Regeneration in Cervical Degenerative Myelopathy
Regeneration in Cervical Degenerative Myelopathy
Degenerative (wear and tear arthritis of the spine) Cervical (concerning the neck) Myelopathy
 (injury to the spinal cord), DCM, is the most common spinal cord disorder of adulthood. In
 DCM, arthritis of the spine causes compression of the spinal cord.

 The symptoms of DCM are often mistaken for natural consequences of ageing, including numb and
 clumsy hands, loss of coordination, imbalance, bladder and bowel problems. The weakness can
 progress to severe paralysis. Every year approximately 4 individuals in 100,000 undergo
 surgery for DCM; however, many more individuals are thought to suffer from DCM.

 The main treatment for DCM is surgery. The aim of surgery is to create space and remove the
 compression of the spinal cord. This is known to prevent further injury. Unfortunately, the
 post-operative improvements are often incomplete and many patients remain severely disabled.
 Improving outcome after surgery represents an important unmet clinical need.

 Clinical and preclinical findings indicate that the drug Ibudilast can stimulate
 neuroprotective and regenerative processes in the spinal cord. Ibudilast is well-tolerated
 and used to treat asthma and post-stroke dizziness in Japan and is currently being
 investigated for use in treating other neurological diseases.

 This study will investigate whether daily oral administration of Ibudilast for a maximum of
 34 weeks can improve hand function, strength, balance, urinary problems and reduce pain.

 The study will initially be conducted at three sites in the UK, with more sites added as
 necessary. Individuals between 18-80 years old, diagnosed with DCM and scheduled for an
 operation for the first time will be invited to participate in the trial. The study will
 entail patient questionnaires and clinical assessments before surgery, shortly after surgery
 and 3, 6, and 12 months after surgery. Moreover, patients will undergo MRI scans
 pre-operatively and at 6-months postoperatively to determine whether the treatment was
 successful.
DCM is a common, disabling disease. It is also a major cause of gait disturbance and
 imbalance in the elderly. As a consequence, DCM contributes to reduced mobility and frailty.
 NHS England recognises 1) reducing premature mortality and 2) enhancing quality of life for
 people with long-term conditions as important. DCM patients are at risk of recurrent falls,
 which is a major concern. In fact, a study investigating patients with hip fractures
 demonstrated that 25% of patients suffered from undiagnosed DCM. Surgical decompression is
 the only form of treatment at present. It is shown to stop disease progression. However
 neurological recovery after surgery is often disappointing. There are no approved drug
 treatments for DCM. Alleviating the long-term disability caused by DCM represents an unmet
 clinical need. Recovery of leg and arm function, as well as an improvement in pain are the
 patient recovery priorities.

 In DCM mechanical pressure on the spinal cord causes progressive loss of nerve cells and
 their processes as well as loss of myelin sheaths, the insulating layers of neurons formed by
 oligodendrocytes. Surgical decompression can halt disease progression, but there is limited
 natural spinal cord repair. Preclinical studies demonstrated that inhibition of PDE4 is able
 to stimulate a regenerative response, which is likely to benefit DCM: remyelination and
 axonal plasticity. Clinical studies using Ibudilast, a phosphodiesterase 4 inhibitor, have
 demonstrated beneficial effects in multiple sclerosis. The observed beneficial effects are
 likely to reflect regeneration-inducing and neuroprotective effects of Ibudilast in the human
 CNS.

 The proposed trial is the first regenerative treatment for DCM, and potentially the first
 drug-based regenerative treatment for neurosurgical disease. It will mark an important
 milestone with regard to translation of preclinical findings into a clinical setting. The
 research questions have been designed to:

 -  Assess safety and tolerability of Ibudilast in patients undergoing surgery for DCM

 -  Assess efficacy of Ibudilast treatment in patients undergoing surgery for DCM

 -  Investigate disease mechanisms using

 -  Advanced imaging techniques, including MRI

 -  Gait analysis

 -  Explore the role of novel clinical outcome measures for studies investigating DCM

 -  Clinical scales

 -  Inform the design of future drug trials for use in DCM

 -  Investigate the impact of DCM on carers

 The following hypothesis will be addressed: Ibudilast improves recovery following surgical
 decompression of degenerative cervical myelopathy.

 RECEDE-Myelopathy is a multi-centre, double blind, phase III randomised, placebo controlled
 trial assessing the use of Ibudilast as an adjuvant treatment to decompressive surgery for
 DCM involving up to 10 UK sites. A total of 362 participants will be recruited.

 Each participant will be on trial for approximately 15 months (±21 days). There is a maximum
 1 week interval from screening to randomisation and a maximum 1 week interval from
 randomisation to treatment commencement. Ibudilast treatment will start within 10 weeks prior
 to surgery and will continue for up to 24 weeks after surgery. Treatment will be halted 5
 days prior to surgery and resumed at the previous maximum dose as soon as possible after two
 days since the operation. Participants will be taking Ibudilast for a maximum of 34 weeks; in
 case surgery is delayed beyond 10 weeks, post-surgery treatment will be shortened accordingly
 to keep the 34 weeks maximum treatment period. Participants will be followed up for a maximum
 of 12 months after surgery.

 The trial aims to run in parallel to standard clinical care. The only difference between the
 trial pathway and the standard NHS pathway is the addition of a course of either Ibudilast or
 placebo, and the additional follow up.DCM is typically managed in the outpatient setting.
 Patients are referred to a surgeon for assessment and management. Patients often already have
 a diagnosis. Sometimes, an allied professional makes a diagnosis acutely and a same day,
 'emergency' referral is made to the regional spinal centre. On occasion, such a situation
 predicates urgent surgery, but typically in such cases an outpatient appointment is made.
 Patients will therefore be identified from participating neurosurgical centres, typically via
 outpatient clinics but also the 'emergency' referrals. Screening of patients to determine
 eligibility for participation in the trial will be undertaken by the parent neurosurgical
 team according to the inclusion / exclusion criteria. Prior to screening, patients with DCM
 will be approached by a delegated member of the local trial team and given a patient
 information sheet (PIS) to take away and read in their own time. Patients will be advised to
 get in touch with the local trial team in order to address any questions that they may have
 on the contents of the PIS. If they decide to participate in the trial, they will be invited
 for a screening visit to provide a written informed consent and assess their eligibility for
 the trial as per inclusion/exclusion criteria described below.

 Once informed consent is obtained, screening assessments will be performed in the same
 outpatient clinic visit.

 Screening assessments to establish eligibility will include:

 -  Age

 -  Medical History including but not limited to

 -  Neurological Disorder(s)

 -  Respiratory Disorder(s)

 -  Diabetes Mellitus

 -  Psychiatric Disorder(s)

 -  Smoking Status

 -  DCM characteristics

 -  Symptoms

 -  Length of DCM symptoms

 -  Date of DCM diagnosis

 -  MRI image findings and causative pathology

 -  Medication review, including allergy status

 -  Neurological examination

 -  mJOA assessment

 -  Laboratory Tests (FBC, LFT, E/U/C)

 -  Pregnancy test (serum beta HCG) - if female of childbearing potential (within 2 weeks of
 trial treatment start)

 -  ECG

 Following screening assessments, trial-specific baseline assessments will be conducted,
 preferably on the same day.

 -  Demographics (weight (Kg), sex, ethnicity, date of birth)

 -  Employment status

 -  30m walk test

 -  VAS pain

 -  SF-36

 -  EQ-5D/Health Resource usage

 -  Carer QoL (for sub-study)

 -  Review of potential AEs (starting from point of giving informed consent)

 -  A serum sample will be taken for PK studies Optional but highly desirable assessments

 -  GRASSP-Cervical Myelopathy

 -  SCIMv3

 -  NDI

 -  Quick-DASH

 At the end of the visit, the dosing diary will be issued to the patient and instructed on how
 to use it. Participants' eligibility will be confirmed on receipt of results of the
 laboratory tests and they will be randomised to either Ibudilast or placebo. Participants
 will start treatment no later than 2 weeks after screening visit. One week after IMP delivery
 or collection, the local research team will make contact with the participant by telephone to
 ensure they have received the IMP and commenced their trial treatment. Any Adverse Events
 which may have occurred since consent will be documented in CRFs. Surgery will be performed,
 ideally, within 10 weeks after start of trial treatment.

 Within 21 days prior to surgery, patients will have an outpatient clinic pre-operative visit
 and the following assessments will be performed:

 -  Laboratory Tests (FBC, LFT, E/U/C, TFTs)

 -  Assessment of any change to Medical or Drug history

 -  WHO performance status

 -  Neurological examination

 -  mJOA

 -  30m walk test

 -  VAS pain

 -  SF-36

 -  EQ-5D/Health Resource usage

 -  Carer QoL (for sub-study)

 -  Review of AEs

 -  IMP compliance assessment (participant medication diary review and capsule count)

 -  Respiratory Physiology

 -  MRI

 -  Gait Lab (sub-study for Addenbrooke's only)

 -  A serum sample for PK studies will be taken Optional but highly desirable assessments

 -  GRASSP-Cervical Myelopathy

 -  SCIMv3

 -  NDI

 -  Quick-DASH

 Intra-operative assessments

 -  Surgery details

 -  Operation Title

 -  Approach (Anterior, Posterior or Combined)

 -  Instrumented Procedure?

 -  Level(s) Treated

 -  ASA

 -  Intra-Operative Complications

 -  A CSF sample will be taken (if possible - optional)

 -  A paired serum sample for PK studies will be taken

 Post-operative assessments on discharge (within 14 days after surgery)

 -  Neurological examination

 -  VAS Pain

 -  Adverse Events (including operative complications)

 -  IMP compliance assessment (participant medication diary review and capsule count)

 -  Further IMP will be dispensed

 Optional but highly desirable assessments

 • NDI

 Follow Up assessments at 3 months post-surgery (±21 days)

 -  Laboratory Tests (FBC, LFT, E/U/C, TFTs)

 -  Neurological examination

 -  Medication review

 -  mJOA

 -  30m walk test

 -  VAS pain

 -  SF-36

 -  Carer QoL (for sub-study)

 -  Review of AEs

 -  IMP compliance assessment (participant medication diary review and capsule count)

 -  A serum sample for PK studies will be taken Further IMP will be dispensed. Optional but
 highly desirable assessments

 -  GRASSP-Cervical Myelopathy

 -  NDI

 -  EQ-5D/Health Resource usage

 -  Quick-DASH

 -  Gait Lab (sub-study at Addenbrooke's only)

 Follow Up assessments at 6 months post surgery (±21 days)

 -  Laboratory Tests (FBC, LFT, E/U/C, TFTs)

 -  Neurological examination

 -  Medication review

 -  mJOA

 -  30m walk test

 -  VAS pain

 -  SF-36

 -  EQ-5D/Health Resource usage

 -  Carer QoL (for sub-study)

 -  Review of AEs

 -  IMP compliance (participant medication diary review and capsule count)

 -  Respiratory physiology

 -  MRI

 -  Gait lab (sub-study at Addenbrooke's only)

 -  A serum sample for PK studies will be taken Optional but highly desirable assessments

 -  GRASSP-Cervical Myelopathy

 -  SCIMv3

 -  NDI

 -  Quick-DASH

 Follow Up assessments at 12 months post surgery (±21 days)

 -  Laboratory Tests (FBC, LFT, E/U/C, TFTs)

 -  Medication review

 -  Neurological examination

 -  mJOA

 -  30m walk test

 -  VAS pain

 -  SF-36

 -  EQ-5D/Health Resource usage

 -  Carer QoL (for sub-study)

 -  Review of AEs

 -  A serum sample for PK studies will be taken Optional but highly desirable assessments

 -  GRASSP-Cervical Myelopathy

 -  NDI

 -  Quick-DASH
Inclusion Criteria:

 -  Patients suffering from degenerative cervical myelopathy as per established criteria
 who have granted informed consent to participate in the trial

 -  Have a preoperative mJOA score ≥8 and ≤14

 -  Scheduled for first surgical decompression as part of usual NHS clinical practice

 Exclusion Criteria:

 -  Previous surgery for DCM

 -  DCM symptoms due to cervical trauma (at the discretion of the investigator)

 -  Hypersensitivity to Ibudilast or any of the formulation components

 -  Evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of
 clinically significant impaired hepatic function through clinical and laboratory
 evaluation including ALP> 1.5x ULN; ALT or AST > 2x ULN; GGT > 3x ULN

 -  Active malignancy defined as history of invasive malignancy, except if the patient has
 received treatment and displayed no clinical signs and symptoms for at least five
 years

 -  Recent history (less than 3 years) of chemical substance dependency or significant
 psychosocial disturbance that may impact the outcome or study participation

 -  Female patients with child bearing potential who are unwilling or unable to use
 reliable methods of contraception

 -  Female patients who are pregnant, lactating or planning pregnancy during the course of
 the trial

 -  Inability to comply with study procedures, IMP regime or follow-up schedule

 -  Unable to take a gelatin based product

 -  Participation in another CTIMP or device within the past 30 days from the time of
 recruitment

 -  Functional disability from a commitment neurological disease that would mask the
 symptoms of DCM (at the discretion of the investigator). Including but not limited to
 stroke with residual disability, cerebellar ataxia, Parkinson's disease, symptomatic
 lumbar stenosis and multiple sclerosis

 -  Resting pulse < 50 bpm, SA or AV block, uncontrolled hypertension, or QTcF > 450 ms

 -  History of stomach or intestinal surgery or any other condition that could interfere
 with or is judged by the Investigator to interfere with absorption, distribution,
 metabolism, or excretion of study drug

 -  Unable to converse, read or write English at primary school level