A Phase II Pilot Single-arm Safety and Tolerability Study of ILB® in Patients With Motor Neurone Disease (MND)/ Amyotrophic Lateral Sclerosis (ALS)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Safety Assessed by SAEs and AEs - Measured by Incidence
研究概览
简要总结
This is a phase II study to determine the safety and tolerability of ILB®, a type of low molecular weight dextran sulfate, in patients with Motor Neurone Disease (MND)/ Amyotrophic Lateral Sclerosis (ALS)
详细描述
Amyotrophic Lateral Sclerosis (ALS) belongs to a wider group of disorders known as motor neuron diseases and mainly involves the nerve cells (neurons) in the body. Voluntary muscles produce movements like chewing, walking and talking. ALS is caused by gradual deterioration (degeneration) and death of these motor neurons. The disease is progressive, meaning the symptoms get worse over time and most people with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first appear. Currently there is no cure for ALS and no effective treatment to halt or reverse the progression of the disease (National Institute of Neurological Disorders and Stroke, Fact Sheet).
The aim of this study is to explore the safety and acceptability of a type of low molecular weight dextran sulfate called ILB®.
The investigators will invite 15 patients to take part from a single centre in the United Kingdom (UK). Participants will be closely monitored for any side-effects; for changes in ALS symptoms and on quality of life during and after the study.
The trial period for patient participation is maximum 56 weeks (12 months), ILB® injections will be administered once weekly for up to a maximum of 48 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients ≥18 years and who have provided written informed consent to participate in the study
- •Prior to trial entry patients will have a definite diagnosis of ALS according to El Escorial Criteria. All patients will demonstrate either:
- •presence of Upper Motor Neuron (UMN) (increased tone, brisk reflexes) as well as Lower Motor Neuron (LMN) (weakness,
- •wasting and fasciculation) signs in the bulbar region and at least two of the other spinal regions (cervical, thoracic or lumbosacral) or
- •presence of UMN and LMN signs in all three spinal regions (cervical, thoracic or lumbosacral)
- •Electrophysiological tests (Electromyography (EMG) / Nerve Conduction Study (NCS)) that supports the diagnosis of Motor Neurone Disease (MND) and to exclude mimic disorders
- •Forced Vital Capacity (FVC) ≥50% of predicted value for gender, height and age at screening and a mean Sniff Nasal Inspiratory Pressure (SNIP) ≥50% of predicted value for age
- •Adequate haematological function (Hb≥10g/dl absolute neutrophil count ≥1.5x109/L and a platelet count ≥60 x109/L
- •International Normalised Ratio (INR) ≤ 1.5, Activated Partial Thromboplastin Time (aPTT) 30 - 40 seconds, Prothrombin Time (PT) 11-13.5 seconds
- •Patient willing and able to comply with schedule visits, treatment plan and other study procedures.
- •Patients taking Riluzole must have discontinued treatment ≥28 days prior to study entry (and following consent to take part in the study)
- •Women Of Child Bearing Potential (WOCBP) who agree to use highly effective means of contraception (as defined in the Heads of Medicines Agencies_Clinical Trials Facilitation Group (HMA_CTFG) guideline (see Appendix 8) and in combination with a barrier contraception method (condom, diaphragm or cap) for the entirety of the study
排除标准
- •Patients classified as either probable or possible ALS according to El Escorial Criteria.
- •Subjects in whom other causes of neuromuscular weakness have not been excluded
- •Assisted ventilation of any type within 3 months before the screening visit or at screening
- •Patients requiring Radiologically Inserted Gastrostomy (RIG) or Percutaneous Endoscopic Gastroscopy (PEG) feeding
- •Involvement in any other interventional study involving use of another Investigational Medicinal Product (IMP) or biological product, within 3 months of screening
- •Any use of antioxidants, edaravone, tirasemtiv or CK-2127107 within 1 month before the screening visit
- •Any botulinum toxin use within 3 months before the screening visit.
- •Any form of stem cell or gene therapy for the treatment of amyotrophic lateral sclerosis (ALS)
- •Neuroimaging of brain and cervical spine with Magnetic Resonance imaging (MRI) indicating compressive myelopathy as an alternate diagnosis
- •Laboratory examinations including Acetylcholine receptor (AChR) antibodies and Muscle Specific Kinase (MuSK) antibodies to exclude Bulbar onset Myasthenia gravis from Bulbar onset Motor neuron disease as an alternate diagnosis and Antinuclear Antibodies (ANA), Anti-neutrophil cytoplasmic antibodies (ANCA), Extractable Nuclear Antigen (ENA) antibodies, Creatine Kinase (CK), electrophoresis and immunoglobulin indicating an alternate diagnosis for muscle disease like Myositis
- •Abnormal liver function defined as Aspartate Transaminase (AST) and/or Alanine Transaminase (ALT) >3 times upper limit of normal
- •Any head trauma, intracranial or spinal surgery within 3 months of trial entry
- •Patients who have had recurrent falls will be excluded to reduce the risk of intracerebral haemorrhage with this IMP
- •Current use of an anticoagulant e.g Warfarin, Aspirin, Clopidogrel, any novel anticoagulants (NOAC)s or low molecular weight subcutaneous heparin
- •Uncontrolled severe hypertension defined as systolic blood pressure (SBP) ≥ 220 mmHg or diastolic blood pressure (DBP) ≥120 mmHg
- •Current or previous history of heparin-induced thrombocytopenia
- •Active peptic ulcer disease
- •Known hypersensitivity to sulphur
- •Severe liver insufficiency
- •Patients with evidence of major psychiatric illness, significant cognitive impairment or clinically evident dementia that may interfere with the patients' ability to comply with study procedures
- •Pulmonary illness (e.g asthma or Chronic Obstructive Pulmonary Disease (COPD)) requiring regular treatment
- •Patient judged to be actively suicidal by the investigator during 3 months before the screening visit
- •Subjects with a diagnosis of another neurodegenerative disease (e.g. Parkinson's disease, Alzheimer's disease and Frontotemporal dementia)
- •Pregnant and/or breastfeeding.
研究组 & 干预措施
ILB® Arm
ILB® subcutaneous injection at a dose of 2mg/kg once per week for up to a maximum of 48 weeks
干预措施: ILB® (Drug)
结局指标
主要结局
Safety Assessed by SAEs and AEs - Measured by Incidence
时间窗: From informed consent up to 30 days after last administration of trial treatment
Measured by the number of serious adverse events (SAEs) and adverse events (AEs) using CTCAE grading v4.0.
Safety Assessed by AEs - Summarised by Grade
时间窗: From informed consent up to 30 days after last administration of trial treatment
Grade refers to the severity of the AE as follows: Grade 1 - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 - Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 - Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 - Life-threatening consequences; urgent intervention indicated. Grade 5 - Death related to AE.
Safety Assessed by AEs - Summarised by Relatedness
时间窗: From informed consent up to 30 days after last administration of trial treatment
Relatedness categories: 1 = unrelated, 2 = unlikely to be related, 3 = possibly related, 4 = probably related, 5 = definitely related
Safety Assessed by SAEs - Summarised by Admitting Event Grade
时间窗: From informed consent up to 30 days after last administration of trial treatment
Grade refers to the severity of the admitting event as follows: Grade 1 - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 - Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3 - Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 - Life-threatening consequences; urgent intervention indicated. Grade 5 - Death related to AE.
Safety Assessed by SAEs - Summarised by Admitting Event Relatedness
时间窗: From informed consent up to 30 days after last administration of trial treatment
Relatedness categories: 1 = unrelated, 2 = unlikely to be related, 3 = possibly related, 4 = probably related, 5 = definitely related
Safety Assessed by SAEs - Summarised by Admitting Event Type
时间窗: From informed consent up to 30 days after last administration of trial treatment
Description of the main event type - primary cause of admission (body system, Adverse event term and grade)
Safety Assessed by SAEs - Summarised by Expectedness
时间窗: From informed consent up to 30 days after last administration of trial treatment
Serious Adverse Events only will be defined as expected or unexpected based on information provided in the Quick Reference Document
Safety Assessed by SAEs - Summarised by Sequelae
时间窗: From informed consent up to 30 days after last administration of trial treatment
Outcome of serious adverse events only: Resolved with sequelae or Resolved without sequelae
Tolerability Assessed by the Incidence of Intolerable Adverse Events
时间窗: From informed consent up to 30 days after last administration of trial treatment
An intolerable adverse event will satisfy all of the following criteria: 1. Associated with a serious adverse event or a drug discontinuation of greater than three weeks; 2. Grade 3, 4 or 5 in severity according to CTCAE version 4; 3. In the opinion of the Investigator is i) definitely related or ii) probably related or iii) possibly related to the study drug treatment. Adverse events which are considered unrelated or probably not related will not be classed as intolerable events.
Quantity of Study Drug Administered - Total Drug Administered
时间窗: From baseline to final treatment visit
Total drug administered over the study period (measured in milligrams)
Quantity of Study Drug Administered - Number of Administrations
时间窗: From baseline to final treatment visit
Numerical count of the number of study drug injections given whilst on the trial
Quantity of Study Drug Administered - Number of Interruptions
时间窗: From baseline to final treatment visit
Numerical count of the number of study drug injections missed whilst on the trial
Quantity of Study Drug Administered - Duration of Interruptions
时间窗: From baseline to final treatment visit
Length of interruptions in weeks between study drug injections for those participants that experienced a treatment interruption whilst on the trial
Quantity of Study Drug Administered - Number of Discontinuations
时间窗: From baseline to final treatment visit
numerical count of patients who have discontinued study drug treatment
次要结局
- Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Score Change(From baseline to final treatment visit)
- Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) Score Change(From baseline to final treatment visit)
- Urinary p75ECD Change(From baseline to final treatment visit)
- Pharmacokinetics (PK; Amount of Detectable Drug) of ILB® in Plasma Following Administration(0.5,1,2,2.5,3,4 and 6 hours post first ILB® administration)
- Pharmacokinetics (PK; Tmax) Statistics of ILB® in Plasma Following Administration(0.5,1,2,2.5,3,4 and 6 hours post first ILB® administration)
- Pharmacokinetics (PK; Cmax) Statistics of ILB® in Plasma Following Administration(0.5,1,2,2.5,3,4 and 6 hours post first ILB® administration)
- Pharmacokinetics (PK; AUC0-last) Statistics of ILB® in Plasma Following Administration(0.5,1,2,2.5,3,4 and 6 hours post first ILB® administration)
- Pharmacokinetics (PK; t1/2) Statistics of ILB® in Plasma Following Administration(0.5,1,2,2.5,3,4 and 6 hours post first ILB® administration)
- NfL in Plasma Change(from baseline to final treatment visit)