgery and continued for 6 months. Patients will be randomly assigned to taking tablets containing the drug or placebo tablets without the drug. To ensure that there is no bias, the study will be blinded; and so until the end neither the patients nor the doctors will know whether the tablets contain the active substance. The proposed study will investigate whether patients are prepared to take the drug and participate in a definitive study answering the question whether drug can help CSM patients. It will also help to identify how many patients will need to be included in the definitive trial. Work package 3 (within the first year): I was not able to find specific patient groups for research in CSM. As part of patient and public involvement, I propose to set up a website dedicated to CSM research linked to social media (Facebook). The webpage will provide information about the disease and create a forum for interaction where individuals with CSM can meet and discuss relevant issues. This will also help to raise awareness for CSM.

Research activity codes: 6.1 PHARMACEUTICALS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: MUSCULOSKELETAL;NEUROLOGICAL