Clinical trial NCT03705390: A Safety and Tolerability Study of ILB in Patients With Amyothrophic Lateral Sclerosis (ALS)
Official title: A Phase II Pilot Single-arm Safety and Tolerability Study of ILB in Patients With Motor Neurone Disease (MND)/ Amyotrophic Lateral Sclerosis (ALS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Keywords: ILB
Amyotrophic Lateral Sclerosis
Motor Neuron Disease
ALS
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: TikoMed AB
name: University Hospital Birmingham
name: Neuregenix
First posted: 2018-10-15
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 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)

Primary outcomes:
measure: Safety assessed by SAEs and AEs - CTCAE grading
timeFrame: 48 weeks
measure: Safety assessed by SAEs and AEs - Relatedness
timeFrame: 48 weeks
measure: Safety assessed by SAEs and AEs - admitted event
timeFrame: 48 weeks
measure: Safety assessed by SAEs and AEs - expectedness
timeFrame: 48 weeks
measure: Safety assessed by SAEs and AEs - sequelae
timeFrame: 48 weeks
measure: Tolerability assessed by SAEs
timeFrame: 48 weeks
measure: Quantity of study drug administered - total drug administered
timeFrame: 48 weeks
measure: Quantity of study drug administered - number of administrations
timeFrame: 48 weeks
measure: Quantity of study drug administered - number and length of interruptions
timeFrame: 48 weeks
measure: Quantity of study drug administered - number of discontinuations
timeFrame: 48 weeks
Secondary outcomes:
measure: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R)
timeFrame: 48 weeks
measure: Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)
timeFrame: 48 weeks
measure: Urinary p75ECD
timeFrame: 48 weeks
measure: NfL in plasma
timeFrame: 48 weeks
Other outcomes:
measure: HPLC analyses of purine-pyrimidine metabolites (serum)
timeFrame: 48 weeks
measure: HPLC analysis of fat-soluble vitamins and antioxidants (serum)
timeFrame: 48 weeks
measure: HPLC analyses of amino acids (AA) and amino-group containing compounds (ACCG) (serum)
timeFrame: 48 weeks
measure: Spectrophotometric analysis of lactate
timeFrame: 48 weeks
Locations:
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
state: West Midlands
Study officials:
affiliation: University of Birmingham
name: Venkataramanan Srinivasan, MD
role: PRINCIPAL_INVESTIGATOR
References: