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

Phase 2

Completed

• Conditions: Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Interventions: Drug: ILB

• Registration Number: NCT03705390
• Lead Sponsor: University of Birmingham

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2018-09-11
• Study First Submitted QC: 2018-10-10
• Study First Posted: 2018-10-15
• Study Start: 2019-03-29
• Primary Completion: 2021-07-28
• Study Completion: 2021-07-28
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-04
• Last Update Posted: 2021-10-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 11

Inclusion Criteria

1. Patients ≥18 years and who have provided written informed consent to participate in the study

2. 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)

3. Electrophysiological tests (Electromyography (EMG) / Nerve Conduction Study (NCS)) that supports the diagnosis of Motor Neurone Disease (MND) and to exclude mimic disorders

4. 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

5. Adequate haematological function (Hb≥10g/dl absolute neutrophil count ≥1.5x109/L and a platelet count ≥60 x109/L

6. International Normalised Ratio (INR) ≤ 1.5, Activated Partial Thromboplastin Time (aPTT) 30 - 40 seconds, Prothrombin Time (PT) 11-13.5 seconds

7. Patient willing and able to comply with schedule visits, treatment plan and other study procedures.

8. Patients taking Riluzole must have discontinued treatment ≥28 days prior to study entry (and following consent to take part in the study)

9. 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

1. Patients classified as either probable or possible ALS according to El Escorial Criteria.

2. Subjects in whom other causes of neuromuscular weakness have not been excluded

3. 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

4. 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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ILB	ILB	ILB subcutaneous injection

Primary Outcome Measures

Name	Time	Method
Quantity of study drug administered - number and length of interruptions	48 weeks	numerical count of injections missed and time period until next injection
Safety assessed by SAEs and AEs - CTCAE grading	48 weeks	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)
Tolerability assessed by SAEs	48 weeks	Measured by the incidence of intolerable adverse events. 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.
Safety assessed by SAEs and AEs - expectedness	48 weeks	The event will be defined as expected or unexpected based on information provided in the Quick Reference Document
Quantity of study drug administered - total drug administered	48 weeks	Total drug administered over the study period (measured in milligrams)
Quantity of study drug administered - number of administrations	48 weeks	numerical count of injections given
Safety assessed by SAEs and AEs - Relatedness	48 weeks	there is an option of 5 responses: 1 = unrelated, 2 = unlikely to be related, 3 = possibly related, 4 = probably related, 5 = definitely related
Safety assessed by SAEs and AEs - admitted event	48 weeks	Description of the event
Safety assessed by SAEs and AEs - sequelae	48 weeks	outcome of event: resolved with or without sequelae
Quantity of study drug administered - number of discontinuations	48 weeks	numerical count of patients who have discontinued treatment

Secondary Outcome Measures

Name	Time	Method
NfL in plasma	48 weeks	This is a blood-based biomarker for neurodegeneration
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R)	48 weeks	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.
Urinary p75ECD	48 weeks	This is a biological fluid-based biomarker of ALS disease progression
Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)	48 weeks	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.

Trial Locations

Locations (1)

University Hospitals Birmingham NHS Foundation Trust; 🇬🇧 Birmingham, West Midlands, United Kingdom