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

Phase 2

Terminated

• 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 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.

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: 2024-07
• Results First Submitted: 2024-07-30
• Results First Submitted QC: 2025-06-25
• Last Update Submitted: 2025-06-25
• Results First Posted: 2025-06-26
• Last Update Posted: 2025-06-26

Recruitment & Eligibility

• Status: TERMINATED
• 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
5. Involvement in any other interventional study involving use of another Investigational Medicinal Product (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)
24. Pregnant and/or breastfeeding.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ILB® Arm	ILB®	ILB® subcutaneous injection at a dose of 2mg/kg once per week for up to a maximum of 48 weeks

Primary Outcome Measures

Name	Time	Method
Safety Assessed by SAEs and AEs - Measured by Incidence	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	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	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	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	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	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	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	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	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	From baseline to final treatment visit	Total drug administered over the study period (measured in milligrams)
Quantity of Study Drug Administered - Number of Administrations	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	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	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	From baseline to final treatment visit	numerical count of patients who have discontinued study drug treatment

Secondary Outcome Measures

Name	Time	Method
Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Score Change	From baseline to final treatment visit	Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). This patient reported outcome measures the subjective well-being of patients. There are 5 scales which are calculated and scored: physical mobility, independence,eating and drinking, communication,emotional functioning. Each is scored between 0-100. An improved condition is represented by a decreasing sub-scale score. These sub scales are then averaged to make a summary index score. The range of the summary index is 0-100 and an improved condition is represented by decreasing summary index score. For each of the sub-scales and summary index. Interpretation is as follows: 0-19 Never or very rarely, 20-39 rarely experience problems, 40-59 sometimes experience problems,60-79 often experience, 80-100 problems (nearly) always or unable to do at all. The scale of the summary score is also 0-100 with analogous interpretation to the sub scales. An increase in score is a worse outcome.
Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) Score Change	From baseline to final treatment visit	Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 . A functional rating scale including assessments of communication, mobility, dressing and respiration. the total score range is 0-40. An improved condition is represented by decreasing sub-scale score. Interpretation is as follows: 0 being the best outcome and 40 being the worst. Minimum value is 0 and Maximum value is 40 per time-point / questionnaire completion
Urinary p75ECD Change	From baseline to final treatment visit	Urinary p75 extracellular domain (p75ECD) is a biological fluid-based biomarker of ALS disease progression
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	This outcome measure quantifies the amount of drug detectable in the blood after administration over time
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	Tmax (the time the peak concentration occurred) was calculated to characterise the kinetic profile of ILB® in plasma post-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	Cmax (peak concentration of ILB® in plasma post-administration) was calculated to characterise the kinetic profile of ILB® in plasma post-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	AUC0-last (area under the curve time 0 (time of administration) to the last value above the limit of quantification) was calculated to characterise the kinetic profile of ILB® in plasma post-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	t1/2 (terminal half-life of ILB® in plasma post-administration) was calculated to characterise the kinetic profile of ILB® in plasma post-administration
NfL in Plasma Change	from baseline to final treatment visit	Plasma neurofilament light chain (NfL) is a blood-based biomarker for neurodegeneration

Trial Locations

Locations (1)

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