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 |
Amyotrophic Lateral Sclerosis is a type of Motor Neurone Disease. It is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. |
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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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of PTC857 in reducing disease progression in subjects with ALS. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives: 1. Safety and tolerability of PTC857 in subjects with ALS 2. Respiratory function in subjects randomized to PTC857 vs placebo 3. Motor/limb and bulbar function in subjects randomized to PTC857 vs placebo 4. Neuropsychological function in subjects randomized to PTC857 vs placebo 5. Survival in subjects randomized to PTC857 vs placebo 6. Quality of life via ALSQ-40 in subjects randomized to PTC857 vs placebo 7. PK of PTC857 Exploratory Objectives: 1. Effects on biomarker activity in subjects randomized to PTC857 vs placebo 2. Quality of life via EQ-5D-5L in subjects randomized to PTC857 vs placebo Long-Term Extension Period Objectives: 1. Disease progression, survival, neuropsychological function,respiratory function, motor/limb and bulbar function, and effects on biomarker activity upon long-term treatment with PTC857 2. Safety and tolerability upon long-term treatment with PTC857 3. Quality of life upon long-term treatment with PTC857 4. PK of PTC857 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetics sub-study |
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E.3 | Principal inclusion criteria |
1. Males or females aged between 18 and 80 years at the time of the initial Screening Visit 2. ALS with preserved function, defined as: a. Onset of the first symptom leading to the diagnosis of ALS ≤24 months at the time of the initial Screening Visit b. Revised El Escorial criteria of either: (i) Clinically definite ALS (ii) Clinically probable ALS 3. A total ALSFRS-R score of at least 34 at the start of the Screening Period 4. No significant respiratory compromise as evidenced by slow vital capacity ≥60% at the start of the Screening Period 5. All chronic concomitant medications (both prescription and over the counter [OTC]) and non pharmacologic therapy regimens, excluding standard-of-care therapy riluzole, edaravone, or sodium phenylbutyrate/taurursodiol, and non pharmacologic therapy regimens should be stable and unchanged from at least 14 days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study 6. Female subjects must have a negative breast cancer imaging screening status (not considered clinically abnormal and/or requiring further evaluation/treatment) within 6 months prior to the Screening Visit or during the Screening Period 7. Standard-of-care therapy for the treatment of ALS (riluzole, edaravone, or sodium phenylbutyrate/taurursodiol) should be stable and unchanged from 30 (-3) days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study
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E.4 | Principal exclusion criteria |
1. Females who are pregnant or nursing or plan to become pregnant during the study 2. Subjects with clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular/ischemic disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the subject or impact the validity of the study results 3. Any clinically significant medical or psychiatric condition or medical history that, in the opinion of the investigator or the medical monitor, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject 4. Current participation in any other investigational study with an investigational product or participation within 30 days prior to the start of the Screening Period or 5 half-lives of the previously taken investigational drug, whichever is longer 5. Subject has previously received PTC857 6. Subject is receiving a combination of edaravone and sodium phenylbutyrate/taurursodiol treatment, where applicable, within 30 (-3) days prior to the start of the Screening Period 7. For female subjects, any past medical history of breast cancer, regardless of remission status, or any first degree relative with history of breast cancer
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) in the modified Intent-to-Treat 1 (ITT1) Analysis Set after 24 weeks of treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints: 1. Change from baseline in ALSFRS-R in the Intent-to-Treat 2 (ITT2) Analysis Set after 24 weeks of treatment 2. Safety and tolerability of PTC857 as measured by the severity and number of TEAEs and TESAEs, and change in clinical laboratory tests, physical examination, vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS), and 12-lead electrocardiograms (ECGs) during the Treatment Period 3. Change from baseline in respiratory function as assessed by pulmonary function tests (PFTs) after 24 weeks of treatment 4. Change from baseline in motor/limb and bulbar function as assessed by the Modified Norris Scale after 24 weeks of treatment 5. Change from baseline in neuropsychological function as assessed by the ALS Cognitive Behavioral Screen (ALS CBS) after 24 weeks of treatment 6. Survival as assessed by rate of and length of time to needing respiratory support/intubation and/or death 7. Survival and functional change as assessed by the Combined Assessment of Function and Survival (CAFS) after 24 weeks of treatment 8. Quality of life as assessed by Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) after 24 weeks of treatment 9. Plasma PK and cerebrospinal fluid (CSF) exposure of PTC857
Exploratory Endpoints: 1. Change from baseline in blood, urine, and CSF biomarker activity after 24 weeks of treatment 2. Quality of life as assessed by the EQ-5D-5L after 24 weeks of treatment Long-Term Extension Endpoints: 1. Severity and number of TEAEs and TESAEs, change in clinical laboratory tests, physical examination, vital signs, and 12-lead ECGs during the LTE Period 2. Change from baseline in ALSFRS-R after 52 weeks of treatment 3. Change from baseline in respiratory function as assessed by PFTs after 52 weeks of treatment 4. Change from baseline in motor/limb and bulbar function as assessed by the Modified Norris Scale after 52 weeks of treatment 5. Change from baseline in neuropsychological function as assessed by the ALS CBS after 52 weeks of treatment 6. Survival after 52 weeks of treatment 7. Time to needing respiratory support/intubation and/or death with long-term treatment 8. Quality of life as assessed by ALSAQ-40 after 52 weeks of treatment 9. Quality of life as assessed by EQ-5D-5L after 52 weeks of treatment 10. Change from baseline in blood and urine biomarker activity after 52 weeks of treatment 11. PK of PTC857 Continued Long-Term Extension Period Endpoints: 1. Severity and number of TEAEs and TESAEs during the Continued LTE Period 2. Change from baseline in ALSFRS-R after 160 weeks of treatment 3. Survival after 160 weeks of treatment 4. Time to needing respiratory support/intubation and/or death after 160 weeks of treatment 5. Quality of life as assessed by ALSAQ-40 after 160 weeks of treatment
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary and Exploratory Endpoints: 24 weeks Long-Term Extension Period Endpoints: 52 weeks Continued Long-Term Extension Period Endpoints: 160 weeks |
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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 | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
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 | 43 |
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 |
Argentina |
Australia |
Brazil |
Japan |
Mexico |
United States |
Belgium |
Czechia |
France |
Germany |
Ireland |
Italy |
Netherlands |
Norway |
Poland |
Spain |
Sweden |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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LVLS - A subject is considered to have completed the study if she/he has completed all Part C study visits (or Part A if they are not participating in the optional LTE Period, or Part A and B if they are not participating in the optional continued LTE Period), including the follow-up telephone call. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 11 |