E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic lateral sclerosis (ALS) |
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E.1.1.1 | Medical condition in easily understood language |
Nervous system disease that attacks nerve cells called neurons in the brain and spinal cord, causing muscles problems. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002026 |
E.1.2 | Term | Amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To evaluate brain microglial reduction, as measured by reduction in TSPO binding, following treatment with BLZ945 in ALS participants by using PET imaging with [11C]-PBR28. - To assess safety-related effects on ECM accumulation under BLZ945 treatment |
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E.2.2 | Secondary objectives of the trial |
- To characterize the PK of BLZ945 in ALS participants - To evaluate safety and tolerability of BLZ945 in ALS participants at the planned doses and dosing regimen(s) - To assess the CYP2C8 pharmacogenomic-PK relationship |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Cohorts 1-5: Able to communicate well with the investigator, to understand and comply with the study visits and procedures of the study. 2. Cohorts 1-5: Written informed consent must be obtained before any assessment is performed. 3. Cohorts 1-5: Male and female participants who are ≥ 18 years at screening, and who are diagnosed with familial or sporadic ALS according to the World Federation of Neurology Revised El Escorial criteria of either bulbar or limb onset. 4. Cohorts 1-4: Able to swallow medication capsules, in the opinion of the investigator. 5. Cohorts 1-5: Disease duration from symptoms onset no longer than 48 months at the screening visit. 6. Cohorts 1-4 and Cohort 5 (PET sub-study): Having a SVC (slow vital capacity) equal to or more than 60% predicted normal value per local standards for gender, height, and age at the screening visit. 7a. Cohorts 1-5: Females of childbearing potential must have a negative pregnancy test at screening and/or baseline. 8. Cohorts 1-4 and Cohort 5 (PET sub-study): High-affinity binders (HAB) to TSPO as evaluated by genotyping for the rs6971 polymorphism in the TSPO gene at the screening visit. 9. Cohorts 1-4 and Cohort 5 (PET sub-study): Baseline PET scan of sufficient image quality, as determined locally by the PET experts, to enable the measurement of [11C]-PBR28 volume of distribution (Vt) in the relevant CNS regions. 10b. Cohort 1-5: Treatment with currently approved therapies is allowed, but participants need to be on a stable dose and regimen for at least 30 days prior to baseline. In case of riluzole, participants need to be on stable dose and regimen for at least 90 days prior to baseline. In case for edaravone, the participant can be included if the initial BLZ945 dosing days can be scheduled off period of the edavarone treatment regimen. 11. Cohorts 1-4 and Cohort 5 (PET sub-study): An Upper Motor Neuron Burden (UMNB) scale ≥25 at the screening visit 12. Cohorts 1-4 and Cohort 5 (PET sub-study): BMI between 18-35 kg/m2 at the screening visit. 13. Cohort 5 extended treatment period: Written informed consent for the extended treatment must be obtained before any assessment in the extended treatment period is performed. 14. Cohort 5 extended treatment period: Having completed the 12-week treatment period. and the 4-week follow-up. 15. Cohort 5 extended treatment period: Females of childbearing potential must have a negative pregnancy test at Week 16 and agree to continue the contraception methods used in the treatment period. |
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E.4 | Principal exclusion criteria |
1a. Cohorts 1-5: A history of clinically significant ECG abnormalities 2. Cohorts 1-5: Active hematologic, hepatic, respiratory disorders that are clinically significant and may jeopardize the patient's safety if participating in the study or limit his/her participation in the study, including ability to tolerate the imaging studies. 3. Cohorts 1-5: Active dementia, neurologic diseases other than ALS, or psychiatric illness that in the opinion of the investigator would limit their participation in the current study. 4. Cohorts 1-5: Use of other investigational drugs within 5 half-lives of screening, or until the expected PD effect has returned to baseline , whichever is longer; or longer if required by local regulations. 5. Cohorts 1-5: History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes. 6. Cohorts 1-5: Presence of human immunodeficiency virus (HIV) infection based on screening lab results . 7. Cohorts 1-5: Evidence of active or latent tuberculosis as assessed by Quantiferon or similar testing as per local practice at screening. 8. Cohorts 1-5: Positive serology for hepatitis B surface antigen, or hepatitis C antibodies confirmed by an appropriate licensed test at screening. 9a. Cohorts 1-5: Signs or symptoms, in the judgement of the investigator, of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to the screening visit. COVID-19 specifically: testing as per local practice for COVID-19 will be completed within 3 days prior to first dosing. Positive COVID-19 test results would exclude participants from being enrolled into this study. 10a. Cohorts 1-5: Cardiac disorders, such as recent cardiac history (within 6 months of screening) of acute coronary syndrome, acute heart failure, or significant ventricular arrhythmia at the screening visit or participants with a history of severe pulmonary hypertension, or cardiac failure class 3 or 4 of the NYHA classification, or history of reduced LVEF (<45%), or individuals with implanted cardiac pacemaker, or defibrillator. 11. Cohorts 1-5: Significant haematological laboratory abnormalities. 12. Cohorts 1-5: Clinical evidence of liver disease or liver injury or any of the following hepatic conditions at the screening visit 13. Cohorts 1-5: Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 14 days after last dose of BLZ945. 14. Cohorts 1-5: Pregnant or nursing female subjects 15. Cohorts 1-5: Sexually active males unless they use condom during intercourse during treatment, for 14 days after stopping BLZ945 and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via semen. 16. Intentionally left blank: removed in amendment 02 17. Cohorts 1-4 and Cohort 5 (PET sub-study): Any contraindications to MRI 18. Cohorts 1-5: Taking medications prohibited by the protocol 19a. Cohorts 1-4 and Cohort 5 (PET sub-study): Any contraindications to the arterial line sampling 20. Cohorts 1-5: History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine or BUN and/or urea values, or abnormal urinary constituents at the screening visit. 21. Cohorts 1-5: Active suicidal ideation 22a. Cohorts 1-5: History of drug abuse or harmful alcohol use within the 12 months prior to dosing within the judgement of the investigator, or as indicated by the laboratory assays conducted during screening. 23. Cohorts 1-5: Inability or unwillingness to undergo repeated venipuncture or arterial cannulation or in the opinion of the investigator, patient would be at increased risk for adverse events related to these procedures. 24. Cohort 5: Active GI conditions such as Barrett's esophagus, achalasia, esophageal varices and active or history of esophageal cancer, pre-existing pancreatic disease at screening visit. 25. Cohort 5: History of active vasculitis or history of autoimmune disease associated with vasculitis (eg., RA, SLE, Sjögrens disease, scleroderma). 26. Cohort 5: History or active cardiac valve disorder, such as clinically significant stenosis or regurgitation (CTCAE grade ≥2), congenital valve disease, or other clinical condition that might affect cardiac valve function (excluding hemodynamically insignificant mitral valve prolapse). 27. Cohort 5: Use of systemic anticoagulation that cannot be temporarily paused before study procedures (lumbar puncture, arterial line placement for PET scan). 28. Cohort 5 extension: Participants planning to initiate treatment with additional approved ALS therapy in the next 24 weeks. 29a. Cohort 5 extension: Clinically relevant changes on CT scan or echocardiography, signs of vasculitis, or evidence of significant medical condition meeting discontinuation criteria at EoT1 or EoS1 even if finding has resolved at EoS1. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Cohort 1-5: Volume of distribution (Vt) in different brain regions for each [11C]-PBR28 PET scan, and change after BLZ945 treatment - Cohort 5: Changes in esophageal wall thickness (based on CT-scans) - Cohort 5: Cardiac valve thickness, cardiac valve function (stenosis and regurgitation based on echocardiography) and Left Ventricular Ejection Fraction (LVEF) as indicator of cardiac function (based on echocardiography) - Cohort 5: Incidence of AEs related to ECM accumulation |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Cohorts 1-4: BS up to Day 5 (or 8); Cohort 5 (PET sub-study): BS up to Week 12
Page 16/33 - BS up to Week 12 - BS up to Week 12 - BS up to EOS |
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E.5.2 | Secondary end point(s) |
- Cohorts 1-4: Plasma: PK parameters (e.g. Cmax, Tmax, AUC, T1/2). - Cohorts 1-4: Urine: renal clearance (CLR) - Cohort 5: BLZ945 plasma concentrations and selected PK parameters (Cmax, Tmax, AUClast, Tlast) - Cohorts 1-5: Relevant clinical findings - as per assessment schedule - on physical examination, neurological examination, vital signs, hematology, chemistry, urinalysis, ECG evaluation, AE and SAE recordings - Cohorts 1-5: CYP2C8 genotype and BLZ945 plasma PK parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Cohorts 1-4: Day 1 and Day 4 (or 7) - Day 1 up to Day 4 (or 7) - Day 1 (Arm#2) and Day 4 (Arm#1) - up to EOS - Cohorts 1-4: Day 1 up to Day 4 (or 7); Cohort 5 (PET sub-study): BS up to Week 9 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Adaptive design (multiple ascending dose study) |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
United States |
Finland |
Sweden |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 27 |