Study to Assess the Effects of PTC857 Treatment in Participants With Amyotrophic Lateral Sclerosis ALS

Study Overview
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Brief Summary
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This study will assess the efficacy and safety of PTC857 treatment in participants diagnosed with ALS.

Detailed Description
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Participants will be randomized to 1 of 2 treatment groups: PTC857 or matching placebo. Following successful completion of the Treatment Period, participants who enter the LTE Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Assess the Efficacy, Safety, Tolerability, PK, and Biomarker Effects of PTC857 in Adult Subjects With Amyotrophic Lateral Sclerosis (CARDINALS)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: PTC857
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: ALS with preserved function, defined as: Onset of the first symptom leading to the diagnosis of ALS ≤24 months at the time of the initial Screening Visit Revised EL Escorial criteria of either: (i) Clinically definite ALS (ii) Clinically probable ALS A total ALSFRS-R score of at least 34 at the start of the Screening Period No significant respiratory compromise as evidenced by slow vital capacity ≥60% at the start of the Screening Period All chronic concomitant medications (both prescription and over the counter), and non-pharmacologic therapy regimens, excluding standard-of-care therapy riluzole, edaravone, or sodium phenylbutyrate/taurursodiol, should be stable and unchanged from 14 days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study Female participants 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. 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. Key Exclusion Criteria: Females who are pregnant or nursing or plan to become pregnant during the study Participants 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 participant or impact the validity of the study results 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 participant's ability to participate in the study or increase the risk of participation for that participant 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 Participant has previously received PTC857 Participant is receiving a combination of edaravone and sodium phenylbutyrate/taurursodiol treatment, where applicable, within 30 days prior to the start of the Screening Period For female participants, any past medical history of breast cancer, regardless of remission status, or any first degree relative with history of breast cancer

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTC857<br>Participants will receive PTC857 during the 24-Week Treatment Period. Following successful completion of the Treatment Period, participants who enter the Long-term Extension (LTE) Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks. | Drug: PTC857<br>* PTC8657 will be administered as an oral solution twice a day.<br>|
| Active Comparator: Placebo<br>Participants will receive matching placebo during the 24-Week Treatment Period. Following successful completion of the Treatment Period, participants who enter the LTE Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks. | Drug: Placebo<br>* Matching placebo will be administered as an oral solution twice a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) Score at Week 24 (Intention-to-Treat [ITT] 1 Analysis Population) | The ITT1 analysis population will include all participants who receive at least 1 dose of study drug and have a decrease in the ALSFRS-R score of between 1 and 4 points (inclusive) during the Screening Period. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in ALSFRS-R Score at Week 24 (ITT2 Analysis Population) | The ITT2 analysis population will include all participants who receive at least 1 dose of study drug. | Baseline, Week 24 | 
| Number of Participants with Treatment-emergent Adverse Events |  | Day 1 through Week 52 | 
| Change from Baseline in Slow Vital Capacity at Week 24 |  | Baseline, Week 24 | 
| Change from Baseline in Sniff Nasal Inspiratory Pressure at Week 24 |  | Baseline, Week 24 | 
| Change from Baseline in Modified Norris Scale Score at Week 24 |  | Baseline, Week 24 | 
| Change from Baseline in ALS Cognitive Behavioral Screen Assessment at Week 24 |  | Baseline, Week 24 | 
| Rate of Needing Respiratory Support/Intubation and/or Death |  | Baseline, Week 24 | 
| Length of Time to Needing Respiratory Support/Intubation and/or Death |  | Baseline, Week 24 | 
| Combined Assessment of Function and Survival (CAFS) Score |  | Week 24 | 
| Change from Baseline in ALS Assessment Questionnaire (ALSAQ-40) Score at Week 24 |  | Baseline, Week 24 | 
| Area under the Concentration-time Curve (AUC) of PTC857 in Plasma |  | Predose through Week 24 | 
| Maximum Observed Concentration (Cmax) of PTC857 in Plasma |  | Predose through Week 24 | 
| AUC of PTC857 in Cerebrospinal Fluid (CSF) |  | Predose through Week 24 | 
| Cmax of PTC857 in CSF |  | Predose through Week 24 |