A Safety and Tolerability Study of ILB in Patients With Amyothrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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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)

Detailed Description
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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 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.

Official Title
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A Phase II Pilot Single-arm Safety and Tolerability Study of ILB in Patients With Motor Neurone Disease (MND)/ Amyotrophic Lateral Sclerosis (ALS)

Conditions
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Amyotrophic Lateral Sclerosis, Motor Neuron Disease

Intervention / Treatment
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* Drug: ILB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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 4 Patients requiring Radiologically Inserted Gastrostomy (RIG) or Percutaneous Endoscopic Gastroscopy (PEG) feeding 5. Involvement in any other interventional study involving use of another IMP or biological product, within 3 months of screening 6. Any use of antioxidants, edaravone, tirasemtiv or CK-2127107 within 1 month before the screening visit 7. Any botulinum toxin use within 3 months before the screening visit. 8. Any form of stem cell or gene therapy for the treatment of amyotrophic lateral sclerosis (ALS) 9. Neuroimaging of brain and cervical spine with Magnetic Resonance imaging (MRI) indicating compressive myelopathy as an alternate diagnosis 10. 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 11. Abnormal liver function defined as Aspartate Transaminase (AST) and/or Alanine Transaminase (ALT) >3 times upper limit of normal 12. Any head trauma, intracranial or spinal surgery within 3 months of trial entry 13. Patients who have had recurrent falls will be excluded to reduce the risk of intracerebral haemorrhage with this IMP 14. Current use of an anticoagulant e.g Warfarin, Aspirin, Clopidogrel, any novel anticoagulants (NOAC)s or low molecular weight subcutaneous heparin 15. Uncontrolled severe hypertension defined as systolic blood pressure (SBP) ≥ 220 mmHg or diastolic blood pressure (DBP) ≥120 mmHg 16. Current or previous history of heparin-induced thrombocytopenia 17. Active peptic ulcer disease 18. Known hypersensitivity to sulphur 19. Severe liver insufficiency 20. 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 21. Pulmonary illness (e.g asthma or Chronic Obstructive Pulmonary Disease (COPD)) requiring regular treatment 22. Patient judged to be actively suicidal by the investigator during 3 months before the screening visit 23. Subjects with a diagnosis of another neurodegenerative disease (e.g. Parkinson's disease, Alzheimer's disease and Frontotemporal dementia)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ILB<br>ILB subcutaneous injection | Drug: ILB<br>* Administration will be weekly subcutaneous injections at a dose of 2mg/kg once per week for up to a maximum of 48 weeks<br>* Other names: IBsolvMIR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessed by SAEs and AEs - CTCAE grading | Measured by the incidence of serious adverse events (SAEs) and adverse events (AEs) using CTCAE grading v4.0. The grading is 1-5 depending on the severity of the event (5 being the most serve) | 48 weeks | 
| Safety assessed by SAEs and AEs - Relatedness | there is an option of 5 responses: 1 = unrelated, 2 = unlikely to be related, 3 = possibly related, 4 = probably related, 5 = definitely related | 48 weeks | 
| Safety assessed by SAEs and AEs - admitted event | Description of the event | 48 weeks | 
| Safety assessed by SAEs and AEs - expectedness | The event will be defined as expected or unexpected based on information provided in the Quick Reference Document | 48 weeks | 
| Safety assessed by SAEs and AEs - sequelae | outcome of event: resolved with or without sequelae | 48 weeks | 
| Tolerability assessed by SAEs | Measured by the incidence of intolerable adverse events. An intolerable adverse event will satisfy all of the following criteria: Associated with a serious adverse event or a drug discontinuation of greater than three weeks; Grade 3, 4 or 5 in severity according to CTCAE version 4; 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. | 48 weeks | 
| Quantity of study drug administered - total drug administered | Total drug administered over the study period (measured in milligrams) | 48 weeks | 
| Quantity of study drug administered - number of administrations | numerical count of injections given | 48 weeks | 
| Quantity of study drug administered - number and length of interruptions | numerical count of injections missed and time period until next injection | 48 weeks | 
| Quantity of study drug administered - number of discontinuations | numerical count of patients who have discontinued treatment | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Revised Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) | This is a functional rating scale, including assessments of communication, mobility, feeding, dressing and respiration. The total score range is 0 - 40; with 0 being the best outcome and 40 being the worst. | 48 weeks | 
| Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) | This patient-reported outcome measures the subjective well-being of patients. It is broader than ALSFRS-R and adds assessment of emotional reactions. There are 5 scales which are calculated and scored: physical mobility, independence, eating and drinking, communication, emotional functioning. | 48 weeks | 
| Urinary p75ECD | This is a biological fluid-based biomarker of ALS disease progression | 48 weeks | 
| NfL in plasma | This is a blood-based biomarker for neurodegeneration | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALS, ILB, Amyotrophic Lateral Sclerosis, Motor Neuron Disease