ILB Trial

Study titleThis 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)
UK Chief InvestigatorDr Venkataramanan Srinivasan
Research summaryAmyotrophic 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. Neurons receive and send messages from the body to the brain and back to the body and are responsible for controlling voluntary muscle movement. Voluntary muscles produce movements like chewing, walking and talking. ALS is caused by gradual deterioration (degeneration) and death of motor neurons. In ALS, the motor neurons degenerate or die, and stop sending messages to the muscles. Unable to function, the muscles gradually weaken and waste away. Eventually the brain loses its ability to initiate and control voluntary movement.

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) https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-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.

ILB has been developed by a small Swedish industry company called TikoMed. TikoMed along with colleagues at the University of Birmingham have tested this drug in a number of pre-clinical (animal studies) and in 79 humans (69 healthy volunteers and 10 patients with diabetes). Results of these studies indicate there may be some beneficial effects to using ILB in a number of diseases including ALS. This will be the first study in this patient group.

We will invite 15 patients to take part from a single centre in the UK.

Patients will be closely monitored for any side-effects; for changes in ALS symptoms and on their quality of life during and after the study. At the end of the study we will know if ILB is safe and if it is acceptable to ALS patients.

The ALS study

Our research will answer an important question: will ILB be safe and acceptable for patients with ALS. We will do this by measuring the number and severity of unanticipated experiences or reactions (both serious and non-serious) that occur when patients are treated with ILB, these events will be graded, recorded and closely monitored. Similarly we also hope to be able to assess how acceptable the treatment is to ALS patients. In addition to the safety and tolerability assessments we would hope to be able to describe the effect of ILB on patients ALS symptoms, and on their quality of life.

We don’t know if ILB will have any effect on the patients in this study or ALS patients generally but the information gained from this study will help researchers develop future studies in this disease area.

The study can be broken down into 5 key stages:

Stage 1 Screening tests
Stage 2 The start of treatment, within 14 days of the screening tests
Stage 3 Weekly hospital visits for 10 weeks for safety checks and study injections
Stage 4 End of treatment visit at week 12 with additional tests for safety checks
Stage 5 Follow up – includes visits to hospital at 16, 20 and 24 weeks for safety checks
Trial duration

The trial period for patient participation is 24 weeks (6 months). We hope to recruit all 15 patients over an 8- 12 month period.

The broad timetable for the study is as follows: we plan to recruit the first patient in September/October 2018.

Once the last patient has completed the last visit, the data collection will be closed and data analysed. We anticipate a trial report within 12 months of the last patient completing the study. This will be end of quarter one 2020.
Inclusion/exclusion criteriaINCLUSION 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 UMN (increased tone, brisk reflexes) as well as 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) 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, aPTT 30 – 40 seconds, 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 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 Neurone 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 AST and/or 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 Investigational Medicinal Product (IMP) 14. Current use of an anticoagulant e.g Warfarin, Aspirin, Clopidogrel, any novel anticoagulants (NOAC)s or low molecular weight heparin 15. Uncontrolled hypertension 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 patient`s 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, Altzheimers disease and Frontotemporal dementia)
Current statusActive – recruiting
LocationsBirmingham
Contact details
Recruitment group(s)Patients with MND
Recruitment target(s)15 patients.
Key datesActual opening date: 11 March 2019
Recruitment planned end date: 01 February 2020
Funder(s)TIKOMED AB
SponsorUniversity of Birmingham
Study designInterventional drug trial
Intervention (if applicable)Drug: ILB
Phase (if applicable)Phase 2
Outcome measuresPrimary outcome measures:

Safety assessed by SAEs and AEs - CTCAE grading [ Time Frame: 24 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)

Safety assessed by SAEs and AEs - Relatedness [ Time Frame: 24 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 [ Time Frame: 24 weeks ]
Description of the event

Safety assessed by SAEs and AEs - expectedness [ Time Frame: 24 weeks ]
The event will be defined as expected or unexpected based on information provided in the Quick Reference Document

Safety assessed by SAEs and AEs - sequelae [ Time Frame: 24 weeks ]
outcome of event: resolved with or without sequelae

Tolerability assessed by SAEs [ Time Frame: 24 weeks ]
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.

Quantity of study drug administered - total drug administered [ Time Frame: 24 weeks ]
Total drug administered over the study period (measured in milligrams)

Quantity of study drug administered - number of administrations [ Time Frame: 24 weeks ]
numerical count of injections given

Quantity of study drug administered - number and length of interruptions [ Time Frame: 24 weeks ]
numerical count of injections missed and time period until next injection

Quantity of study drug administered - number of discontinuations [ Time Frame: 24 weeks ]
numerical count of patients who have discontinued treatment

Secondary Outcome Measures :
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) [ Time Frame: 24 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.

Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) [ Time Frame: 24 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.


Urinary p75ECD [ Time Frame: 24 weeks ]
This is a biological fluid-based biomarker of ALS disease progression

NfL in plasma [ Time Frame: 24 weeks ]
This is a blood‐based biomarker for neurodegeneration


Other Outcome Measures:
HPLC analyses of purine-pyrimidine metabolites (serum) [ Time Frame: 24 weeks ]
Biomarker analysis - exploratory disease status

HPLC analysis of fat-soluble vitamins and antioxidants (serum) [ Time Frame: 24 weeks ]
Biomarker analysis - exploratory disease status

HPLC analyses of amino acids (AA) and amino-group containing compounds (ACCG) (serum) [ Time Frame: 24 weeks ]
Biomarker analysis - exploratory disease status

Spectrophotometric analysis of lactate [ Time Frame: 24 weeks ]
Biomarker analysis - exploratory disease status
Publications / Results reportsLinks will be provided when papers are published.
Participant Information Sheet