A Study to Evaluate the Safety, Tolerability and Efficacy of ILB in Patients With Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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This is a Phase 2a single-centre, open single-arm study in patients with Amyotrophic Lateral Sclerosis (ALS) of intermediate progression rate. Eligible subjects will be administered weekly doses of ILB. A total of 5 subcutaneous (s.c.) doses will be administered at the study clinic. The study consists of 10 visits; One 2-part screening visit, 5 ILB administration visits, and 3 follow-up visits. Each individual patient's study participation will be 4 months, including the screening and follow-up visits. Fifteen patients are planned to be included. The primary objective of the study is to evaluate the safety and tolerability of ILB in patients diagnosed with ALS. ILB is a solution for subcutaneous (s.c.) injection in saline solution. The dose administered will depend on the subject's body weight at the second study visit, prior to the first ILB administration. No formal sample size calculation has been performed for this study. The proposed sample size is considered sufficient in this early phase 2 development to provide adequate information on the patients. Categorical data will be presented as counts and percentages. Continuous data will be summarised using descriptive statistics.

Official Title
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A Single-centre, Open Single-arm Study Where the Safety, Tolerability and Efficacy of Subcutaneously Administered ILB Will be Evaluated in Patients With Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: ILB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the study. Clinical diagnosis of Amyotrophic Lateral Sclerosis (ALS). Male or female patients between 18 to 80 years (inclusive). Forced Vital Capacity (FVC) 65% of predicted value for gender, height and age at screening. Evaluated with ALSFRS-R and Norris clinical rating scales for at least the past 4 weeks before study drug administration. Exclusion criteria Unable to understand information about the study or are expected not to collaborate with the study team. Concurrent serious disease, other than ALS, at the discretion of the nvestigator. Pregnancy. Patients of childbearing potential not willing to use adequate double contraception with less than 1 percentage failure rate after the screening visit until the last visit. Addiction to drugs or alcohol. Confirmed HIV, hepatitis B or hepatitis C. Known bleeding disorders or abnormal bleeding events. Treatment with anticoagulant drugs warfarin and novel oral anticoagulants (NOAC) within the last 14 days prior to screening. Treatment with Riluzole or Lamotrigine within the last 28 days prior to study drug administration. Hypersensitivity to dextran sulfate. Poor venous access. Patients with clinically significant abnormal PK-INR, fibrinogen, von Willebrand factor and activated partial thromboplastin time (APTT) at screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 treatment | Drug: ILB<br>* The investigational medicinal product ILB will be given as single short-term s.c. injections in the abdomen, the thigh or the buttock, in that order of priority. Subjects will be observed for at least 3 hours after injection.The IMP is a sterile, colourless to pale yellow solution for subcutaneous injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency, seriousness and intensity of Treatment-emergent Adverse Events (TEAEs) | A TEAE is any adverse event (AE) not present prior to the initiation of IMP administration or any event already present that worsens in either intensity or frequency following exposure to the IMP. AEs (including baseline events) identified using any of the following methods will be recorded: AEs spontaneously reported by the subject AEs observed by the Investigator or medical personnel AEs elicited based on non-leading questions from the Investigator or medical personnel | up to 3 months | 
| Change in physical status | A complete physical examination according to clinical praxis will be performed, including assessment of the head, eyes, ears, nose, throat (EENT), cardiac, peripheral vascular, pulmonary, musculoskeletal, neurologic, abdominal, lymphatic and dermatological functions. According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in vital signs - blood pressure | Percent change in blood pressure (mmHg) from baseline at 3 months | up to 3 months | 
| Change in electrocardiogram (ECG) recordings | Change in single 12-lead ECG (PQ/PR (ms), QRS (ms), QT (ms) and QTcF (ms)) from baseline at 3 months | up to 3 months | 
| Change in vital signs - heart rate | Percent change in heart rate (bpm, beats per minute) from baseline at 3 months | up to 3 months | 
| Change in vital signs - body temperatue | Percent change in body temperature (degrees Celsius) from baseline at 3 months | up to 3 months | 
| Change in safety laboratory measurements - sodium, potassium, chloride, calcium, glucose (non-fasting) | According to clinical praxis, laboratory tests for sodium, potassium, chloride, calcium, glucose (non-fasting) will be analysed. Unit of measure is mmol/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in safety laboratory measurements - albumin | According to clinical praxis, laboratory test for albumin will be analysed. Unit of measure is g/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in safety laboratory measurements - AST, ALT, CK, alkaline phosphatase | According to clinical praxis, laboratory tests for aspartate amino-transferase (AST), alanine amino-transferase (ALT), creatine kinase (CK) and alkaline phosphatase will be analysed. Unit of measure is micro-kat/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in safety laboratory measurements - creatinine and total bilirubin | According to clinical praxis, laboratory tests for creatinine and total bilirubin will be analysed. Unit of measure is micro-mol/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in safety laboratory measurements - myoglobin | According to clinical praxis, laboratory test for myoglobin will be analysed. Unit of measure is micro-g/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in safety laboratory measurements - CRP | According to clinical praxis, laboratory test for C-reactive protein (CRP) will be analysed. Unit of measure is milli-g/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in hematology laboratory measurements - Hemoglobin and fibrinogen | According to clinical praxis, laboratory tests for hemoglobin (Hb) and fibrinogen will be analysed. Unit of measure is g/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in hematology laboratory measurements - Red blood cell count | According to clinical praxis, laboratory test for blood cell count (RBC) will be analysed. Unit of measure is 10x12/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in hematology laboratory measurements - WBC, platelets, basophils, eosinophils, lymphocytes, monocytes, neutrophils | According to clinical praxis, laboratory tests for white blood cell count (WBC), platelets, basophils, eosinophils, lymphocytes, monocytes and neutrophils will be analysed. Unit of measure is 10x9/L According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in hematology laboratory measurements - APTT | According to clinical praxis, laboratory test for activated partial thromboplastin time (aPTT) will be analysed. Unit of measure is s According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 
| Change in hematology laboratory measurements - PK-INR | According to clinical praxis, laboratory test for prothrombin kinase international normalized ratio (PK-INR) will be analysed. Unitless measure According to clinical praxis each function is judged as either normal or abnormal, and either clinically significant (CS) or not clinically significant (NCS) Change from baseline at 3 months. | up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in functional rating with Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) | The ALSFRS-R provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The ALSFRS-R includes questions that ask the physician to rate his/her impression of the patients level of functional impairment in performing one of twelve common tasks. Each task is rated on a five-point scale from 0 = can't do, to 4 = normal ability. Individual item scores are summed to produce a reported score of between 0=worst and 48=best Absolute change from baseline at 3 months | up to 3 months | 
| Change in functional rating with Norris rating scale | The Norris rating scale provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The Norris rating scale includes questions that ask the physician to rate his/her impression of the patients level of functional impairment in performing one of 34 common tasks and bodily functions. Each task or function is rated on a four-point scale from 0 = can't do, to 3 = normal ability. Individual item scores are summed to produce a reported score of between 0=worst and 100=best Absolute change from baseline at 3 months | up to 3 months | 
| Change in pulmonary function (FVC) from baseline |  | up to 3 months | 
| Change in Quality of Life (QoL) assessed by visual analogue scale (VAS) | Questionnaire with three questions for patient and next-of-kin self reporting of: general health status physical health status mental health status Each item is rated on a millimeter scale from 0 = very bad, to 100 = very good Absolute change from baseline at 3 months | up to 1.5 months | 
| Change in functional rating of autonomous and sensory symptoms | The autonomous and sensory rating scale provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The rating scale includes questions that ask the physician to rate his/her impression of the patients level of impairment in 16 autonomous and sensory functions. Each function is rated on a four-point scale from 0 = not impaired, to 3 = very impaired. Absolute change from baseline at 3 months | up to 3 months | 
| Change in maximum plasma concentration (Cmax) of ILB |  | up to 1 month | 
| Change in exposure (Area Under the Curve, AUC) of ILB |  | up to 1 month | 
| Changes in APTT (effect APTT) from day of dosing (day 1) |  | up to 1 month | 
| Change in plasma concentration of hepatocyte growth factor (HGF) |  | up to 1 month |