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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 400
- 试验地点
- 1
- 主要终点
- Change in Visual Analogue Scale (VAS) neck pain
研究概览
简要总结
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.
详细描述
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:
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Assess safety and tolerability of Ibudilast in patients undergoing surgery for DCM
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Assess efficacy of Ibudilast treatment in patients undergoing surgery for DCM
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Investigate disease mechanisms using
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Advanced imaging techniques, including MRI
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Gait analysis
-
Explore the role of novel clinical outcome measures for studies investigating DCM
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double blind
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Ibudilast
Increasing dose of Ibudilast up to 100mg/day for up to 10 weeks prior to cervical decompressive surgery and up to 24 weeks after cervical decompressive surgery
干预措施: Ibudilast (Drug)
Ibudilast
Increasing dose of Ibudilast up to 100mg/day for up to 10 weeks prior to cervical decompressive surgery and up to 24 weeks after cervical decompressive surgery
干预措施: Cervical decompressive surgery (Procedure)
Placebo
Increasing dose of matched placebo containing mannitol instead of ibudilast up to 10 pills/day for up to 10 weeks prior to cervical decompressive surgery and up to 24 weeks after cervical decompressive surgery
干预措施: Cervical decompressive surgery (Procedure)
Placebo
Increasing dose of matched placebo containing mannitol instead of ibudilast up to 10 pills/day for up to 10 weeks prior to cervical decompressive surgery and up to 24 weeks after cervical decompressive surgery
干预措施: Matching placebo (Drug)
结局指标
主要结局
Change in Visual Analogue Scale (VAS) neck pain
时间窗: From baseline to 6 months follow-up
VAS Neck pain is a 10cm horizontal line, on which a patient indicates their level of neck pain from 0 (no pain) to 10 (worst pain).
Change in modified Japanese Orthopaedic Association (mJOA) scale
时间窗: From baseline to 6 months follow-up
The mJOA is an 18-point clinician administered scale (0 worst to 18 best), which evaluates motor dysfunction in upper and lower extremities, loss of sensation and sphincter dysfunction.
次要结局
- MCS-SF36(From baseline to 6 months follow-up)
- PCS-SF36(From baseline to 6 months follow-up)
研究者
Mark R Kotter
Chief Investigator
Cambridge University Hospitals NHS Foundation Trust