Clinical trial NCT04631471: Regeneration in Cervical Degenerative Myelopathy
Official title: Regeneration in Cervical Degenerative Myelopathy - a Multi-centre, Double-blind, Randomised, Placebo Controlled Trial Assessing the Efficacy of Ibudilast as an Adjuvant Treatment to Decompressive Surgery for Degenerative Cervical Myelopathy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Myelopathy
Spinal Cord Diseases
Keywords: Degenerative
Cervical
Myelopathy
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
First posted: 2020-11-17
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Placebo controlled trial
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: 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

Primary outcomes:
measure: Change in modified Japanese Orthopaedic Association (mJOA) scale
timeFrame: From baseline to 6 months follow-up
measure: Change in Visual Analogue Scale (VAS) neck pain
timeFrame: From baseline to 6 months follow-up
Secondary outcomes:
measure: PCS-SF36
timeFrame: From baseline to 6 months follow-up
measure: MCS-SF36
timeFrame: From baseline to 6 months follow-up
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
Study officials:
affiliation: Cambridge University Hospital, Department of Neurosurgery
name: Benjamin Davies, MD
role: PRINCIPAL_INVESTIGATOR
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