Conditions: Amyotrophic Lateral Sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 336
Healthy volunteers: no

Brief summary:
This study will assess the efficacy and safety of PTC857 treatment in participants diagnosed with ALS.

Detailed description:
Participants will be randomized to 1 of the 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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: PTC857 intervention 2: Placebo
Intervention descriptions: intervention 1: PTC8657 will be administered as an oral solution twice a day. intervention 2: Matching placebo will be administered as an oral solution twice a day.

Protocol document:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
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) 
PTC857-CNS-001-ALS 
14 JUNE 2024 
VERSION 6.0 
PTC THERAPEUTICS, INC. 
500 WARREN CORPORATE CENTER DRIVE 
WARREN, NJ 07059 US 
NCT #: NCT05349721


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Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach of this 
obligation, PTC Therapeutics, Inc. should be notified promptly.


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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC857 
Therapeutic Area 
Amyotrophic Lateral Sclerosis (ALS) 
PTC Therapeutics Substance Identiﬁer 
PTC857 
Protocol Number 
PTC857-CNS-001-ALS 
Protocol Version 
6.0 
Protocol Version Date 
14 June 2024 
Protocol Phase 
Phase 2 
EudraCT Number 
2021-006511-29 
EU CT Number 
2023-510317-26-00 
Protocol Title 
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) 
PTC Clinical Lead 
 
PTC Therapeutics, Inc. 
500 Warren Corporate Center Drive 
Warren, NJ 07059 US 
Telephone: 
 
Email: 
 
PTC Medical Monitor 
 
PTC Therapeutics, Inc. 
500 Warren Corporate Center Drive 
Warren, NJ 07059 US 
Telephone: 
 
Email: 
 
PTC Study Manager 
 
PTC Therapeutics, Inc. 
500 Warren Corporate Center Drive 
Warren, NJ 07059 US 
Telephone: 
 
Email: 
 


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PTC Biostatistician 
 
PTC Therapeutics, Inc. 
500 Warren Corporate Center Drive 
Warren, NJ 07059 US 
Telephone: 
 
Email: 
 


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PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
 
Date 


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The eSignature Page is located on the last page. 


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PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE 
 
I have read the protocol document and, on behalf of my institution, agree to comply with the protocol and 
all applicable regulations. 
 
 
 
 
 
Principal Investigator 
 
Date 
 
 
 
 
 
 
Institution: 
 
Address: 
 
City: 
 
State/Province: 
 
Country: 
 
Telephone: 
 
Fax: 
 
Email: 
 


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SYNOPSIS 
Name of Sponsor/Company: PTC Therapeutics, Inc. (PTC) 
Name of Investigational Product: PTC857 
Name of Active Ingredient: PTC857 
Protocol Number: PTC857-CNS-001-ALS 
Phase: 2 
Regions: 
1. Global 
Title of Study: 
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) 
Study Period: 
The entire study duration for each subject is approximately 172 weeks: 
• Screening Period: Approximately 8 weeks 
• Treatment Period (Part A): Approximately 24 weeks 
• Long-Term Extension (LTE) Period (Part B): Approximately 28 weeks 
• Continued LTE Period (Part C): Approximately 108 weeks 
• Post-Treatment Follow-Up Period: Approximately 4 weeks 
Objectives: 
Primary Objective 
To evaluate the eﬃcacy of PTC857 in reducing disease progression in subjects with amyotrophic lateral 
sclerosis (ALS). 
Secondary Objectives 
The secondary objectives of the study are to assess the following in subjects with ALS: 
• Safety and tolerability of PTC857 
• Respiratory function in subjects randomized to PTC857 versus placebo 
• Motor/limb and bulbar function in subjects randomized to PTC857 versus placebo 
• Survival in subjects randomized to PTC857 versus placebo 
• Quality of life via 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire 
(ALSAQ-40) in subjects randomized to PTC857 versus placebo 
• Evaluate the efficacy of PTC857 in reducing disease progression in subjects with ALS 
with any baseline rate of functional decline 
• Effects on plasma neurofilament light chain (NfL) activity in subjects randomized to 
PTC857 versus placebo 
• Pharmacokinetics (PK) of PTC857 
Exploratory Objectives 
The exploratory objectives of the study are to assess the following in subjects with ALS: 
• Neuropsychological function in subjects randomized to PTC857 versus placebo 


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• Effects on mechanistically- and clinically-based biomarker activity in subjects 
randomized to PTC857 versus placebo 
• Quality of life via the five-level European quality of life five-dimensional 
questionnaire (EQ-5D-5L) in subjects randomized to PTC857 versus placebo 
• Exposure-response relationships 
Long-Term Extension Period Objectives 
The objectives of the LTE Period of the study are to assess the following in subjects with ALS: 
• Disease progression, survival, neuropsychological function, respiratory function, 
motor/limb and bulbar function, and effects on biomarker activity upon long-term 
treatment with PTC857 
• Safety and tolerability upon long-term treatment with PTC857 
• Quality of life upon long-term treatment with PTC857 
• PK of PTC857 
Continued Long-Term Extension Period Objectives 
The objectives of the Continued LTE Period of the study are to assess the following in subjects with 
ALS: 
• Safety and tolerability upon continued long-term treatment with PTC857 
• Disease progression and survival upon continued long-term treatment with PTC857 
• Quality of life upon continued long-term treatment with PTC857 
Endpoints: 
Primary Endpoint 
The primary endpoint is subject ranks based on the combined assessment of ALS Functional Rating 
Scale-Revised (ALSFRS-R) and survival after 24 weeks of treatment in the Intent-to-Treat 1 (ITT1) 
Analysis Set. 
Secondary Endpoints 
The secondary endpoints of the study are the following: 
• Subject ranks based on the combined assessment of ALSFRS-R and survival after 
24 weeks of treatment in the Intent-to-Treat 2 (ITT2) Analysis Set 
• Change from baseline in ALSFRS-R in the ITT1 Analysis Set after 24 weeks of 
treatment 
• Change from baseline in ALSFRS-R in the ITT2 Analysis Set after 24 weeks of 
treatment 
• Safety and tolerability of PTC857 as measured by the severity and number of 
treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse 
events (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 
• Change from baseline in slow vital capacity as assessed by pulmonary function tests 
(PFTs) after 24 weeks of treatment 


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• Change from baseline in motor/limb and bulbar function as assessed by the Modified 
Norris Scale after 24 weeks of treatment 
• Survival as assessed by rate of and length of time to death 
• Quality of life as assessed by ALSAQ-40 after 24 weeks of treatment 
• Change from baseline in plasma NfL activity after 24 weeks of treatment 
• Plasma PK and cerebrospinal fluid (CSF) exposure of PTC857 
Exploratory Endpoints 
The exploratory endpoints of the study are the following: 
• Change from baseline in neuropsychological function as assessed by the ALS 
Cognitive Behavioral Screen (ALS CBS) after 24 weeks of treatment 
• Change from baseline in blood, urine, and CSF biomarker activity after 24 weeks of 
treatment 
• Quality of life as assessed by the EQ-5D-5L after 24 weeks of treatment 
• Exposure-response relationships after 24 weeks of treatment 
Long-Term Extension Period Endpoints 
The LTE Period endpoints of this study are the following: 
• Severity and number of TEAEs and TESAEs, change in clinical laboratory tests, 
physical examination, vital signs, and 12-lead ECGs during the LTE Period 
• Change from baseline in ALSFRS-R after 52 weeks of treatment 
• Change from baseline in slow vital capacity as assessed by PFTs after 52 weeks of 
treatment 
• Change from baseline in motor/limb and bulbar function as assessed by the Modified 
Norris Scale after 52 weeks of treatment 
• Change from baseline in neuropsychological function as assessed by the ALS CBS 
after 52 weeks of treatment 
• Survival after 52 weeks of treatment 
• Quality of life as assessed by ALSAQ-40 after 52 weeks of treatment 
• Quality of life as assessed by EQ-5D-5L after 52 weeks of treatment 
• Change from baseline in blood and urine biomarker activity after 52 weeks of 
treatment 
• PK of PTC857 
Continued Long-Term Extension Period Endpoints 
The Continued LTE Period endpoints of this study are the following: 
• Severity and number of TEAEs and TESAEs during the Continued LTE Period 
• Change from baseline in ALSFRS-R after 160 weeks of treatment 
• Survival after 160 weeks of treatment 
• Quality of life as assessed by ALSAQ-40 after 160 weeks of treatment 
Study Design and Methodology: 


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This is a Phase 2, randomized, double-blind, placebo-controlled, parallel study to assess the eﬀects of 
PTC857 treatment in adult male and female subjects diagnosed with ALS. 
The objectives of the study are to evaluate the eﬃcacy, safety, tolerability, PK, and eﬀects on 
biomarkers of PTC857 therapy in subjects with ALS. The study consists of 5 periods: Screening, 
Treatment, LTE, Continued LTE, and Follow-Up. 
Screening Period 
After the written informed consent is signed, all subjects will enter the Screening Period. The 
Screening Period will last approximately 8 weeks. Subjects will complete all activities as per the 
Schedule of Assessments. All subjects who complete the full Screening Period and continue to meet 
the inclusion and exclusion criteria of the study will be eligible to enter the Treatment Period. 
Treatment Period (Part A) 
At the end of the Screening Period, subjects will return to the study center for the Baseline Visit. All 
subjects will be assessed to conﬁrm that they still meet the inclusion and exclusion criteria of the 
study. All subjects who return to the study center and maintain study eligibility at completion of the 
Screening Period will be randomized to 1 of 2 treatment groups: PTC857 (250 mg BID) or matching 
placebo at a 2:1 ratio with 2 stratiﬁcation factors:  
(1) Amount of change in ALSFRS-R score during the Screening Period by points total loss: 
a. <1 
b. 1-2 
c. 3-4 
d. >4  
(2) Use of edaravone, sodium phenylbutyrate/taurursodiol, or neither for the treatment of ALS at 
Screening as standard-of-care therapy: 
a. Edaravone 
b. Sodium phenylbutyrate/taurursodiol 
c. Neither edaravone nor sodium phenylbutyrate/taurursodiol 
Subjects will undergo ALSFRS-R assessment during the Screening Period to determine whether they 
will be included in the ITT1 Analysis Set. 
Study visits will occur as described in the Schedule of Assessments and will include eﬃcacy, PK, 
biomarker eﬀects, and safety assessments. Eﬃcacy assessments will include evaluation of disease 
progression, motor/limb and bulbar function, neuropsychological function, and respiratory function. 
Pharmacokinetic assessments will consist of blood and CSF sampling, and biomarker assessments will 
consist of blood, urine, and CSF sampling. Safety assessments consist of collecting information on 
TEAEs, TESAEs, clinical laboratory tests (hematology, serum chemistry, urinalysis), C-SSRS, physical 
examination, vital signs, and 12-lead ECGs. 
At the successful completion of the Treatment Period, all subjects will be oﬀered the opportunity to 
enter the LTE Period of the study. Those who choose to enter will continue treatment with PTC857 
(250 mg BID) as described below. Those who choose not to enter the LTE Period will stop treatment, 


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and a Telephone Follow-Up Visit will be conducted 4 weeks (±3 days) after the last dose of study 
treatment. 
Long-Term Extension Period (Part B) 
Subjects who enter the LTE Period of the study will continue treatment for an additional 28 weeks. All 
subjects will be treated with open-label PTC857 (250 mg BID) during the LTE Period. Subjects will 
remain blinded to their original treatment from the Treatment Period (Part A). 
Subjects will complete all activities as per the Schedule of Assessments. At the end of the LTE 
Period, those who choose not to enter the Continued LTE Period will stop treatment, and a 
Telephone Follow-Up Visit will be conducted 4 weeks (±3 days) after the last dose of study 
treatment. 
Continued Long-Term Extension Period (Part C) 
Subjects who enter the Continued LTE Period (Part C) will continue treatment for an additional 108 
weeks. All subjects will be treated with open-label PTC857 (250 mg BID) during the Continued LTE 
Period. Subjects will remain blinded to their original treatment from the Treatment Period (Part A). 
Subjects participating in the Continued LTE Period will complete all activities as per the 
Schedule of Assessments. At the end of this period, a Telephone Follow-Up Visit will be 
conducted 4 weeks (±3 days) after the last dose of study treatment. 
Results from the Treatment Period (Part A), the LTE Period (Part B), and the Continued LTE 
Period (Part C) will be reported separately. 


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Sample Size Justiﬁcation: 
For the primary eﬃcacy endpoint, the combined assessment of ALSFRS-R and survival after 24 weeks 
of treatment, 307 subjects in the ITT1 Analysis Set (205 in the PTC857 group and 102 in the placebo 
group, based on a 2:1 randomization ratio) will provide approximately 85% power to detect a 
treatment diﬀerence of 2.5 points with a standard deviation of 5.3, based on a 2-sided 0.05 level Joint 
Rank Test, and assuming 24-week survival rates of 96.5% and 95% in the PTC857 and placebo groups, 
respectively. Data from the 2 recently concluded clinical studies in ALS reported overall death rates of 
5% and 0% (Edaravone (MCl-186) ALS 19 Study Writing Group 2017, Paganoni 2020). In addition, the 
edaravone study reported a standard deviation of 5.3 points for the ALSFRS-R score at Week 24, 
among treated subjects.  
Assuming approximately 10% of randomized subjects will not meet the ITT1 Analysis Set deﬁnition, 
then approximately 340 subjects will be randomized to ensure that 307 subjects are randomized into 
the ITT1 Analysis Set. Given that the primary analysis incorporates deaths as a combined endpoint, 
and a fully imputed analysis dataset is utilized in the analysis, additional sampling for missing data is 
not planned. 
Number of Subjects (Planned): 
The study is targeted to have approximately 307 subjects in the ITT1 Analysis Set (205 in the PTC857 
group and 102 in the placebo group, based on a 2:1 randomization ratio).  
A subset of approximately 36 subjects from select sites participating in the PK Sub-Study will 
participate in serial blood sampling to characterize the PK of PTC857 in subjects with ALS.  
Diagnosis and Main Criteria for Inclusion: 
Individuals eligible to participate in this study include those who meet all the inclusion criteria 
at both the Screening Visit and the Baseline Visit, unless otherwise stated: 
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 (refer to the laboratory manual for specific requirements)  
5. Subjects or their designee (ie, legal authorized representative or caregiver) must 
understand the nature of the study and must provide signed and dated written informed 
consent prior to conducting any study-related procedures 
6. Females must be either postmenopausal for ≥1 year (cessation of menses for 
12 consecutive months) or surgically sterile (having undergone tubal ligation, 
hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing 
potential and not abstinent, willing to use a highly effective method of contraception 


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from the start of the Screening Period through 90 days after the last dose of study drug. 
Females who are abstinent will not be required to use a contraceptive method unless 
they become sexually active 
7. Females must refrain from ova (egg cell) donation from the start of the Screening 
Period through 90 days after the last dose of study drug 
8. Males, if not surgically sterilized, with female partners of childbearing potential must 
agree to use barrier contraceptive (ie, condom) and their female partners must use a 
highly effective method of contraception from the start of the Screening Period through 
90 days after the last dose of study drug 
9. Males must refrain from sperm donations from the start of the Screening Period 
through 90 days after the last dose of the study drug 
10. Willing and able to comply with all protocol procedures 
11. 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 (refer to inclusion criterion 13), 
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 
12. 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 
13. 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. Note: should a subject be discontinued from standard-of-care 
therapy due to removal of the therapy from the market, this will not be considered a 
protocol deviation. 
Main Criteria for Exclusion: 
Individuals are not eligible to participate in this study if they have met or meet any of the 
following exclusion criteria at either the Screening Visit or the Baseline Visit, unless otherwise 
stated: 
1. History of allergies or adverse reactions to any of the excipients in the study drug 
formulation 
2. Females who are pregnant or nursing or plan to become pregnant during the study 
3. 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 
4. 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 
Note: The lumbar puncture may be skipped for an individual subject if the investigator 
deems it appropriate, and after discussion with the medical monitor. Subjects with a 
contraindication to lumbar punctures, such as but not limited to space-occupying lesion 


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with mass effect, increase of intracranial pressure due to increased CSF pressure, 
posterior fossa mass, Arnold-Chiari malformation, anticoagulation medication use, 
coagulopathy, uncorrected bleeding diathesis, congenital spine abnormality, previous 
adverse event associated with a lumbar puncture or skin infection at the puncture site, 
should not undergo the lumbar punctures as listed in the Schedule of Events. These 
subjects may still enroll in the study and should undergo all other study procedures. 
5. Hepatic insufficiency, defined as liver function tests (LFTs) (ie, AST and/or ALT) ≥3× 
the upper limit of normal (ULN), or bilirubin ≥1.5× the ULN (except in the case of 
Gilbert’s disease) 
6. Moderate or worse renal insufficiency, defined as an estimated glomerular filtration 
rate (eGFR) of <60 mL/min 
7. 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 
8. History of alcohol or drug abuse within the last 6 months prior to the start of the 
Screening Period or current evidence of substance dependence 
9. Any surgery within 30 days prior to the start of the Screening Period that may affect 
the subject’s ability to complete all study procedures 
10. Subject has previously received PTC857 
11. 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 
12. For female subjects, any past medical history of breast cancer, regardless of remission 
status, or any first degree relative with history of breast cancer 
13. Subject is taking a non-approved form of sodium phenylbutyrate and/or taurursodiol 
for the treatment of ALS 
Investigational Product, Dosage, and Mode of Administration: 
Subjects will receive 1 of 2 treatment regimens during the 24-week Treatment Period: 
• PTC857 (250 mg) administered orally BID for 24 weeks 
• Matching placebo (250 mg) administered orally BID for 24 weeks 
All subjects will receive open-label PTC857 250 mg BID during the 28-week LTE Period and during the 
108-week Continued LTE Period. 
Of note, since this is a double-blind study, all subjects will be given an equal number of bottles 
of either active drug or placebo to maintain the blind setting. 
Duration of Treatment: 
All subjects will receive 24 weeks of treatment during the Treatment Period, an additional 
28 weeks of treatment in the LTE Period, and an additional 108 weeks of treatment in the 
Continued LTE Period. 
Reference Therapy, Dosage, and Mode of Administration: 
Placebo for PTC857 will be administered orally twice a day. 
Criteria for Evaluation: 


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The following eﬃcacy assessments will be collected according to the Schedule of Assessments: 
• Disease progression as assessed by the ALSFRS-R score: 
The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the 
subjects’ capability and independence in 12 functional activities across 4 subdomains of 
bodily function (bulbar, gross motor, ﬁne motor, and breathing) relevant in ALS. Each 
activity is recorded to the closest approximation from a list of 5 choices, scored 0 (total 
loss of function) to 4 (no loss of function), with the total score ranging from 0 to 48 and 
higher scores indicating better function. 
• Respiratory function as assessed by PFTs: 
Pulmonary function tests will assess slow vital capacity and Sniﬀ Nasal Inspiratory Pressure 
(SNIP). Forced vital capacity, vital capacity, forced expiratory volume, and maximum 
inspiratory pressure will not be measured. Oxygen saturation (SpO2), respiratory rate, and 
heart rate will be assessed in both upright and supine positions. The SNIP test will assess 
nasal pressure in each unilaterally occluded nostril during a maximal sniﬀ to assess 
inspiratory muscle strength. 
• Motor/limb and bulbar function as assessed by the Modified Norris Scale: 
The Modiﬁed Norris Scale is a rating scale for ALS that consists of 2 parts: the Limb Norris 
Scale and the Norris Bulbar Scale. The Limb Norris Scale has 21 items to evaluate 
extremity function, and the Norris Bulbar Scale has 13 items to evaluate bulbar function. 
Each item is rated in 4 ordinal categories. 
• Neuropsychological function as assessed by the ALS CBS: 
The ALS CBS is a measure of cognition and behavior in patients with ALS. The cognitive 
section assesses attention, concentration, tracking/monitoring, and initiation and 
retrieval. The behavioral section compares changes in personality and behavior since the 
onset of ALS, as well as mood, pseudobulbar aﬀect, and fatigue. 
• Disease-specific measure of health-related quality of life as assessed by 
ALSAQ-40: 
The ALSAQ-40 is a disease-speciﬁc measure of health-related quality of life for ALS. It is 
speciﬁcally used to measure the subjective well-being of patients with ALS and provides 
scores for 5 scales: physical mobility, activities of daily living and independence, eating and 
drinking, communication, and emotional reactions. 
• 
Health-related quality of life as assessed by EQ-5D-5L: 
The EQ-5D-5L is used for respondents to rate their own health in 5 diﬀerent dimensions, 
including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
• Blood-, urine-, and CSF-based biomarkers: 
Blood, urine, and CSF biomarker levels will evaluate PTC857 biochemical activity and 
ability to modulate key aspects of disease pathology. 


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• Plasma and CSF for PTC857 PK: 
− Blood samples will be collected following the first dose and at steady state to 
evaluate PTC857 PK in subjects. 
− CSF samples will be collected during the study to assess the change of PTC857 
PK in CSF following multiple doses. 
Safety: 
Safety will be assessed by the occurrence of TEAEs, TESAEs, clinical laboratory tests 
(hematology, serum chemistry, urinalysis), C-SSRS, physical examination, vital signs, and 
12-lead ECG in subjects with ALS on PTC857 versus placebo. 
Statistical Methods: 
Intent-to-Treat 1 Analysis Set: 
All subjects who are randomized after the Screening Period and take at least 1 dose of double-blind 
study drug in the Treatment Period and who have a decrease in the ALSFRS-R score of ≤4 points during 
the Screening Period will be included in the ITT1 Analysis Set. Subjects will be analyzed according to 
their randomized treatment. The ITT1 Analysis Set will be used for analysis of the primary endpoint. 
Intent-to-Treat 2 Analysis Set: 
All subjects who are randomized after the Screening Period and take at least 1 dose of study drug in 
the Treatment Period will be included in the ITT2 Analysis Set. Subjects will be analyzed according to 
their randomized treatment. 
Per Protocol Analysis Set: 
All subjects in the ITT1 Analysis Set who have no major protocol deviations that aﬀect the validity of 
the eﬃcacy measurements will be included in the PP Analysis Set. The PP Analysis Set will be used for 
sensitivity analysis of the eﬃcacy endpoint. The criteria for inclusion in the PP Analysis Set will be 
ﬁnalized prior to study unblinding and detailed in the Statistical Analysis Plan (SAP). 
Safety Analysis Set: 
All subjects in the ITT2 Analysis Set who receive at least 1 dose of study drug will be included in the 
Safety Analysis Set. Subjects will be analyzed according to the actual treatment received. 
PK Analysis Set: 
All subjects in the ITT2 Analysis Set who have at least 1 measurable plasma or CSF PTC857 
concentration will be included in the PK Analysis Set. 
The null hypothesis of this study is that the subject ranks based on the composite survival and 
change from baseline in ALSFRS-R after 24 weeks of treatment are the same in the PTC857 
(250 mg BID) and in the placebo versus the alternative that they are different; a 2-sided test at 
the 5% alpha level will be applied. 
The primary efficacy endpoint will be analyzed on the ITT1 Analysis Set at the significance 
level of 0.05 (2-sided). If p<0.05, then the study will be declared positive. 


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For the primary efficacy endpoint, subject ranks based on the Combined Assessment of 
Function and Survival (CAFS) ranking method, will be analyzed when all subjects in the ITT1 
Analysis Set finish the Treatment Period (Part A). This analysis will be performed using an 
analysis of covariance (ANCOVA) model following multiple imputation. Subjects who 
discontinue from the study prior to Week 24 will have their Week 24 ALSFRS-R score 
imputed using multiple imputation. The ANCOVA model will include the following 
covariates: treatment arm (PTC857 and placebo), baseline ALSFRS-R score, the amount of 
change in the subject’s ALSFRS-R score during the Screening Period (<1, 1-2, and 3-4 points 
total loss), and standard-of-care exposure with rank scores as the response variable. A p value 
for the difference will be presented. 
Safety endpoints (severity and number of TEAEs and TESAEs, change from baseline in 
clinical laboratory tests, physical examination, vital signs, C-SSRS, and 12-lead ECGs) will be 
descriptively compared between PTC857 and placebo. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ...........................................................3 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES..............................................5 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE............................................7 
SYNOPSIS 8 
TABLE OF CONTENTS ...............................................................................................................19 
LIST OF TABLES .........................................................................................................................24 
LIST OF FIGURES .......................................................................................................................24 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................25 
1. 
INTRODUCTION ......................................................................................................28 
1.1. 
Background Information .............................................................................................28 
1.2. 
Name and Description of Investigational Product ......................................................28 
1.3. 
Mechanism of Action .................................................................................................28 
1.4. 
Findings From Nonclinical and Clinical Studies ........................................................29 
1.4.1. 
Nonclinical Studies .....................................................................................................29 
1.4.2. 
Clinical Studies ...........................................................................................................30 
1.5. 
Risk/Benefit Assessment ............................................................................................32 
1.5.1. 
Risk Assessment .........................................................................................................32 
1.5.2. 
Potential Benefits of Study Participation ....................................................................32 
1.5.3. 
Summary of Safety Risks ...........................................................................................33 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................34 
2.1. 
Objectives ...................................................................................................................34 
2.1.1. 
Primary Objective .......................................................................................................34 
2.1.2. 
Secondary Objectives .................................................................................................34 
2.1.3. 
Exploratory Objectives ...............................................................................................34 
2.1.4. 
Long-Term Extension Period Objectives ...................................................................34 
2.1.5. 
Continued Long-Term Extension Period Objectives ..................................................35 
2.2. 
Endpoints ....................................................................................................................35 
2.2.1. 
Primary Endpoints ......................................................................................................35 
2.2.2. 
Secondary Endpoints ..................................................................................................35 
2.2.3. 
Exploratory Endpoints ................................................................................................36 


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2.2.4. 
Long-Term Extension Period Endpoints ....................................................................36 
2.2.5. 
Continued Long-Term Extension Period Endpoints ...................................................36 
3. 
STUDY DESIGN .......................................................................................................37 
3.1. 
Overall Study Design ..................................................................................................37 
3.2. 
Treatment Assignment ................................................................................................37 
3.3. 
Number of Subjects ....................................................................................................49 
3.4. 
Sample Size Justification ............................................................................................49 
3.5. 
Rationale for Study Duration, Dosing Regimens, and Design ...................................49 
3.5.1. 
Justification for Study Design and Duration ..............................................................49 
3.5.2. 
Justification of Selected Doses ...................................................................................50 
3.5.3. 
Justification of Selected Study Objectives .................................................................50 
3.5.4. 
Justification of Selected Study Population .................................................................51 
3.6. 
End of Study Definition ..............................................................................................51 
3.7. 
Criteria for Study Termination/Interruption ...............................................................52 
3.8. 
COVID-19 Risk Mitigation ........................................................................................52 
4. 
STUDY POPULATION .............................................................................................53 
4.1. 
Overview .....................................................................................................................53 
4.2. 
Inclusion Criteria ........................................................................................................53 
4.3. 
Exclusion Criteria .......................................................................................................54 
4.4. 
Treatment Compliance ................................................................................................55 
4.5. 
Screen Failures ............................................................................................................55 
4.6. 
Subject Withdrawal Criteria .......................................................................................55 
5. 
STUDY INTERVENTION ........................................................................................57 
5.1. 
Study Intervention Administration .............................................................................57 
5.1.1. 
Study Intervention Description ...................................................................................57 
5.1.2. 
Dosing and Administration .........................................................................................57 
5.2. 
Preparation/Handling/Storage/Accountability ............................................................58 
5.2.1. 
Preparation of PTC857 Oral Solution .........................................................................58 
5.2.2. 
Storage and Accountability .........................................................................................58 
5.2.3. 
Formulation, Appearance, Packaging, and Labeling ..................................................58 
5.2.3.1. 
Formulation and Appearance ......................................................................................58 
5.2.3.2. 
Study Drug Packaging ................................................................................................58 


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5.2.3.3. 
Study Drug Labeling ...................................................................................................59 
5.2.4. 
Handling of Study Drug ..............................................................................................59 
5.3. 
Measures to Minimize Bias: Randomization ..............................................................59 
5.3.1. 
Randomization ............................................................................................................59 
5.3.2. 
Treatment Assignment ................................................................................................60 
5.4. 
Study Intervention and Compliance ...........................................................................60 
5.5. 
Concomitant Therapy .................................................................................................60 
6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................62 
6.1. 
Premature Termination or Suspension of the Study ...................................................62 
6.2. 
Participant Discontinuation/Withdrawal From the Study ...........................................62 
6.3. 
Lost to Follow-Up .......................................................................................................62 
6.4. 
Subject’s Follow-Up After Study Discontinuation .....................................................62 
7. 
STUDY ASSESSMENT AND PROCEDURES ........................................................63 
7.1. 
Efficacy Assessments .................................................................................................63 
7.1.1. 
PFT Assessments ........................................................................................................63 
7.1.2. 
Modified Norris Scale Assessment .............................................................................63 
7.1.3. 
ALS Cognitive Behavioral Screen Assessment ..........................................................63 
7.1.4. 
ALSAQ-40 Assessment ..............................................................................................63 
7.1.5. 
EQ-5D-5L Assessment ...............................................................................................64 
7.1.6. 
ALSFRS-R Assessment ..............................................................................................64 
7.1.7. 
Plasma-, Urine-, and CSF-Based Biomarkers ............................................................64 
7.1.8. 
Plasma and CSF for PTC857 PK ................................................................................64 
7.1.8.1. 
Sparse Blood Sample Collection (Subjects Not in the PK Sub-Study) ......................64 
7.1.8.2. 
Serial Blood Sample Collection (PK Sub-Study) .......................................................65 
7.1.8.3. 
CSF Sample Collection (PK Sub-Study) ....................................................................65 
7.1.8.4. 
Pharmacokinetic Parameters .......................................................................................66 
7.1.8.5. 
Analytical Method ......................................................................................................66 
7.1.8.6. 
Timing for Sampling ...................................................................................................66 
7.1.8.7. 
Procedures for Sampling .............................................................................................66 
7.1.8.8. 
Labeling ......................................................................................................................66 
7.1.8.9. 
Shipping Procedures ...................................................................................................67 


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7.2. 
Safety Assessments .....................................................................................................67 
7.2.1. 
Vital Signs ..................................................................................................................67 
7.2.2. 
Weight and Height ......................................................................................................67 
7.2.3. 
Physical Examination .................................................................................................67 
7.2.4. 
12-Lead Electrocardiogram ........................................................................................67 
7.2.5. 
Clinical Laboratory Assessments ...............................................................................68 
7.2.6. 
Pregnancy Test ............................................................................................................69 
7.2.7. 
Columbia-Suicide Severity Rating Scale ....................................................................69 
7.2.8. 
Breast Cancer Imaging Surveillance ..........................................................................69 
7.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................69 
7.3.1. 
Definition of Adverse Events .....................................................................................69 
7.3.2. 
Definition of Serious Adverse Event ..........................................................................70 
7.3.3. 
Adverse Events Reporting ..........................................................................................71 
7.3.4. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................72 
7.3.4.1. 
Serious Adverse Event Reporting ...............................................................................73 
7.3.5. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................73 
7.3.5.1. 
Assessments of Severity of Adverse Events ...............................................................73 
7.3.5.2. 
Describing Adverse Event Relationship to Study Intervention ..................................74 
7.3.6. 
Treatment of Adverse Events and Serious Adverse Events .......................................75 
7.3.7. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................75 
7.3.8. 
Regulatory Reporting Requirements for Serious Adverse Events .............................76 
7.3.9. 
PTC Expedited Reporting of SUSARs to EudraVigilance .........................................76 
7.3.10. 
Exposure During Pregnancy or Breastfeeding ...........................................................76 
7.3.10.1. 
Exposure During Pregnancy .......................................................................................76 
7.3.10.2. 
Exposure During Breastfeeding ..................................................................................77 
7.3.11. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ...............................................................................................................78 
7.3.11.1. 
Progression of Underlying Disease ............................................................................78 
7.3.11.2. 
Abnormal Findings Associated with the Disease Being Studied ...............................78 
7.3.12. 
Contraceptive Guidance ..............................................................................................78 
7.3.12.1. 
Male Participant Reproductive Inclusion Criteria ......................................................78 
7.3.12.2. 
Female Participant Reproductive Inclusion Criteria ...................................................79 


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7.3.12.3. 
Women of Childbearing Potential ..............................................................................79 
7.3.12.4. 
Contraception Methods ...............................................................................................79 
7.3.13. 
Adverse Events of Special Interest .............................................................................80 
7.3.14. 
Medication Errors .......................................................................................................80 
7.3.15. 
Safety Oversight .........................................................................................................81 
8. 
STATISTICAL CONSIDERATOINS .......................................................................82 
8.1. 
Statistical Hypotheses .................................................................................................82 
8.2. 
Sample Size Determination ........................................................................................82 
8.3. 
Population for Analyses ..............................................................................................82 
8.4. 
Statistical Analyses .....................................................................................................83 
8.4.1. 
Primary Efficacy Endpoint .........................................................................................83 
8.4.2. 
Secondary Efficacy Endpoints (Part A) ......................................................................83 
8.4.3. 
Long-Term Extension Period Efficacy Endpoints (Part B) ........................................83 
8.4.4. 
Continued Long-Term Extension Period Efficacy Endpoints (Part C) ......................84 
8.4.5. 
Safety Analyses ..........................................................................................................84 
8.4.6. 
Pharmacokinetic Analyses ..........................................................................................85 
8.5. 
Interim Analysis ..........................................................................................................85 
9. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................86 
9.1. 
Study Monitoring ........................................................................................................86 
9.2. 
Audits and Inspections ................................................................................................87 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................88 
10.1. 
Protocol Deviations ....................................................................................................88 
11. 
ETHICS ......................................................................................................................89 
11.1. 
Ethics Review .............................................................................................................89 
11.2. 
Ethical Conduct of the Study ......................................................................................89 
11.3. 
Written Informed Consent ..........................................................................................89 
12. 
DATA HANDLING AND RECORDKEEPING .......................................................91 
12.1. 
Inspection of Records .................................................................................................91 
12.2. 
Retention of Records ..................................................................................................91 
12.3. 
Future Use of Stored Specimens and Data .................................................................92 
13. 
PUBLICATION POLICY ..........................................................................................94 
14. 
PROTOCOL AMENDMENT HISTORY ..................................................................95 


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14.1. 
Version 6.0: 14 June 2024 ..........................................................................................95 
14.2. 
Version 5.0: 08 September 2023 ................................................................................96 
14.3. 
Version 4.0: 31 October 2022 .....................................................................................98 
14.4. 
Version 3.0: 13 July 2022 .........................................................................................100 
14.5. 
Version 2.0: 14 March 2022 .....................................................................................101 
15. 
REFERENCES .........................................................................................................103 
16. 
APPENDICES ..........................................................................................................105 
16.1. 
Prohibited Medications During the Course of the Study ..........................................105 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments for Screening and Treatment Periods (Part A) ..................39 
Table 2: 
Schedule of Assessments for the Long-Term Extension Period (Part B) ...................45 
Table 3: 
Schedule of Assessments for the Continued Long-Term Extension Period 
(Part C) ........................................................................................................................47 
Table 4: 
Investigational Product ...............................................................................................57 
Table 5: 
Summary of Clinical Laboratory Tests .......................................................................68 
Table 6: 
Investigator Site Requirements for Recording/Reporting Adverse Events ................72 
Table 7: 
Grading of Adverse Events .........................................................................................74 
Table 8: 
Relationship of Study Intervention to Adverse Event ................................................75 
Table 9: 
Investigator Site Requirements for Recording/Reporting Medication Errors ............80 
Table 10: Strong/Moderate Inhibitors of CYP Enzymes ..........................................................106 
Table 11: Strong/Moderate Inducers of CYP Enzymes ............................................................106 
 
LIST OF FIGURES 
Figure 1: 
Proposed Mechanism of Action of PTC857 ...............................................................29 
Figure 2: 
Study Design ...............................................................................................................37 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialized Term 
Explanation 
β-HCG 
Beta human chorionic gonadotropin 
λz 
Apparent terminal rate constant 
12-HETE 
12-Hydroxyeicosatetraenoic acid 
15-HETE 
15-Hydroxyeicosatetraenoic acid 
15-LO 
15-Lipoxygenase 
4HNE 
4-Hydroxynonenal 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALS 
Amyotrophic lateral sclerosis 
ALS CBS 
Amyotrophic lateral sclerosis Cognitive Behavioral Screen 
ALSAQ-40 
40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-inf 
AUC from time zero to infinity 
AUC0-t 
AUC from time zero to time of last non-zero (measurable or sampled) 
concentration 
BMI 
Body mass index 
CAFS 
Combined Assessment of Function and Survival 
Cavg 
Average concentration over a dosing interval 
CL/F 
Total body clearance 
Cmax 
Maximum observed concentration 
CNG 
Cynomolgus 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTIS 
Clinical Trials Information System 
Ctrough 
Plasma concentration on Day 29 prior to the morning dose 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EQ-5D-5L 
Five-level European quality of life five-dimensional questionnaire 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GPX4 
Glutathione peroxidase 4 
HDL 
High-density lipoprotein 


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Abbreviation or 
Specialized Term 
Explanation 
HETE 
Hydroxyeicosatetraenoic acid 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IEC 
Independent ethics committee 
IH 
In-home 
INR 
International normalized ratio 
IP 
In-person 
IRB 
Institutional Review Board 
ITT1 
Intent-to-Treat 1 
ITT2 
Intent-to-Treat 2 
IUPAC 
International Union of Pure and Applied Chemistry 
K2-EDTA 
Dipotassium ethylenediaminetetraacetic acid 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LFT 
Liver function test 
LTE 
Long-Term Extension 
MedDRA 
Medical Dictionary for Regulatory Activities 
NfL 
Neurofilament light chain 
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect level 
OTC 
Over-the-counter 
p75NTR 
p75 neurotrophin receptor  
PC 
Telephone call 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PFT 
Pulmonary function test 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PT 
Prothrombin time 
RBC 
Red blood cell 
ROS 
Reactive oxygen species 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
RSL3 
RAS-selective lethal 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SNIP 
Sniff Nasal Inspiratory Pressure 
SOC 
System Organ Class 
SpO2 
Oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
T½ 
Apparent terminal half-life 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
Tmax 
Time to reach Cmax 
ULN 
Upper limit of normal 
UN 
Unstructured covariance matrix 
USM 
Urgent safety measure 
WBC 
White blood cell 
WHO 
World Health Organization 


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Abbreviation or 
Specialized Term 
Explanation 
WOCBP 
Woman of childbearing potential 


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1. 
INTRODUCTION 
1.1. 
Background Information 
PTC857 (also known as utreloxastat) is an orally bioavailable small molecule (a proprietary 
cyclohexadiene-dione compound) being developed by PTC Therapeutics (PTC) for the treatment 
of neurological diseases characterized by high levels of oxidative stress and mitochondrial 
pathology, including amyotrophic lateral sclerosis (ALS). In diseases characterized by high 
levels of oxidative stress, reactive oxygen species (ROS) production outstrips the available 
supply of glutathione, resulting in depletion of glutathione and ROS-mediated cell injury and cell 
death. PTC857 functions as an inhibitor of the oxidoreductase 15-lipoxygenase (15-LO) enzyme 
to reduce oxidative stress and spare reduced glutathione. 
This study is intended to assess the efficacy, safety, tolerability, pharmacokinetic (PK), and 
biomarker effects of PTC857 in adult male and female subjects diagnosed with ALS. 
1.2. 
Name and Description of Investigational Product 
The International Union of Pure and Applied Chemistry (IUPAC) chemical name for PTC857 is 
2,3,5-trimethyl-6-nonyl-2,5-cyclohexadiene-1,4-dione. The drug substance is a pale yellow to 
yellow crystalline solid. It is physically and chemically stable in solid state at long-term and 
accelerated conditions. The drug product for this study is a solubilized formulation of PTC857 at 
a concentration of 60 mg/mL (unflavored formulation) or 62.5 mg/mL (flavored formulation) 
filled in amber glass bottles with child-resistant closures. Refer to Section 5.1.1 for additional 
details. 
1.3. 
Mechanism of Action 
Pharmacologically, PTC857 can be classified as a redox-active inhibitor of ferroptosis. PTC857 
functions as an inhibitor of the oxidoreductase 15-LO enzyme to reduce oxidative stress and 
spare reduced glutathione. 
Reduced glutathione is an essential intermediary metabolite that serves as the primary native 
cellular antioxidant and the cell’s primary defense against ROS. It is an important cofactor for 
the enzyme glutathione peroxidase 4 (GPX4), which regulates ferroptosis by catalyzing the 
reduction of lipid hydroperoxides to lipid alcohols. The role of GPX4 is important in handling 
the accumulation of lipid peroxides, thereby preventing oxidative damage and ferroptotic cell 
death (Masaldan 2019). Under disease conditions, 15-LO is upregulated and produces lipid 
peroxide products that increase oxidative stress, activate pro-inflammatory glial cells, deplete 
glutathione, accumulate iron, and ultimately cause ferroptosis (Wenzel 2017, Ye and Stockwell 
2017). These biochemical events, in particular the production of oxidized lipids, inflammation, 
oxidative stress, and glutathione depletion, are known contributors to neuronal cell death and 
ALS pathogenesis (Masaldan 2019). 
Neurodegenerative diseases (Lin and Beal 2006), including ALS, are characterized by high 
levels of oxidative stress (Ferrante 1997, Barber and Shaw 2010, Maarouf 2012, Reale 2012) and 
low levels of peripheral and neuronal glutathione (Riederer 1989, Weiduschat 2014). 
The schematic representation of the PTC857 mechanism of action is presented in Figure 1. 


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Figure 1: 
Proposed Mechanism of Action of PTC857 
 
Abbreviations: 15-HETE, 15-hydroxyeicosatetraenoic acid; GPX4, glutathione peroxidase 4 
1.4. 
Findings From Nonclinical and Clinical Studies 
1.4.1. 
Nonclinical Studies 
Nonclinical pharmacodynamic (PD) studies on PTC857 completed to date include 1 enzyme 
inhibition study, 4 cell pharmacology studies, 1 in vivo PK/PD study, and 2 in vivo efficacy 
studies. The findings of nonclinical pharmacology studies support the clinical development of 
PTC857 in neurodegenerative diseases such as ALS. 
Results from an in vitro study evaluating the protective activity and potency of PTC857 against 
ferroptotic cell death in human spinal astrocytes demonstrated that PTC857 prevented 
RAS-selective lethal compound 3-induced ferroptotic cell death and was 70-fold more potent 
than edaravone, and riluzole conferred no protection at preventing ferroptotic cell death. 
Nonclinical pharmacology studies have demonstrated protection of the neuromuscular junction 
in an animal model of ALS. In an in vivo study evaluating the efficacy of PTC857 in the 
SOD1*G93A mouse model of ALS, PTC857 was demonstrated to protect innervation of the 
neuromuscular junction. In a second study, PTC857 improved grip strength and delayed 
morbidity of SOD1*G93A mice. 
Safety pharmacology studies were conducted in Sprague Dawley rats to assess the effects of 
PTC857 on respiratory and neurobehavioral function. The effect of PTC857 on cardiovascular 
(CV) function was assessed in a single-dose study conducted in cynomolgus (CNG) monkeys 
and in 1-, 3-, and 9-month repeat-dose monkey GLP toxicity studies. These safety pharmacology 
studies did not identify any risk factors for the administration of PTC857 in subjects. 
PTC857 was neither mutagenic nor clastogenic in 2 in vitro (bacterial reverse mutation test and 
TK6 cell in vitro micronucleus test) and 1 in vivo (rat micronucleus test) genotoxicity studies. 
One- and 3-month repeat-dose GLP toxicology studies were conducted in rats and monkeys with 
PTC857. In the 1-month rat toxicology study, rats were orally administered PTC857 at doses of 
0, 100, 300, and 1000 mg/kg/day. The dose-limiting PTC857-associated toxicities observed in 
the 1-month rat study included moderate increases in prothrombin time in males at 
1000 mg/kg/day and microscopic changes in the stomach in both sexes at ≥300 mg/kg/day. 
Changes in the stomach included mild to moderate submucosal edema, which was observed in 
non-glandular and glandular sections of the stomach in conjunction with adverse findings in the 


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mucosa of the non-glandular stomach. The no-observed-adverse effect level was determined to 
be 100 mg/kg/day. There were no dose-limiting toxicities observed in the 1-month monkey 
toxicology study or in the 3-month rat and monkey toxicology studies. 
A 6-month repeat-dose GLP toxicology study was performed in rats with PTC857 at dose levels 
of 0, 30, 100, and 200 mg/kg/day. Two of the 14 female rats whose mammary glands were 
examined in the 200 mg/kg/day group at the end-of-dosing necropsy and 1 of the 4 female rats 
whose mammary glands were examined in the 100 mg/kg/day group at recovery necropsy had 
mammary gland adenocarcinomas. The no-observed-effect-level (NOEL) for the mammary 
gland findings was determined to be 30 mg/kg/day in females. AUC exposure multiples at the 
NOEL dose in females were approximately 2× anticipated clinical exposures. Mammary gland 
findings in the female rat were observed at ≥9× AUC exposure multiples compared with 
anticipated clinical exposures. No findings of adenocarcinomas were observed in male rats at any 
dose level tested. These findings are likely due to a non-genotoxic mechanism of action, since 
PTC857 was negative in the Ames mutagenicity and in vitro and in vivo micronucleus 
genotoxicity assays. 
A 9-month repeat-dose GLP toxicology study was performed in monkeys with PTC857 at dose 
levels of 0, 50, 100, and 300 mg/kg/day. There were no PTC857-related microscopic or 
macroscopic findings at the end of dosing or recovery necropsies, and no PTC857-related 
mortality occurred. There were no mammary gland findings in this study. 
The phototoxic potential of PTC857 was measured by the relative reduction in viability of 
BALB/c 3T3 mouse fibroblasts exposed to PTC857 with and without ultraviolet radiation. 
PTC857 demonstrated phototoxic potential in this assay. The phototoxic potential of PTC857 
was further evaluated in an in vivo study in Long-Evans rats administered at dose levels of 0, 30, 
100, or 300 mg/kg/day for 3 days. Target skin and eye effects were not observed; there was no 
evidence of phototoxic potential. Hence, measures to protect against sun and ultraviolet light 
exposure are not necessary with PTC857 treatment. 
An embryo-fetal development study in rats has shown no adverse effects of PTC857 up to the 
highest dose tested (300 mg/kg/day; ~19× anticipated human exposures at 250 mg BID). An 
embryo-fetal development study in rabbits showed fetal skeletal abnormalities in the presence of 
maternal toxicity, which were limited to delayed ossification of the parietals, at the highest dose 
tested (800 mg/kg/day). The developmental no-observed-adverse-effect level (NOAEL) in 
rabbits was 300 mg/kg/day (~4.6× anticipated human exposures at 250 mg BID). In a fertility 
and early embryonic development study in rats, there were no signs of general toxicity observed 
and there were no effects on reproductive parameters. 
1.4.2. 
Clinical Studies 
PTC857 was evaluated in Study PTC857-CNS-001-PD, a 3-part, Phase 1, single-center, 
double-blind, randomized, placebo-controlled, single- and multiple-ascending-dose, as well as 
food effect study of PTC857 in healthy volunteers. There were no treatment-emergent serious 
adverse events (TESAEs), no treatment-emergent adverse events (TEAEs) leading to 
discontinuation of PTC857, and no TEAEs leading to death. 
PTC857 was also evaluated in 6 additional completed Phase 1 studies:  


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• Study PTC857-CNS-002-HV was a Phase 1, 2-period, crossover, relative 
bioavailability study of 2 formulations in healthy volunteers.  
• Study PTC857-CNS-003-HV was a Phase 1, randomized, open-label, 3-period, 
6-sequence crossover study to investigate the effect of food on the PK and safety of 
PTC857 in healthy volunteers.  
• Study PTC857-DDI-101-HV was a Phase 1, open-label, fixed-sequence, 3-part study 
to investigate the effect of multiple doses of PTC857 on the PK of caffeine (a 
cytochrome P450 [CYP] 1A2 substrate), midazolam (a CYP3A4 substrate), and 
bupropion (a CYP2B6 substrate).  
• Study PTC857-JPB-102-HV was a Phase 1, open-label, single-dose study to evaluate 
the PK, safety, and tolerability of PTC857 in healthy Japanese and Caucasian adult 
subjects. 
• Study PTC857-CNS-004-HV was a Phase 1, open-label, multiple-dose, absorption, 
metabolism, and excretion study in healthy male participants to assess the 
metabolism, rates and routes of excretion, mass balance, and PK of 14C-PTC857. 
• Study PTC857-PAL-104-HV was a Phase 1, single-part, randomized, single-blind 
study designed to evaluate the taste profile of PTC857 Oral Solution. 
There were no TESAEs, no TEAEs leading to discontinuation of PTC857, and no TEAEs 
leading to death in these studies, with the exception of 1 TEAE of acne that led to 
discontinuation of a subject in Study PTC857-CNS-003-HV. 
Exposure to PTC857 in completed clinical studies included 191 subjects (healthy volunteers) at 
doses ranging from 100 to 1000 mg. The longest treatment duration was 14 days. The clinical 
safety data suggest that PTC857 is safe and well tolerated. No TESAEs were reported. 
Based on the results of Study PTC857-CNS-003-HV, the PK parameters of PTC857 were higher 
under low- and high-fat conditions when compared with fasted conditions, but were comparable 
between the 2 fed states; hence, PTC857 should be taken with food.  
Based on the results of Study PTC857-DDI-101-HV, PTC857 can be classified as a weak 
CYP1A2 inhibitor and a weak CYP3A4 inducer, and CYP2B6 substrates will not be affected by 
PTC857 co-administration. Hence, dose adjustments are not warranted when drugs metabolized 
by CYPs 1A2, 3A4, or 2B6 are co-administered with PTC857.  
Study PTC857-JPB-102-HV demonstrated a slightly higher, but not clinically meaningful 
different plasma exposures for Japanese subjects compared with Caucasian participants across all 
dose levels evaluated; hence, no dose adjustments are required in Japanese subjects.  
Study PTC857-CNS-004-HV demonstrated that 88.4% of dosed radioactivity was recovered in 
combined urine and feces (64.0% in urine and 24.4% in feces) by 264 hours post-dose, with the 
majority of radioactivity recovered within the first 24 hours post-dose. Metabolism of 
utreloxastat was extensive and 21 metabolites were detected in plasma, urine, and feces. No 
unique or disproportionate human metabolites were identified. 


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Study PTC857-PAL-104-HV demonstrated that the unsweetened/unflavored study drug had poor 
taste acceptability, and use of sweetener alone or in combination with flavorants improved the 
taste acceptability. 
Refer to the Investigator’s Brochure (IB) for additional details on the nonclinical and clinical 
studies conducted so far. 
1.5. 
Risk/Benefit Assessment 
1.5.1. 
Risk Assessment 
Reversible changes in the lipid profile were observed with short-term exposure in healthy human 
volunteers but not observed in the monkey toxicology studies at exposure multiples 11.8× 
clinical exposures. Overall, PTC857 has been safe and well tolerated in subjects in the 2 studies 
of healthy volunteers. 
As described in Section 1.4.1, few cases of breast adenocarcinoma were observed in female rats 
in a 6-month toxicity study. However, there were no mammary gland findings in the 9-month 
toxicity study in monkeys. The clinical relevance of the findings is yet to be established and will 
be further investigated in nonclinical studies. Based on the likely non-genotoxic mechanism of 
action, safety margin to the clinical dose, and low incidence of findings seen, an adequate risk-
benefit is present for subjects with ALS in this study. 
1.5.2. 
Potential Benefits of Study Participation 
Amyotrophic lateral sclerosis is a neurodegenerative disease that affects the motor neuron 
system, resulting in progressive paralysis and eventual death due to respiratory failure, typically 
within 2 to 5 years after onset. Amyotrophic lateral sclerosis is typically diagnosed between the 
ages of 50 and 60 years. This population is expected to experience continued moderate decline 
after randomization. Due to the nature of ALS disease progression, it is anticipated that subjects 
who may not be able to provide ongoing written informed consent throughout the duration, but 
could provide ongoing nonwritten informed consent, may be included in the study. Hence, 
nonwritten consent, which may require the presence of a witness, may be provided in accordance 
with country-specific legislations as applicable. In addition, disease progression may make it 
difficult to attend on-site visits; hence, subjects may provide informed consent remotely, in 
accordance with site process and local requirements/regulations. See Section 11.3 for additional 
information.  
Currently, there is no cure for ALS, and treatment of patients with ALS is largely limited to 
management of symptoms (Petrov 2017). The only approved treatments, in some countries, for 
ALS are riluzole (Rilutek, administered orally; Tiglutik, oral solution; and Exservan, oral film), 
edaravone (Radicava, administered intravenously and/or orally), and sodium 
phenylbutyrate/taurursodiol (Relyvrio, administered orally). As these existing approved therapies 
are limited in efficacy of altering disease progression, there remains a high unmet medical need 
for new treatments for ALS. 
In in vitro studies, the protective activity and potency of PTC857 against ferroptotic cell death in 
human astrocytes were demonstrated. 


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In an ALS mouse model study, PTC857 was demonstrated to protect innervation of the 
neuromuscular junction. Due to the benefits demonstrated by PTC857 in these pathways for 
ALS, further studies with PTC857 are warranted in subjects with ALS to understand its potential 
clinical benefits in this population. 
1.5.3. 
Summary of Safety Risks 
There are no important identified or important potential risks for PTC857. 
The following potential risks have been recognized to date for PTC857: 
• Lipoprotein changes 
For further details on each risk, risk mitigation strategies, as well as adverse drug reactions 
recognized to date, and other important safety topics for PTC857, see the IB. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of PTC857 in reducing disease 
progression in subjects with ALS. 
2.1.2. 
Secondary Objectives 
The secondary objectives of this study are to assess the following in subjects with ALS: 
• Safety and tolerability of PTC857 in subjects with ALS 
• Respiratory function in subjects randomized to PTC857 versus placebo 
• Motor/limb and bulbar function in subjects randomized to PTC857 versus placebo 
• Survival in subjects randomized to PTC857 versus placebo 
• Quality of life via 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire 
(ALSAQ-40) in subjects randomized to PTC857 versus placebo 
• Evaluate the efficacy of PTC857 in reducing disease progression in subjects with 
ALS with any baseline rate of functional decline 
• Effects on plasma neurofilament light chain (NfL) activity in subjects randomized to 
PTC857 versus placebo 
• Pharmacokinetics of PTC857 
2.1.3. 
Exploratory Objectives 
The exploratory objectives of the study are to assess the following in subjects with ALS: 
• Neuropsychological function in subjects randomized to PTC857 versus placebo 
• Effects on mechanistically- and clinically-based biomarker activity in subjects 
randomized to PTC857 versus placebo 
• Quality of life via the five-level European quality of life five-dimensional 
questionnaire (EQ-5D-5L) in subjects randomized to PTC857 versus placebo 
• Exposure-response relationships 
2.1.4. 
Long-Term Extension Period Objectives 
The objectives of the Long-Term Extension (LTE) Period of this study are to assess the 
following in subjects with ALS: 
• Disease progression, survival, neuropsychological function, respiratory function, 
motor/limb and bulbar function, and effects on biomarker activity upon long-term 
treatment with PTC857 
• Safety and tolerability upon long-term treatment with PTC857 


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• Quality of life upon long-term treatment with PTC857 
• PK of PTC857 
2.1.5. 
Continued Long-Term Extension Period Objectives 
The objectives of the Continued LTE Period of the study are to assess the following in subjects 
with ALS: 
• Safety and tolerability upon continued long-term treatment with PTC857 
• Disease progression and survival upon continued long-term treatment with PTC857 
• Quality of life upon continued long-term treatment with PTC857 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoint is subject ranks based on the combined assessment of ALS Functional 
Rating Scale-Revised (ALSFRS-R) and survival after 24 weeks of treatment in the Intent-to-
Treat 1 (ITT1) Analysis Set. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints of this study are the following: 
• Subject ranks based on the combined assessment of ALSFRS-R and survival after 
24 weeks of treatment in the Intent-to-Treat 2 (ITT2) Analysis Set 
• Change from baseline in ALSFRS-R in the ITT1 Analysis Set after 24 weeks of 
treatment. 
• Change from baseline in ALSFRS-R in the ITT2 Analysis Set after 24 weeks of 
treatment. 
• 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 
• Change from baseline in slow vital capacity as assessed by pulmonary function tests 
(PFTs) after 24 weeks of treatment 
• Change from baseline in motor/limb and bulbar function as assessed by the Modified 
Norris Scale after 24 weeks of treatment 
• Survival as assessed by rate of and length of time to death 
• Quality of life as assessed by ALSAQ-40 after 24 weeks of treatment 
• Change from baseline in plasma NfL activity after 24 weeks of treatment 
• Plasma PK and cerebrospinal fluid (CSF) exposure of PTC857 


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2.2.3. 
Exploratory Endpoints 
The exploratory endpoints of the study are the following: 
• Change from baseline in neuropsychological function as assessed by the ALS 
Cognitive Behavioral Screen (ALS CBS) after 24 weeks of treatment 
• Change from baseline in blood, urine, and CSF biomarker activity after 24 weeks of 
treatment 
• Quality of life as assessed by the EQ-5D-5L after 24 weeks of treatment 
• Exposure-response relationships after 24 weeks of treatment 
2.2.4. 
Long-Term Extension Period Endpoints 
The LTE Period endpoints of this study are the following: 
• Severity and number of TEAEs and TESAEs, change in clinical laboratory tests, 
physical examination, vital signs, and 12-lead ECGs during the LTE Period 
• Change from baseline in ALSFRS-R after 52 weeks of treatment 
• Change from baseline in slow vital capacity as assessed by PFTs after 52 weeks of 
treatment 
• Change from baseline in motor/limb and bulbar function as assessed by the Modified 
Norris Scale after 52 weeks of treatment 
• Change from baseline in neuropsychological function as assessed by the ALS CBS 
after 52 weeks of treatment 
• Survival after 52 weeks of treatment 
• Quality of life as assessed by ALSAQ-40 after 52 weeks of treatment 
• Quality of life as assessed by EQ-5D-5L after 52 weeks of treatment 
• Change from baseline in blood and urine biomarker activity after 52 weeks of 
treatment 
• PK of PTC857 
2.2.5. 
Continued Long-Term Extension Period Endpoints 
The Continued LTE Period endpoints of this study are the following: 
• Severity and number of TEAEs and TESAEs during the Continued LTE Period 
• Change from baseline in ALSFRS-R after 160 weeks of treatment 
• Survival after 160 weeks of treatment 
• Quality of life as assessed by ALSAQ-40 after 160 weeks of treatment 


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3. 
STUDY DESIGN 
3.1. 
Overall Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel study to assess the 
effects of PTC857 treatment in adult male and female subjects diagnosed with ALS (Figure 2). 
The objectives of the study are to evaluate the efficacy, safety, tolerability, PK, and effects on 
biomarkers of PTC857 therapy in subjects with ALS. The study consists of 5 periods: Screening, 
Treatment (Part A), LTE (Part B), Continued LTE (Part C), and Follow-Up. 
Figure 2: 
Study Design 
 
Abbreviations: PK, pharmacokinetic 
3.2. 
Treatment Assignment 
Screening Period 
If a subject is not receiving standard-of-care therapy for the treatment of ALS at the time of 
entering the Screening Period, the investigator must evaluate whether the individual subject 
should begin treatment with standard-of-care therapy before entering the clinical study. 
After the written informed consent is signed, all subjects will enter the Screening Period. The 
Screening Period will last approximately 8 weeks. Subjects will complete all activities as per the 
Schedule of Assessments (Table 1). All subjects who complete the full Screening Period and 
continue to meet the inclusion and exclusion criteria of the study will be eligible to enter the 
Treatment Period. 
Treatment Period (Part A) 
At the end of the Screening Period, subjects will return to the study center for the Baseline Visit. 
All subjects will be assessed to confirm that they still meet the inclusion and exclusion criteria of 
the study. Eligible subjects will be randomized 2:1 to 1 of 2 treatment groups: PTC857 (250 mg 
BID) or matching placebo with 2 stratification factors:  
1. Amount of change in ALSFRS-R score during the Screening Period by points total loss: 
a. <1 
b. 1-2 
c. 3-4 
d. >4 
2. Use of edaravone, sodium phenylbutyrate/taurursodiol, or neither for the treatment of 
ALS at Screening as standard-of-care therapy: 
a. Edaravone 


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b. Sodium phenylbutyrate/taurursodiol 
c. Neither edaravone nor sodium phenylbutyrate/taurursodiol  
Subjects will undergo ALSFRS-R assessment during the Screening Period to determine whether 
they will be included in the ITT1 Analysis Set. 
Study visits will occur as described in the Schedule of Assessments and will include efficacy, 
PK, biomarker effects, and safety assessments. Efficacy assessments will include evaluation of 
disease progression, motor/limb and bulbar function, neuropsychological function, and 
respiratory function. Pharmacokinetic assessments will consist of blood and CSF sampling, and 
biomarker assessments will consist of blood, urine, and CSF sampling. Safety assessments 
consist of collecting information on TEAEs, TESAEs, clinical laboratory tests (hematology, 
serum chemistry, urinalysis), C-SSRS, physical examination, vital signs, and 12-lead ECGs. 
At the successful completion of the Treatment Period, all subjects will be offered the opportunity 
to enter the LTE Period of the study. Those who choose to enter will sign an additional Informed 
Consent Form (ICF) and continue treatment with PTC857 250 mg BID, as described below. 
Those who choose not to enter the LTE Period will stop treatment, and a Telephone Follow-Up 
Visit will be conducted 4 weeks (±3 days) after the last dose of study treatment. 
Long-Term Extension Period (Part B) 
Subjects who enter the LTE Period of the study will continue treatment for an additional 28 
weeks. All subjects will receive open-label PTC857 (250 mg BID) in the LTE Period. Subjects 
will remain blinded to their original treatment from the Treatment Period (Part A). 
Subjects will complete all activities as per the Schedule of Assessments (Table 2). At the end of 
the LTE Period, those who choose not to enter the Continued LTE Period will stop treatment, 
and a Telephone Follow-Up Visit will be conducted 4 weeks (±3 days) after the last dose of 
study treatment. 
Continued Long-Term Extension Period (Part C) 
Subjects who enter the Continued LTE Period (Part C) will continue treatment for an additional 
108 weeks. All subjects will be treated with open-label PTC857 (250 mg BID) during the 
Continued LTE Period. Subjects will remain blinded to their original treatment from the 
Treatment Period (Part A). 
Subjects participating in the Continued LTE Period will complete all activities as per the 
Schedule of Assessments (Table 3). At the end of this period, a Telephone Follow-Up Visit will 
be conducted 4 weeks (±3 days) after the last dose of study treatment. 
Results from the Treatment Period (Part A), the LTE Period (Part B), and the Continued LTE 
Period (Part C) will be reported separately. 
Pharmacokinetic Sub-Study 
Subjects from select sites will participate in the PK Sub-Study. Approximately 36 subjects will 
take part in an optional PK Sub-Study. These subjects will undergo additional assessments 
during the study as per the Schedule of Assessments (Table 1). 


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Table 1: 
Schedule of Assessments for Screening and Treatment Periods (Part A) 


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Treatment Period 
(24 W) 
EOS/ 
FU  
Early 
Termination 
Study Day 
Screening 
(-56 Days) 
(±5) 
Day -28 
(±3) 
Day 1 
(-3)a 
Day 14 
(±3) 
Day 29 
(±3) 
Day 57 
(±3) 
Day 85 
(±3) 
Day 113 
(±3) 
Day 141 
(±3) 
Day 169 
(±3) 
Day 197 
(±3) 
 
 
 
 
Baselinea 
 
 
 
 
 
 
End of 
Treatmentb 
Follow-
Upc 
ETd 
Telephone call/in-home 
or in-person visitf 
IP 
PC 
IP 
PC/IH 
PC/IHe,f 
PC/IHf 
IP 
PC/IHf 
PC/IHf 
IP 
PC 
IP 
COVID-19 PCR 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Xg 
 
 
Xh 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Re-evaluation eligibility 
 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight and BMI 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum/urine pregnancy 
test (females only)i 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
FSH measurementj 
X 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGk 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
Vital signsl 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Physical examm 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
Sparse PK blood 
samplingn 
 
 
X 
 
 
 
X 
 
 
X 
 
X 


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Treatment Period 
(24 W) 
EOS/ 
FU  
Early 
Termination 
Study Day 
Screening 
(-56 Days) 
(±5) 
Day -28 
(±3) 
Day 1 
(-3)a 
Day 14 
(±3) 
Day 29 
(±3) 
Day 57 
(±3) 
Day 85 
(±3) 
Day 113 
(±3) 
Day 141 
(±3) 
Day 169 
(±3) 
Day 197 
(±3) 
 
 
 
 
Baselinea 
 
 
 
 
 
 
End of 
Treatmentb 
Follow-
Upc 
ETd 
Clinical laboratory testso 
X 
 
X 
Xp 
X 
X 
X 
 
 
X 
 
X 
CSF for biomarkersq,r 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Laboratory biomarkers 
(blood and urine)s 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
ALSFRS-Rt 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PFTsu 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
ALS CBS 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
Modified Norris Scale 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
ALSAQ-40 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
EQ-5D-5L 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
C-SSRSv 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensation 
 
 
X 
 
 
 
X 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mammogramw 
X 
 
 
 
 
 
 
 
 
X 
 
Xx 


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Treatment Period 
(24 W) 
EOS/ 
FU  
Early 
Termination 
Study Day 
Screening 
(-56 Days) 
(±5) 
Day -28 
(±3) 
Day 1 
(-3)a 
Day 14 
(±3) 
Day 29 
(±3) 
Day 57 
(±3) 
Day 85 
(±3) 
Day 113 
(±3) 
Day 141 
(±3) 
Day 169 
(±3) 
Day 197 
(±3) 
 
 
 
 
Baselinea 
 
 
 
 
 
 
End of 
Treatmentb 
Follow-
Upc 
ETd 
PK Sub-Study Assessmentsy 
Telephone call or in-
person visit 
IP 
IP 
IP 
PC/IH 
IP 
PC/IH 
IP 
PC 
PC 
IP 
PC 
IP 
Serial PTC857 PK blood 
sampling 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Riluzole PK blood 
sampling 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Edaravone PK blood 
sampling 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Sodium 
phenylbutyrate/taurursod
iol PK sampling 
 
X 
X 
 
X 
 
 
 
 
 
 
 
CSF for PKz 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
Additional ECGs 
 
 
X 
 
X 
 
 
 
 
 
 
 
Abbreviations: ALS, amyotrophic lateral sclerosis; ALS CBS, ALS Cognitive Behavioral Screen; ALSAQ-40, ALS Assessment Questionnaire; ALSFRS-R, ALS 
Functional Rating Scale-Revised; BMI, body mass index; COVID-19, coronavirus disease 2019; CSF, cerebrospinal fluid; C-SSRS, Columbia-Suicide Severity 
Rating Scale; ECG, electrocardiogram; EOS, end of study; EQ-5D-5L, five-level European quality of life five-dimensional questionnaire; ET, early termination; 
FSH, follicle-stimulating hormone; FU, follow-up; ICF, Informed Consent Form; IH, in-home; IP, in-person; LTE, Long-Term Extension; p75NTR, p75 neurotrophin 
receptor; PC, telephone call; PCR, polymerase chain reaction; PFT, pulmonary function test; PI, Principal Investigator; PK, pharmacokinetic; SAE, serious adverse 
event 
a The Baseline Visit will be defined as Day 1 of the study. Baseline Visit procedures may be performed within the 3 days before the day that study drug is first 
administered. The day in which the first dose of study drug is administered will be Day 1. For subjects taking part in the PK Sub-Study, the PK laboratory tests 
must be completed on the same day as the first dose of study drug. 
b Day 169 will be considered the End of Treatment Visit only for those who choose not to enter the LTE Period (Part B). 
c Follow-up Visit on Day 197 only for subjects who choose not to enter the LTE Period (Part B). 
d For subjects who terminate early from the study and consent to continued follow-up, the investigator should attempt to gain vital status on the participant and 
conduct the ALSFRS-R assessment approximately every 28 days for the remaining duration of the study, in accordance with local requirements/regulations. 


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e The Day 29 Visit will be conducted in-person for subjects participating in the PK Sub-Study only. 
f For the telephone call/in-home visits, where applicable, the ALSFRS-R, C-SSRS, adverse events, and prior/concomitant medications assessments will be 
conducted via a telephone call. Vital signs assessments and samples for clinical laboratory tests will be collected via a home health nurse during applicable in-
home visits at the subject’s home during these visits. Subjects may go to the site for an in-person visit at the discretion of the PI. Visits indicated as in-person only 
may be conducted remotely (ie, in-home) following discussion between the site and the medical monitor. In-person visits that are conducted remotely must include 
the following assessments, at minimum (if such assessments are typically included during the visit): serum/urine pregnancy test (females only), vital signs, clinical 
laboratory tests, ALSFRS-R, C-SSRS, adverse events, prior/concomitant medications, sparse PK blood sampling, laboratory biomarkers, and ALSAQ-40. 
g The ICF for Part B should be provided to the subject at the Day 85 visit to allow the subject adequate time to consider transitioning into Part B. 
h The ICF for Part B should be signed by the subject at the Day 169 visit if they choose to enroll into Part B. 
i Women of childbearing potential will have a serum pregnancy test at the initial Screening Visit and then undergo monthly urine pregnancy testing starting from 
Day 1 prior to randomization through the Follow-up Visit. If a urine pregnancy test is positive, a serum pregnancy test will be conducted for confirmation and dosing 
should be immediately suspended and evaluated for continued study participation based upon the result of the serum pregnancy test and in discussion with the 
medical monitor. For months where an on-site visit is not scheduled, subjects will complete a urine pregnancy test at home, if local requirements allow, to be 
reported to the investigator and documented in the eCRF. 
j Postmenopausal female subjects only. 
k Single 12-lead ECG measurements will always be performed prior to the dose of medication administered at the clinic. Subjects should be resting for at least 
5 minutes in supine position prior to 12-lead ECG procedures. 
l Vital signs will consist of measurements of supine blood pressure, heart rate, body temperature, and respiratory rate. Vital sign measurements will be collected 
after the subject has been resting for 5 minutes. Blood pressure and heart rate measurements will be performed with subjects in a supine position, except when 
they semi reclined because of study procedures and/or AEs (eg, nausea, dizziness) or if deemed necessary by the PI or designee. 
m A full physical examination will be completed during Screening Period. A targeted physical examination, including neurological examination, will be completed at 
all other timepoints. 
n Blood samples for PK evaluation will be collected from all subjects not participating in the PK Sub-Study at predose (prior to the first dose of the day) and at 
1 hour (±15 minutes) and 4 hours (±1 hour) post-dose on Day 1 and Day 85. The first 36 subjects that enroll in the study will have a 6-hour (±1 hour) post-dose 
blood sampling on Day 1 and Day 85; this 6-hour post-dose blood sampling must be at least 2 hours following the 4-hour post-dose blood sampling. Subjects 
enrolled after the first 36 subjects may optionally have the 6-hour (±1 hour) post-dose blood sampling on Day 1 and Day 85, if feasible. Time of last dose of study 
drug prior to the study visit should be recorded. On all other visits with blood samples for PTC857 PK, blood samples will only be collected predose. If any SAEs 
are observed, ad hoc PK sample(s) may be collected, if possible, to measure the levels of PTC857, riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol 
to determine the causality. 
o Clinical laboratory tests will consist of fasting lipid profile, hematology, coagulation, blood chemistry, and urinalysis. Urinalysis will only be performed at in-person 
clinic visits (ie, Screening, Day 1, Day 85, and Day 169). 
p Clinical laboratory tests on Day 14 will consist only of a fasting lipid profile. Hematology and blood chemistry will not be evaluated during this visit. 
q It is the intention of the protocol that all subjects will consent to undergo lumbar punctures. Cerebrospinal fluid samples for biomarkers and PK will be collected at 
predose (first dose of the day) on both the Baseline Visit and the Day 169 Visit; lumbar punctures on these days may be conducted up to 5 days prior to the 
Baseline Visit and the Day 169 Visit. CSF biomarkers will be assessed as listed in Section 7.1.7. 
r  The lumbar puncture that is required may be skipped for an individual subject if the PI deems it appropriate, and after discussion with the medical monitor. 
s Laboratory (blood and urine) biomarkers (aligned with the timing for the clinical laboratory tests) as per Section 7.1.7. Urine creatinine should be tested when 
urine p75NTR is sampled. 
t The ALSFRS-R assessment must be performed by a certified rater. 
u Pulmonary function tests will assess slow vital capacity and Sniff Nasal Inspiratory Pressure. Forced vital capacity, vital capacity, forced expiratory volume, and 
maximum inspiratory pressure will not be measured. Refer to the laboratory manual for specific requirements at Screening. Oxygen saturation, respiratory rate, 
and heart rate will be assessed in both upright and supine positions. The Sniff Nasal Inspiratory Pressure test will assess nasal pressure in each unilaterally 
occluded nostril during a maximal sniff to assess inspiratory muscle strength. 


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v During the Screening Visit (Day -56), the “baseline” version of the C-SSRS will be administered. At all other visits, the “since last visit” version will be 
administered. 
w Mammograms to be conducted for female subjects only. A mammogram is not required during the Screening Period if the subject has had a negative breast 
cancer imaging status (ie, not considered clinically abnormal and/or requiring further evaluation/treatment) within 6 months prior to the Screening Visit. If clinically 
indicated, an ultrasound or MRI may also be conducted for breast cancer imaging, per the investigator’s discretion. If a subject cannot complete the Screening 
mammogram or any necessary follow-up procedures during the Screening Period, the Screening Period may be extended after discussion and agreement with the 
medical monitor. 
x Women who have been exposed to study drug for at least 3 months and discontinue treatment before reaching the Day 169 Visit will have breast cancer 
surveillance imaging performed at the Early Termination Visit. Women who have been exposed to study drug for <3 months and discontinue treatment before 
reaching the Day 169 Visit may have breast cancer surveillance imaging performed at the investigator’s discretion. 
y The following additional procedures will be conducted only in subjects taking part in the optional PK Sub-Study: 
- Blood samples for riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol PK will be collected at Day -28 predose (prior to the first dose of riluzole, 
edaravone, and/or sodium phenylbutyrate/taurursodiol on Day -28) and 1 hour (±15 minutes) post-dose. Subjects should be instructed not to take riluzole, 
edaravone, and/or sodium phenylbutyrate/taurursodiol on Day -28 prior to the study visit. 
- Blood samples for PTC857, riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol PK will be collected from those subjects taking part in the PK 
Sub-Study at predose (prior to the first dose of the day) and at 1, 2, 4, 5, 6, 8, and 12 hours (±15 minutes) (prior to the second dose) post-dose on Day 1 and 
Day 29. Blood samples for PTC857 PK only will be collected predose (prior to the first dose of the day) and at 1 hour (±15 minutes) and 4 hours (±1 hour) 
post-dose on Day 85, and predose only at all subsequent visits with blood PK sampling. Subjects should be instructed not to take riluzole, edaravone, and/or 
sodium phenylbutyrate/taurursodiol on Day 1 or Day 29 prior to the study visit. Time of last dose of study drug and riluzole, edaravone, and/or sodium 
phenylbutyrate/taurursodiol prior to the study visit should be recorded. 
- Additional samples of predose (trough) CSF will be collected for PK evaluation at all lumbar puncture timepoints. 
- Additional ECG measurements will be performed at the time of the 4-hour and 8-hour post-dose PK samples (±15 minutes from PK sample blood draw). 
z The lumbar punctures for CSF collection in the PK Sub-Study may occur within 5 days prior to or after the scheduled visit day. 


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Table 2: 
Schedule of Assessments for the Long-Term Extension Period (Part B) 
 
Long-Term Extension Period 
EOS/ 
Follow-Up 
Early 
Termination 
Study Day 
Day 169 
(±3) 
Day 183 
(±3) 
Day 197 
(±3) 
Day 225 
(±3) 
Day 253 
(±3) 
Day 365 
(±5) 
Day 393 
(±3)a  
ETb 
 
 
 
 
 
 
End of Treatment c 
 
 
Telephone call/in-home or in-person visitd 
IP 
PC/IHd 
PC/IHd 
PC/IHd 
IP 
IP 
PC 
IP 
Informed consent 
Xe 
 
 
 
Xf 
Xg 
 
 
Weight and BMI 
 
 
 
 
X 
X 
 
X 
Serum/urine pregnancy test  
(female subjects only)h  
 
 
 
(Monthly [Days 197, 225, 253, 281, 309, 337, and 365]) 
X 
X 
12-Lead ECGi 
 
 
 
 
X 
X 
 
X 
Vital signsj 
 
 
X 
X 
X 
X 
 
X 
Physical examk 
 
 
 
 
X 
X 
 
X 
PK blood samplel 
 
 
 
 
X 
X 
 
X 
Clinical laboratory testsm 
 
Xn 
X 
X 
X 
X 
 
X 
Laboratory biomarkers (blood and urine)o 
 
 
 
 
X 
X 
 
X 
ALSFRS-Rp 
 
 
X 
X 
X 
X 
X 
X 
PFTsq 
 
 
 
 
X 
X 
 
X 
ALS CBS 
 
 
 
 
X 
X 
 
X 
Modified Norris Scale 
 
 
 
 
X 
X 
 
X 
ALSAQ-40 
 
 
 
 
X 
X 
 
X 
EQ-5D-5L 
 
 
 
 
X 
X 
 
X 
C-SSRSr 
 
 
X 
X 
X 
X 
X 
X 
Study drug dispensation 
X 
 
 
 
X 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
Mammograms 
X 
 
 
 
 
X 
 
Xt 
Abbreviations: ALS, amyotrophic lateral sclerosis; ALS CBS, ALS Cognitive Behavioral Screen; ALSAQ-40, ALS Assessment Questionnaire; ALSFRS-R, ALS 
Functional Rating Scale-Revised; BMI, body mass index; CAFS, Combined Assessment of Function and Survival; CSF, cerebrospinal fluid; 
C-SSRS, Columbia-Suicide Severity Rating Scale; ECG, electrocardiogram; EOS, end of study; EQ-5D-5L, five-level European quality of life five-dimensional 
questionnaire; ET early termination; ICF, Informed Consent Form; IH, in-home; IP, In-person; LTE, Long-Term Extension; PC, telephone call; PFT, pulmonary 
function test; PI, Principal Investigator; PK, pharmacokinetic 
a Follow-up Visit on Day 393 only for subjects who choose not to enter the Continued LTE Period (Part C). 
b For subjects who early terminate from the study and consent to continued follow-up, the investigator should attempt to gain vital status on the participant and 
conduct the ALSFRS-R assessment approximately every 28 days for the remaining duration of the study, in accordance with local requirements/regulations. 
c Day 365 will be considered the End of Treatment Visit only for those who choose not to enter the Continued LTE Period (Part C). 
d For the telephone call/in-home visit, where applicable, the ALSFRS-R, C-SSRS, adverse events, and prior/concomitant medications assessments will be 
conducted via a telephone call. Vital signs assessments and samples for clinical laboratory tests will be collected via a home health nurse during applicable in-
home visits at the subject’s home during these visits. Subjects may go to the site for an in-person visit at the discretion of the PI. Visits indicated as in-person only 
may be conducted remotely (ie, in-home) following discussion between the site and the medical monitor. In-person visits that are conducted remotely must include 
the following assessments, at minimum (if such assessments are typically included during the visit): serum/urine pregnancy test (females only), vital signs, clinical 
laboratory tests, ALSFRS-R, C-SSRS, adverse events, prior/concomitant medications, sparse PK blood sampling, laboratory biomarkers, and ALSAQ-40. 
e Subjects who decide to enter the LTE Period should sign the consent form before the start of the LTE Period. 


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f The ICF for Part C should be provided to the subject at the Day 253 visit to allow the subject adequate time to consider transitioning into Part C. 
g The ICF for Part C should be signed by the subject at the Day 365 visit if they choose to enroll into Part C. 
h Women of childbearing potential will undergo monthly urine pregnancy testing on Days 197, 225, 253, 281, 309, 337, and 365, and at the Follow-up Visit. If a 
urine pregnancy test is positive, a serum pregnancy test will be conducted for confirmation and dosing should be immediately suspended and evaluated for 
continued study participation based upon the result of the serum pregnancy test and in discussion with the medical monitor. For months where an on-site visit is 
not scheduled, subjects will complete a urine pregnancy test at home, if local requirements allow, to be reported to the investigator and documented in the eCRF. 
i Single 12-lead ECG measurements will always be performed prior to the dose of medication administered at the clinic. Subjects should be resting for at least 5 
minutes in supine position prior to 12-lead ECG procedures. 
j Vital signs will consist of measurements of supine blood pressure, heart rate, body temperature, and respiratory rate. Vital sign measurements will be collected 
after the subject has been resting for 5 minutes. Blood pressure and heart rate measurements will be performed with subjects in a supine position, except when 
they semi reclined because of study procedures and/or AEs (eg, nausea, dizziness) or if deemed necessary by the PI or designee. 
k A targeted physical examination, including neurological examination, will be completed at all timepoints. 
l Blood samples for PK evaluation will be collected from all subjects at predose only. 
m Clinical laboratory tests will consist of fasting lipid profile, hematology, coagulation, blood chemistry, and urinalysis. Urinalysis will only be performed at in-person 
clinic visits (ie, Day 253 and Day 365). 
n Clinical laboratory tests on Day 183 will consist only of a fasting lipid profile. Hematology and blood chemistry will not be evaluated during this visit. 
o Laboratory (blood and urine) biomarkers (aligned with the timing for the clinical laboratory tests) as per Section 7.1.7. Urine creatinine should be tested when 
urine p75NTR is sampled. 
p The ALSFRS-R assessment must be performed by a certified rater. 
q Pulmonary function tests will assess slow vital capacity and Sniff Nasal Inspiratory Pressure. Forced vital capacity, vital capacity, forced expiratory volume, and 
maximum inspiratory pressure will not be measured. Oxygen saturation, respiratory rate, and heart rate will be assessed in both upright and supine positions. The 
Sniff Nasal Inspiratory Pressure test will assess nasal pressure in each unilaterally occluded nostril during a maximal sniff to assess inspiratory muscle strength. 
r At all visits, the Since Last Visits C-SSRS will be administered. 
s Mammograms to be conducted for female subjects only. If clinically indicated, an ultrasound or MRI may also be conducted for breast cancer imaging, per the 
investigator’s discretion. 
t Women who have been exposed to study drug for at least 3 months and discontinue treatment before reaching the Day 365 Visit will have breast cancer 
surveillance imaging performed at the Early Termination Visit. Women who have been exposed to study drug for <3 months and discontinue treatment before 
reaching the Day 365 Visit may have breast cancer surveillance imaging performed at the investigator’s discretion. 


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Table 3: 
Schedule of Assessments for the Continued Long-Term Extension Period (Part C) 
 
Continued LTE Period 
EOS/ 
Follow-Up 
Study Day/ 
Recurring Visita 
Day 365 
(±5) 
Day 449 
(±7) 
Day 533 
(±7) 
Day 617 
(±7) 
Day 701 
(±7) 
Day 785 
(±7) 
Day 869 
(±7) 
Day 953 
(±7) 
Day 1037 
(±7) 
Day 1121 
(±7) 
Day 1149 
(±3)  
 
 
 
 
 
 
 
 
 
 
End of 
Treatment
/ETb 
 
Telephone call/in-
home or in-person 
visita 
IP 
IP 
IP 
IP 
IP 
IP 
IP 
IP 
IP 
IP 
PC 
Informed consent 
Xc 
 
 
 
 
 
 
 
 
 
 
Serum/urine 
pregnancy test 
(female subjects 
only)d  
 
(Monthly  
[Days 393, 421, 449, 477, 505, 533, 561, 589, 617, 645, 673, 701, 729, 757, 785,  
813, 841, 869, 897, 925, 953, 981, 1009, 1037, 1065, 1093, and 1121]) 
X 
Weight and BMI 
 
 
X 
 
X 
 
X 
 
X 
X 
 
12-Lead ECGe 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital signsf 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Physical examg 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Clinical laboratory 
testsh 
 
 
X 
 
X 
 
X 
 
X 
X 
 
ALSFRS-Ri 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALSAQ-40 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mammogramk 
X 
 
 
 
X 
 
 
 
 
Xl 
 
Abbreviations: ALSAQ-40, ALS Assessment Questionnaire; ALSFRS-R, ALS Functional Rating Scale-Revised; C-SSRS, Columbia-Suicide Severity Rating 
Scale; ECG, electrocardiogram; EOS, end of study; ET, early termination; IP, in-person; PC, telephone call; PI, Principal Investigator 
a All study visits during the Continued LTE Period should be conducted on-site. Visits indicated as in-person only may be conducted remotely (ie, in-home) 
following discussion between the site and the medical monitor. In-person visits that are conducted remotely must include the following assessments, at minimum (if 
such assessments are typically included during the visit): serum/urine pregnancy test (females only), vital signs, clinical laboratory tests, ALSFRS-R, C-SSRS, 
adverse events, prior/concomitant medications, and ALSAQ-40. 
b For subjects who early terminate from the study and consent to continued follow-up, the investigator should attempt to gain vital status on the participant and 
conduct the ALSFRS-R assessment approximately every 28 days for the remaining duration of the study, in accordance with local requirements/regulations. 
c Subjects who decide to enter the Continued LTE Period should sign the consent form before the start of the Continued LTE Period. 
d Women of childbearing potential will undergo monthly urine pregnancy testing for the duration of the Continued LTE Period, and at the EOS/Follow-up visit or 
Early Termination. If a urine pregnancy test is positive, a serum pregnancy test will be conducted for confirmation and dosing should be immediately suspended 
and evaluated for continued study participation based upon the result of the serum pregnancy test and in discussion with the medical monitor. Subjects will 
complete a urine pregnancy test at home, if local requirements allow, to be reported to the investigator and documented in the eCRF. 


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e Single 12-lead ECG measurements will always be performed prior to the dose of medication administered at the clinic. Subjects should be resting for at least 
5 minutes in supine position prior to 12-lead ECG procedures. 
f Vital signs will consist of measurements of supine blood pressure, heart rate, body temperature, and respiratory rate. Vital sign measurements will be collected 
after the subject has been resting for 5 minutes. Blood pressure and heart rate measurements will be performed with subjects in a supine position, except when 
they are semi reclined because of study procedures and/or adverse events (eg, nausea, dizziness) or if deemed necessary by the PI or designee. 
g A targeted physical examination, including neurological examination, will be completed at all indicated timepoints. 
h Clinical laboratory tests will consist of hematology, coagulation, blood chemistry, and urinalysis. 
i The ALSFRS-R assessment must be performed by a certified rater. 
j At all visits, the Since Last Visits C-SSRS will be administered. 
k Mammograms to be conducted for female subjects only. If clinically indicated, an ultrasound or MRI may also be conducted for breast cancer imaging, per the 
investigator’s discretion. ALS is a progressive disease, that over time causes severe disability. Thus, if the PI believes that continued breast cancer surveillance is 
no longer feasible for a specific patent, this test may be skipped, after discussion with the medical monitor. 
l Women who discontinue from the study prior to the End of Treatment Visit may have breast cancer surveillance imaging performed at the Early Termination Visit, 
at the investigator’s discretion. 


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3.3. 
Number of Subjects 
The study is targeted to have approximately 307 subjects in the ITT1 Analysis Set (205 in the 
PTC857 group and 102 in the placebo group, based on a 2:1 randomization ratio).  
Approximately 36 subjects from select sites participating in the PK Sub-Study will participate in 
serial blood sampling to characterize the PK of PTC857 in subjects with ALS. 
3.4. 
Sample Size Justification 
For the primary efficacy endpoint, the combined assessment of ALSFRS-R and survival after 
24 weeks of treatment, 307 subjects in the ITT1 Analysis Set (205 in the PTC857 group and 102 
in the placebo group, based on a 2:1 randomization ratio) will provide approximately 85% power 
to detect a treatment difference of 2.5 points with a standard deviation of 5.3, based on a 2-sided 
0.05 level Joint Rank Test, and assuming 24-week survival rates of 96.5% and 95% in the 
PTC857 and placebo groups, respectively. Data from the 2 recently conducted clinical studies in 
ALS reported overall death rates of 5% and 0% (Edaravone (MCl-186) ALS 19 Study Writing 
Group 2017, Paganoni 2020). In addition, the edaravone study reported a standard deviation of 
5.3 points for the ALSFRS-R score at Week 24, among treated subjects. Assuming 
approximately 10% of subjects will not meet the ITT1 Analysis Set definition, then 
approximately 340 subjects will be randomized to ensure that 307 evaluable subjects are 
randomized into the ITT1 Analysis Set. Given that the primary analysis incorporates deaths as a 
combined endpoint, and a fully imputed analysis dataset is utilized in the analysis, additional 
sampling for missing data is not planned. 
If the attrition rate during the study is higher than expected, additional subjects may be enrolled 
in order to achieve the planned number of evaluable subjects. 
3.5. 
Rationale for Study Duration, Dosing Regimens, and Design 
3.5.1. 
Justification for Study Design and Duration 
The 24-week Treatment Period duration was selected in order to assess the effects of exposure of 
PTC857 on efficacy, safety, and biomarker activity. The study should provide robust data on the 
risk/benefit profile of PTC857 for the treatment of subjects with ALS. 
The Treatment Period duration of 24 weeks was selected based on the following reasons: 
• This duration of evaluation is considered appropriate to demonstrate statistically 
and/or clinically meaningful drug effects and/or potential trends over placebo on 
disease progression. 
• This duration of evaluation is considered adequate to provide a better understanding 
of the safety and tolerability of PTC857 compared with placebo. 
• This duration of evaluation is considered minimally sufficient to provide a better 
understanding of the relationship between effects on biomarker activity and clinical 
efficacy of PTC857. 
The LTE Period duration of 28 weeks was chosen to provide for a total of 52 weeks of 
continuous treatment without interruption between the Treatment and LTE Periods with PTC857 


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to allow for adequate duration to evaluate the long-term safety, tolerability, efficacy, and 
biomarker effects of PTC857. 
The Continued LTE Period duration was chosen to ensure that subjects have the opportunity to 
continue to receive PTC857 for an additional 108 weeks for continuing assessments of long-term 
safety and efficacy. 
3.5.2. 
Justification of Selected Doses 
The dose of PTC857 (250 mg BID) being evaluated in this study was selected based on 
nonclinical PK/PD and clinical PK data, as summarized below. 
In vitro, PTC857 functions as an inhibitor of the oxidoreductase 15-LO enzyme to reduce 
oxidative stress and spare reduced glutathione. Such inhibition could be demonstrated via the 
reduction of 15-LO lipid mediator 15-hydroxyeicosatetraenoic acid (15-HETE) in whole blood. 
A PK/PD study in mouse indicated that PTC857 reduced the 12/15-LO lipid mediator 
12-hydroxyeicosatetraenoic acid (12-HETE) in whole blood following a single-dose of PTC857. 
The inhibition of 12-HETE production is dose dependent and reached maximum inhibition 
effects (approximately 60% inhibition of 12-HETE production) at a dose of approximately 
100 mg/kg. There was a small increase in inhibition of 12-HETE production in whole blood 
when the dose was increased from 100 to 300 mg/kg. At a dose of 10 mg/kg PTC857, half of the 
maximum inhibition (inhibition reduced from 60% to 30%) of 12-HETE production in whole 
blood was observed. 
A preliminary population PK model was developed based on blinded data from the 
first-in-human study in healthy subjects (Study PTC857-CNS-001-PD) for the single ascending 
dose cohorts at PTC857 doses of 100, 250, and 500 mg with nominal sampling times. Based on 
the observed 12-HETE inhibition seen in the mouse model, the projected exposure for 250 mg 
BID is 1.7× of the exposure for maximum therapeutic effect and 7.7× of the exposure for half 
maximum therapeutic effect. It is expected that clinical therapeutic effects could be achieved at 
this dose with sufficient margin of safety (10×) based on the 3-month GLP toxicology study in 
the most sensitive species (rats). Mammary gland findings in female rats in the 6-month rat 
toxicology study were observed at ≥9× AUC exposure multiples compared with anticipated 
clinical exposures. AUC exposure multiples at the NOEL dose in female rats (30 mg/kg/day) for 
mammary gland findings were approximately 2× anticipated clinical exposures. 
In addition, PTC857 250 mg BID for up to 14 days of administration was demonstrated to be 
safe and well tolerated in a Phase 1 study in healthy subjects. There were no serious adverse 
events (SAEs), adverse events (AEs) leading to study drug discontinuation, or deaths in the 
study. In addition, the majority of AEs were mild in intensity and had resolved by the end of the 
study. The favorable safety profile observed with the use of PTC857 250 mg BID for up to 
14 days in healthy subjects further supports the dose selection for this study. 
3.5.3. 
Justification of Selected Study Objectives 
The selected clinical efficacy objectives were determined based upon their acceptance and 
precedence for evaluating and establishing therapeutic value of investigational interventions 
within the ALS clinical study space. The safety and tolerability objective will be assessed by 
monitoring of TEAEs, TESAEs, changes in laboratory parameters, and other safety measures 
during the study. Biomarker efficacy objectives were determined based on the following to 


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demonstrate and explore effects on target engagement and ALS-associated biomarker activity: 
(1) existing preclinical evidence of specific targets of engagement by PTC857 and existing 
clinical evidence of compounds that operate mechanistically similarly to PTC857; and 
(2) existing preclinical and clinical evidence of biomarker activity implicated and with potential 
for modulation in ALS and its disease course. 
Pharmacokinetic data will be used to characterize the PK of PTC857 in subjects with ALS and 
explore the relationships, if any, between the PTC857 levels and the safety and efficacy 
endpoints. Riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol plasma concentration 
is being measured to help characterize any exposure-response relationship and to inform data 
interpretation on PK, efficacy, and safety of PTC857. Additionally, efforts will be made to assess 
the relationships, if any, between exploratory biomarkers and drug concentrations in either 
plasma, urine, or CSF. 
The LTE Period of the study will further evaluate the effects of long-term treatment with 
PTC857 on safety and tolerability, efficacy, biomarker effects, and PK in subjects with ALS. The 
Continued LTE Period will further evaluate the effects of long-term treatment with PTC857 on 
safety and tolerability and efficacy in subjects with ALS. 
3.5.4. 
Justification of Selected Study Population 
The inclusion and exclusion criteria for this study were selected to provide a robust population of 
subjects with ALS with similar features, including, notably, disease progression, who may 
benefit from treatment with PTC857, while controlling for potential confounders to enable 
proper evaluation of the product. 
Of note, subjects are allowed to continue their current medications, including standard-of-care 
treatment (riluzole, edaravone, and sodium phenylbutyrate/taurursodiol), to ensure subjects are 
receiving therapy for their disease if indicated by their treating physician and the medication 
(riluzole, edaravone, and sodium phenylbutyrate/taurursodiol) regimen is standard and 
unchanged prior to the study for at least 30 (-3) days and is intended to remain stable and 
unchanged throughout the course of the study. The concomitant treatment with a combination of 
edaravone plus sodium phenylbutyrate/taurursodiol is excluded from this study. Furthermore, the 
use of any non-approved form of sodium phenylbutyrate and/or taurursodiol for the treatment of 
ALS is also excluded from this study. 
3.6. 
End of Study Definition 
A subject is considered to have completed Part A if they have completed the final Part A study 
visit (ie, either the Day 169 visit for Part A or the follow-up telephone call if they are not 
participating in the LTE Period [Part B]). The end of Part A is defined as the date of the last 
scheduled study procedure for the last subject in Part A. 
A subject is considered to have completed Part B if they have completed the final Part B study 
visit (ie, either the Day 365 visit for Part B or the follow-up telephone call if they are not 
participating in the Continued LTE Period [Part C]). The end of Part B is defined as the date of 
the last scheduled study procedure for the last subject in Part B. 


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A subject is considered to have completed Part C if they have completed the final Part C study 
visit, including the follow-up telephone call after the End of Treatment Visit. The end of Part C 
is defined as the date of the last scheduled study procedure for the last subject in Part C. 
The end of study (EOS) is defined as the date of the last scheduled study procedure of the last 
subject. 
3.7. 
Criteria for Study Termination/Interruption 
The investigator must temporarily interrupt or permanently discontinue the study drug if 
continued administration of the study drug is believed to be contrary to the best interests of the 
subject(s). If possible, the medical monitor should be consulted prior to interrupting or 
discontinuing the study drug. The reason for study drug interruption or premature 
discontinuation must be documented in the electronic case report form (eCRF), and PTC must be 
informed. 
If a subject terminates treatment with study drug, all efforts should be made to keep the subject 
in the study and to complete all study activities as per the Schedule of Events, excepting 
distribution of study drug. 
3.8. 
COVID-19 Risk Mitigation 
This study will be conducted in accordance with guidance from applicable regulatory bodies in 
each country on conducting Phase 2 studies in clinical research centers during the coronavirus 
disease 2019 (COVID-19) pandemic. 
During the entire study, the clinical research center will implement all recommendations issued 
by the applicable government, including specific guidelines related to clinical research executed 
in clinical research centers with respect to minimizing the risk of disease spreading (eg, social 
distancing, disinfection, hygiene, and wearing of personal protection equipment by study staff). 
In cases where subjects are not able to attend study visits due to an infection with severe acute 
respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the investigator will discuss with PTC 
potential mitigation approaches (including, but not limited to, extending the visit window, 
conducting evaluations via video link or telephone call, allowing for safety procedures to be 
conducted at a local facility). The rationale (eg, the specific limitation imposed by the 
SARS-CoV-2 infection that led to the inability to perform the protocol-specified assessment) and 
outcome of the discussion will be documented in the eCRF. 


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4. 
STUDY POPULATION 
4.1. 
Overview 
The study population will include adult subjects diagnosed with ALS who satisfy all entry 
criteria and do not meet any exclusion criteria. 
4.2. 
Inclusion Criteria 
Individuals eligible to participate in this study include those who meet all the inclusion criteria at 
both the Screening Visit and the Baseline Visit, unless otherwise stated: 
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: 
− Clinically definite ALS 
− 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 (refer to the laboratory manual for specific requirements)  
5. Subjects or their designee (ie, legal authorized representative or caregiver) must 
understand the nature of the study and must provide signed and dated written informed 
consent prior to conducting any study-related procedures 
6. Females must be either postmenopausal for ≥1 year (cessation of menses for 
12 consecutive months) or surgically sterile (having undergone tubal ligation, 
hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing 
potential and not abstinent, willing to use a highly effective method of contraception from 
the start of the Screening Period through 90 days after the last dose of study drug. 
Females who are abstinent will not be required to use a contraceptive method unless they 
become sexually active 
7. Females must refrain from ova (egg cell) donation from the start of the Screening Period 
through 90 days after the last dose of study drug 
8. Males, if not surgically sterilized, with female partners of childbearing potential must 
agree to use barrier contraceptive (ie, condom) and their female partners must use a 
highly effective method of contraception from the start of the Screening Period through 
90 days after the last dose of study drug 
9. Males must refrain from sperm donations from the start of the Screening Period through 
90 days after the last dose of the study drug 
10. Willing and able to comply with all protocol procedures 


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11. 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 (refer to inclusion criterion 13), 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. 
12. 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. 
13. 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. Note: should a subject be discontinued from standard-of-care 
therapy due to removal of the therapy from the market, this will not be considered a 
protocol deviation. 
4.3. 
Exclusion Criteria 
Individuals are not eligible to participate in this study if they have met or meet any of the 
following exclusion criteria at either the Screening Visit or the Baseline Visit, unless otherwise 
stated: 
1. History of allergies or adverse reactions to any of the excipients in the study drug 
formulation 
2. Females who are pregnant or nursing or plan to become pregnant during the study 
3. Subjects with clinically significant gastrointestinal, renal, hepatic, neurologic, 
hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or 
CV/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 
4. 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 
Note: The lumbar puncture may be skipped for an individual subject if the investigator 
deems it appropriate, and after discussion with the medical monitor. Subjects with a 
contraindication to lumbar punctures, such as but not limited to space-occupying lesion 
with mass effect, increase of intracranial pressure due to increased CSF pressure, 
posterior fossa mass, Arnold-Chiari malformation, anticoagulation medication use, 
coagulopathy, uncorrected bleeding diathesis, congenital spine abnormality, previous 
adverse event associated with a lumbar puncture or skin infection at the puncture site, 
should not undergo the lumbar punctures as listed in the Schedule of Events. These 
subjects may still enroll in the study and should undergo all other study procedures. 
5. Hepatic insufficiency, defined as liver function tests (LFTs) (ie, AST and/or ALT) ≥3× 
the upper limit of normal (ULN), or bilirubin ≥1.5× the ULN (except in the case of 
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6. Moderate or worse renal insufficiency, defined as an estimated glomerular filtration 
rate (eGFR) of <60 mL/min 
7. 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 
8. History of alcohol or drug abuse within the last 6 months prior to the start of the 
Screening Period or current evidence of substance dependence 
9. Any surgery within 30 days prior to the start of the Screening Period that may affect the 
subject’s ability to complete all study procedures 
10. Subject has previously received PTC857 
11. 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 
12. For female subjects, any past medical history of breast cancer, regardless of remission 
status, or any first degree relative with history of breast cancer 
13. Subject is taking a non-approved form of sodium phenylbutyrate and/or taurursodiol for 
the treatment of ALS 
4.4. 
Treatment Compliance 
The study drug will be dispensed based on the Schedule of Assessments (Table 1 and Table 2). 
The extent of exposure to study medication is defined as the last dose date minus the first dose 
date +1 day. Compliance will be assessed in terms of the percentage of drug taken relative to the 
amount that should have been taken during the study. Exposure and compliance will be 
summarized descriptively. 
4.5. 
Screen Failures 
Any subject who does not meet inclusion or exclusion criteria within the defined screening 
window prior to randomization will be considered a screen failure. Screen failures will be 
captured in the electronic data capture (EDC) system. Screen failures may be rescreened after 
consultation with the medical monitor. 
4.6. 
Subject Withdrawal Criteria 
Subjects will receive study treatment until protocol-specified study completion or treatment 
discontinuation for one of the reasons listed below. However, subjects may discontinue study 
treatment or withdraw their consent to participate in the study at any time without prejudice. In 
the event that a subject discontinues from study treatment, the subject should be encouraged to 
continue in the study and complete all study visits and planned study procedures other than 
administration of study drug. 
In the event that a subject completely withdraws from the study prematurely, and unless consent 
is withdrawn, all efforts must be made to collect efficacy and safety data and to complete the 
Early Termination Visit. The following conditions require subject discontinuation from all study 
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• At their own request or at the request of their legally authorized representative 
• If a subject experiences an AE that is deemed related to treatment with PTC857 and 
in the investigator’s or PTC’s medical judgment continuation of treatment would be 
detrimental to the subject 
• At the specific request of a regulatory agency or Data and Safety Monitoring Board 
(DSMB) for termination of treatment of an individual subject or all subjects under the 
protocol 
• Subject participation in another clinical study using an investigational agent or 
investigational medical device 
• Refusal of sexually active fertile subjects (excluding female subjects who have been 
sterilized) to use medically accepted methods of contraception 
• If a subject becomes pregnant 
• Significant noncompliance with the protocol in the opinion of the investigator or PTC 
• Any situation in which the investigator determines that the subject should not 
continue in the study 
The date PTC857 is discontinued and the reason for discontinuation will be recorded in the 
source documents and in the eCRF. The medical monitor (and designee) should be informed via 
email when a subject discontinues study drug. 
When PTC857 is discontinued, the investigator is expected to perform all the evaluations 
according to the subject’s original schedule and as required at the Early Termination Visit and 
any additional evaluations that may be necessary to ensure that the subject is free of untoward 
effects. 
Should a subject be discontinued from standard-of-care therapy due to removal of the therapy 
from the market, this will not be considered a protocol deviation. 


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5. 
STUDY INTERVENTION 
5.1. 
Study Intervention Administration 
5.1.1. 
Study Intervention Description 
The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the 
route/mode(s) of administration, and the Treatment Period(s), including the follow-up period(s) 
for subjects for each investigational product treatment/study treatment group/arm of the study are 
presented in Table 4. The Schedule of Assessments is presented in Table 1 and Table 2. 
Table 4: 
Investigational Product 
 
Investigational Product 
Product Name 
PTC857 oral solution 
Dosage Form 
Solution 
Unit Dosage Strength 
4.2 mL of PTC857 Oral Solution, 60 mg/mL (unflavored formulation) 
OR 
4.0 mL of PTC857 Oral Solution, 62.5 mg/mL (flavored formulation) 
 
All subjects will receive the unflavored formulation in Part A. Upon 
completion of Part A, subjects will progressively transition to receive the 
flavored formulation. 
Total Dose 
Subjects will receive 1 of 2 treatment regimens during the 24-week 
Treatment Period: PTC857 250 mg BID or placebo. 
Route of Administration 
Oral 
Physical Description 
Clear to translucent yellow to orange liquid 
Treatment Period 
All subjects will receive 24 weeks of treatment, an additional 28 weeks in 
the LTE Period, and an additional 108 weeks in the Continued LTE 
Period. 
Abbreviations: LTE, Long-Term Extension 
Refer to the IB for additional information. 
5.1.2. 
Dosing and Administration 
In all parts of the study, the dosing will take place in the morning and evening, approximately 
12 hours apart, with water and a meal (ie, with breakfast and dinner). 
Subjects will receive 1 of 2 treatment regimens during the 24-week Treatment Period: 
• PTC857 (250 mg) administered orally BID for 24 weeks 
• Matching placebo administered orally BID for 24 weeks 
Of note, since this is a double-blind study, all subjects will be given an equal number of bottles 
of either active drug or placebo to maintain the blind setting. 
All subjects will receive open-label PTC857 250 mg BID during the 28-week LTE Period and 
during the 108-week Continued LTE Period. 
When clinically indicated, nasogastric and/or percutaneous endoscopic gastrostomy feeding 
tubes made of polyurethane or silicone may be used for administration of PTC857. Any 
questions regarding usage of other materials for administration of PTC857 should be discussed 
with the Medical Monitoring Team. 


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5.2. 
Preparation/Handling/Storage/Accountability 
5.2.1. 
Preparation of PTC857 Oral Solution 
The drug product will be manufactured under cGMP conditions at a contract facility. 
5.2.2. 
Storage and Accountability 
Upon receipt of the study drugs, the responsible pharmacist or his/her designee will inspect all 
study drugs. Subsequently, he/she must immediately return the enclosed acknowledgment of 
receipt form, duly completed and signed (the date of receipt must be noted). 
The pharmacist or his/her designee is responsible for storage of the study drugs (placebo and 
PTC857 active pharmaceutical ingredient solution) at the study site in an appropriate secure 
locked area according to the instructions provided by PTC and/or the manufacturer. Only the 
pharmacist or his/her designee should handle the study drug. 
A Drug Accountability Record must be kept current and should at least contain the following 
information: 
• Subject number for whom the drug was prepared 
• Date and initials of the person who prepared the study drug 
• Date(s) on which drug was prepared, quantity of the drug prepared, and the relevant 
lot numbers 
The inventory must be available for inspection by the monitor. 
After PTC confirmation, all unused investigational material (drugs and packaging) must be 
returned to PTC or destroyed by the site on termination of the study and after a drug 
accountability check by the monitor, listing the following: 
• All PTC857 administered 
• All unused PTC857 
• All PTC857 returned at the EOS and the date of return/destroyed by the site 
The pharmacist will be responsible for the inventory and accountability of all clinical study 
material, exercising accepted pharmaceutical practices. An accurate, timely record of the clinical 
study material will be maintained. The clinical study material and the inventory will be available 
for inspection by the designated representatives of PTC upon request. The original Drug 
Preparation Protocol and Drug Accountability Record are considered as source data and will be 
archived at the site. 
5.2.3. 
Formulation, Appearance, Packaging, and Labeling 
5.2.3.1. 
Formulation and Appearance 
The appearance of the drug product is a clear to translucent yellow to orange liquid. 
5.2.3.2. 
Study Drug Packaging 
The study drug solution will be packaged in amber glass bottles with child-resistant closures. 


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5.2.3.3. 
Study Drug Labeling 
The labeling will comply with the applicable (local) laws and regulations. 
5.2.4. 
Handling of Study Drug 
Drug supplies must be kept in an appropriate, secure area and stored according to the conditions 
specified on the drug labels. The site must maintain an accurate record of the shipment and 
dispensing of study drug(s) on an accountability form. 
The pharmacist is responsible for keeping accurate records of the packaged and labeled drug 
product received from PTC or designee contract facility, and clinical supplies received from PTC 
or contract facility designee, including, but not limited to, the date received, lot number, amount 
received, amount returned, and the disposition of all study drug products. Drug accountability 
records must also be maintained by the site that include the subject’s assigned study number, 
date and amount of study drug dispensed, and relevant lot numbers. 
All drug supplies are to be used only for this protocol and not for any other purpose. The 
responsible person must not destroy any drug labels or unused drug supply. Used and unused 
drug containers can be destroyed at the site once drug accountability is final and checked by PTC 
or its deputy and written permission for destruction has been obtained from PTC. A certificate of 
destruction will be issued and shared with PTC. 
5.3. 
Measures to Minimize Bias: Randomization 
This is a double-blind study. The Interactive Web/Voice Response Systems (Interactive 
Response Technology) will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
subject’s intervention assignment is warranted. Subject safety must always be the first 
consideration in making such a determination. If a subject’s intervention assignment is 
unblinded, the sponsor per the medical monitoring plan must be notified within 24 hours of this 
occurrence. The outcome of the unblinding (ie, whether the subject was receiving active or 
placebo) must not be communicated to the sponsor. The date and reason for the unblinding must 
be recorded. 
Sponsor safety staff may unblind the intervention assignment for any subject with an SAE. 
5.3.1. 
Randomization 
After the written informed consent is signed, all subjects will enter the Screening Period. The 
Screening Period will last approximately 8 weeks. Subjects will complete all activities as per the 
Schedule of Assessments. All subjects who complete the full Screening Period and continue to 
meet the inclusion and exclusion criteria of the study will be eligible to be randomized and enter 
the Treatment Period. 
Subjects will be randomized 2:1 to either PTC857 (250 mg BID) or placebo using a central 
randomization process. The randomization will be stratified for the 2 stratification factors: 
1. Amount of change in ALSFRS-R score during the Screening Period by points total loss: 
a. <1 
b. 1-2 


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c. 3-4 
d. >4 
2. Use of edaravone, sodium phenylbutyrate/taurursodiol, or neither for the treatment of 
ALS at Screening as standard-of-care therapy: 
a. Edaravone 
b. Sodium phenylbutyrate/taurursodiol 
c. Neither edaravone nor sodium phenylbutyrate/taurursodiol 
The LTE Period and the Continued LTE Period are both open-label and non-randomized. 
The randomization schedules will be incorporated into the interactive response technology 
system. 
5.3.2. 
Treatment Assignment 
All subjects who return to the study center and maintain study eligibility at completion of the 
Screening Period will be randomized to 1 of 2 treatment groups: PTC857 (250 mg BID) or 
matching placebo at a 2:1 ratio with 2 stratification factors as outlined in Section 5.3.1. The 
Schedule of Assessments for the Treatment Period is presented in Table 1. 
All subjects who enter the LTE Period of the study will continue treatment for an additional 28 
weeks, and all subjects who enter the Continued LTE Period will continue treatment for an 
additional 108 weeks. All subjects will receive open-label 250 mg BID PTC857 during the LTE 
Period and during the Continued LTE Period. The Schedule of Assessments for the LTE and 
Continued LTE Periods are presented in Table 2 and Table 3, respectively. 
5.4. 
Study Intervention and Compliance 
Records of study drug used, dosages administered, and intervals between visits are kept during 
the study. Study drug accountability is performed on an ongoing basis by the study staff and 
checked by the monitor during site visits and at the completion of the study. 
5.5. 
Concomitant Therapy 
If a subject is not receiving standard-of-care therapy for the treatment of ALS at the time of 
entering the Screening Period, the investigator must evaluate whether the individual subject 
should begin treatment with standard-of-care therapy before entering the clinical study. 
Subjects are permitted to continue their current medications, including standard-of-care 
treatment (with the exception of the combination of edaravone plus sodium 
phenylbutyrate/taurursodiol), to ensure they are receiving appropriate therapy for their disease if 
indicated by their treating physician, so long as the standard-of-care therapy regimen is stable 
and unchanged prior to the study and is intended to remain stable and unchanged throughout the 
course of the study. Specific requirements for concomitant therapy are presented herein. 
All medications, including OTC treatments, should be kept at a stable and unchanged dose from 
14 days prior to the start of the Screening Period and throughout the study. New medications 
should not be started and/or the dose of a medication should not be changed unless needed to 
treat an AE or palliative management of progression of symptoms of ALS. 


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Subjects receiving standard-of-care therapy (riluzole, edaravone, or sodium 
phenylbutyrate/taurursodiol) for ALS must be on a stable and unchanged dose for at least 
30 (-3) days prior to the start of the Screening Period and intend to remain stable and unchanged 
throughout the course of the study. 
The combination of edaravone plus sodium phenylbutyrate/taurursodiol is not permitted for 
enrollment to this study. Furthermore, the use of any non-approved form of sodium 
phenylbutyrate and/or taurursodiol for the treatment of ALS is also excluded from this study. 
Subjects may not begin standard-of-care therapy (riluzole, edaravone, or sodium 
phenylbutyrate/taurursodiol) for ALS during the placebo-controlled Treatment Period (Part A). 
No other regionally approved treatments for ALS may be ongoing at the start of the Screening 
Period. 
Beginning upon entry to the LTE Period, participants may continue their established standard-of-
care treatment and/or initiate treatment with standard-of-care therapy based on their treating 
physician’s discretion where applicable or available without restriction to the number or 
combination of therapies. 
If concomitant medication is needed during the study, this medication must be recorded on the 
eCRF, stating its generic name, time of administration, dose, route, frequency, duration (start and 
stop date), and reason for administration. 
A list of prohibited concomitant medications during the course of the study is provided in 
Section 16.1. 


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6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
6.1. 
Premature Termination or Suspension of the Study 
PTC reserves the right to terminate the study at any time. If a study is prematurely terminated or 
suspended, PTC will promptly inform the investigators, the institutional review boards 
(IRBs)/independent ethics committees (IECs), and health authorities, as appropriate, and provide 
the reason(s) for the termination or suspension. 
6.2. 
Participant Discontinuation/Withdrawal From the Study 
Subjects may withdraw from the study at any time without prejudice to their future medical care 
by the physician or at the institution. 
The withdrawal of a subject from the study should be discussed where possible with the medical 
monitor before the subject stops taking the investigational product. If the investigational product 
is discontinued, the subject should be encouraged to continue in the study and complete all study 
visits and planned study procedures, other than administration of study drug. If a subject plans to 
completely withdraw from the study, the Early Termination procedures should be completed. 
6.3. 
Lost to Follow-Up 
Subjects are considered lost to follow-up if the attempts to contact the subject are unsuccessful. 
Efforts must be made on the part of the site to avoid any subject being lost to follow-up during 
the study. Before subjects are considered lost to follow-up, a minimum of 2 documented 
telephone contact attempts and 1 certified letter within 6 weeks of the most recent planned study 
visit must be sent in efforts to contact the subject. After being considered lost to follow-up, a 
subject’s status may be changed if the subject makes contact at a later time provided the study is 
ongoing. 
6.4. 
Subject’s Follow-Up After Study Discontinuation 
The subjects will be advised that participation in these investigations is voluntary. Furthermore, 
the subjects may request that from the timepoint of withdrawal, no more data will be recorded 
unless otherwise specified by the investigator and consent is provided by the subject (or 
designee). 
Subjects who prematurely discontinue from study drug intake should be encouraged to continue 
study participation. Subjects should continue to follow all activities as per the Schedule of 
Events, excepting the dispensation of study drug. 
In the case of premature discontinuation after study drug intake, the assessments scheduled for 
the EOS examination will be performed as soon as possible after study drug intake, as per 
investigator judgment, unless the subject withdrew informed consent. 
Every effort will be made to obtain follow-up information for all subjects whether or not they 
continue on treatment in the LTE Period or in the Continued LTE Period. 
With the subject’s consent, PTC will continue to follow-up on the subject’s long-term outcomes, 
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7. 
STUDY ASSESSMENT AND PROCEDURES 
The scheduled timepoints and study parameters are delineated in the Schedule of Assessments 
(Table 1 [Part A], Table 2 [Part B], and Table 3 [Part C]). 
In case several study procedures are scheduled at the same timepoint, the following sequence 
should be followed predose: 12-lead ECG, vital signs, PK blood sampling, and blood sampling 
for clinical laboratory tests. Likewise, for post-dose, the following sequence should be followed: 
12-lead ECG, vital signs, PK blood sampling, and blood sampling for clinical laboratory tests. 
During the Day 1, Day 85, and Day 169 Visits, the following testing clinical measures should be 
performed predose: ALSFRS-R, PFTs, ALS CBS, Modified Norris Scale, C-SSRS, and 
ALSAQ-40. The ALSFRS-R should be the first test performed; all other tests may be performed 
in any order. 
7.1. 
Efficacy Assessments 
Efficacy will be monitored through investigation of the following assessments, which will be 
collected according to the Schedule of Assessments (Table 1, Table 2, and Table 3). 
7.1.1. 
PFT Assessments 
Pulmonary function tests will assess slow vital capacity and Sniff Nasal Inspiratory Pressure 
(SNIP). Forced vital capacity, vital capacity, forced expiratory volume, and maximum 
inspiratory pressure will not be measured. Oxygen saturation, respiratory rate, and heart rate will 
be assessed in both upright and supine positions. The SNIP test will assess nasal pressure in each 
unilaterally occluded nostril during a maximal sniff to assess inspiratory muscle strength. 
7.1.2. 
Modified Norris Scale Assessment 
Motor/limb and bulbar function is assessed by the Modified Norris Scale (Oda 1996, Cedarbaum 
and Stambler 1997, Jenkinson 1999). 
The Modified Norris Scale is a rating scale for ALS that consists of 2 parts: the Limb Norris 
Scale and the Norris Bulbar Scale. The Limb Norris Scale has 21 items to evaluate extremity 
function, and the Norris Bulbar Scale has 13 items to evaluate bulbar function. Each item is rated 
in 4 ordinal categories. 
7.1.3. 
ALS Cognitive Behavioral Screen Assessment 
The ALS CBS is a brief measure of cognition and behavior in patients with ALS. The ALS CBS 
is composed of 2 sections: cognitive and behavioral. The cognitive section includes commonly 
used elements of standard testing batteries, consisting of 8 tasks that assess attention, 
concentration, tracking/monitoring, and initiation and retrieval. The behavioral section is 
composed of questions sensitive to organic brain changes. It consists of a set of questions that 
compare changes in personality and behavior since the onset of ALS, as well as yes/no questions 
about mood, pseudobulbar affect, and fatigue. 
7.1.4. 
ALSAQ-40 Assessment 
The ALSAQ-40 is a disease-specific measure of health-related quality of life for ALS. It is 
specifically used to measure the subjective well-being of patients with ALS and provides scores 


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for 5 scales: physical mobility, activities of daily living and independence, eating and drinking, 
communication, and emotional reactions.  
The ALSAQ-40 is a subjective health measure designed specifically to assess areas of 
importance in subjects with ALS. 
7.1.5. 
EQ-5D-5L Assessment 
The EQ-5D-5L is a measure of quality of life, where respondents rate their own health on 5 
different dimensions; each dimension has 5 levels of severity. Dimensions include mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. 
7.1.6. 
ALSFRS-R Assessment 
Disease progression will be assessed by ALSFRS-R score. 
The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the 
subjects’ capability and independence in 12 functional activities across 4 subdomains of bodily 
function (bulbar, gross motor, fine motor, and breathing) relevant in ALS. Each activity is 
recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 
4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating 
better function. 
7.1.7. 
Plasma-, Urine-, and CSF-Based Biomarkers 
Plasma- and CSF-based biomarker levels will be performed to evaluate PTC857’s biochemical 
activity and ability to modulate key aspects of disease pathology. 
Plasma-based biomarkers will be collected in all subjects. CSF-based biomarkers will only be 
collected at a subset of clinical sites, as follows: 
• Plasma: (target engagement) hydroxyeicosatetraenoic acid panel, (disease-specific 
biomarkers) NfL and ferritin, and (oxidative stress) 4-hydroxynonenal (4HNE) 
• Urine: p75 neurotrophin receptor (p75NTR) fragment extracellular domain 
normalized to creatinine 
• CSF: (disease-specific biomarker) NfL 
7.1.8. 
Plasma and CSF for PTC857 PK 
Blood samples will be collected following the first dose and at steady state to evaluate PTC857 
PK in subjects. 
CSF samples will be collected during the study to assess the change of PTC857 in CSF following 
multiple doses. 
Instruction for blood and CSF sampling, collection, processing, and sample shipment will be 
provided separately in a laboratory manual. 
7.1.8.1. 
Sparse Blood Sample Collection (Subjects Not in the PK Sub-Study) 
All subjects not participating in the PK Sub-Study will undergo sparse blood sampling to 
contribute toward a population PK model for PTC857. Blood samples will be collected from all 


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subjects not participating in the PK Sub-Study at predose (prior to the first dose of the day) and 
at 1 hour (±15 minutes) and 4 hours (±1 hour) post-dose on Day 1 and Day 85. The first 
36 subjects that enroll in the study will have a 6-hour (±1 hour) post-dose blood sampling on 
Day 1 and Day 85; this 6-hour post-dose blood sampling must be at least 2 hours following the 
4-hour post-dose blood sampling. Subjects enrolled after the first 36 subjects may optionally 
have the 6-hour (±1 hour) post-dose blood sampling on Day 1 and Day 85, if feasible. Time of 
last dose of study drug prior to the study visit should be recorded. On all other visits with blood 
samples for PTC857 PK, blood samples will only be collected predose. If any SAEs are 
observed, an ad hoc PK sample(s) may be collected, if possible, to measure the levels of 
PTC857, riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol to determine the 
causality. 
7.1.8.2. 
Serial Blood Sample Collection (PK Sub-Study) 
Approximately 36 subjects from select sites participating in the PK Sub-Study will participate in 
serial blood sampling to characterize the PK of PTC857 in subjects with ALS. Blood samples for 
the determination of PTC857 will be collected in blood collection tubes with dipotassium 
ethylenediaminetetraacetic acid (K2-EDTA). Blood sampling for PK will be collected as follows: 
• Blood samples for riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol PK 
will be collected at Day -28 predose (prior to the first dose of riluzole, edaravone, 
and/or sodium phenylbutyrate/taurursodiol on Day -28) and 1 hour (±15 minutes) 
post-dose. Subjects should be instructed not to take riluzole, edaravone, and/or 
sodium phenylbutyrate/taurursodiol on Day -28 prior to the study visit. 
• Blood samples for PTC857, riluzole, edaravone, and/or sodium 
phenylbutyrate/taurursodiol PK will be collected from those subjects taking part in 
the PK Sub-Study at predose (prior to the first dose of the day) and at 1, 2, 4, 5, 6, 8, 
and 12 hours (±15 minutes) (prior to the second dose) post-dose on Day 1 and Day 
29.  
• Blood samples for PTC857 PK only will be collected predose (prior to the first dose 
of the day) and at 1 hour (±15 minutes) and 4 hours (±1 hour) post-dose on Day 85, 
and predose only at all subsequent visits with blood PK sampling. Subjects should be 
instructed not to take riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol 
on Day 1 or Day 29 prior to the study visit. Time of last dose of study drug and 
riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol prior to the study visit 
should be recorded. 
7.1.8.3. 
CSF Sample Collection (PK Sub-Study) 
CSF samples will be collected predose (first dose of the day) on the Baseline Visit, Day 29 Visit, 
and the End of Treatment Visit (Table 1). The samples will be tested for biomarkers as per 
Section 7.1.7 and for PTC857 PK (PK Sub-Study only). Additional samples of predose (trough) 
CSF will be collected for PTC857 PK evaluation at all lumbar puncture time points. 
For subjects not taking part in the PK Sub-Study, the CSF samples will only be tested for 
biomarkers as per Section 7.1.7 but not for PTC857 PK. 


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7.1.8.4. 
Pharmacokinetic Parameters 
The following PK parameters will be calculated for PTC857 in plasma when appropriate: 
• AUC0-t: Area under the concentration-time curve (AUC) from time zero to time of 
last non-zero (measurable or sampled) concentration 
• AUC0-inf: AUC from time zero to infinity 
• Cmax: Maximum observed concentration 
• Cavg: Average concentration over a dosing interval 
• Tmax: Time to reach Cmax. If the maximum value occurs at more than 1 timepoint, Tmax 
is defined as the first timepoint with this value 
• Ctrough: Plasma concentration on Day 29 prior to the morning dose 
• λz: Apparent terminal rate constant calculated by linear regression of the terminal 
linear portion of the log concentration versus time curve 
• T½: Apparent terminal half-life 
• CL/F: Total body clearance 
• Sparse PK sampling collected for subjects not participating in the PK Sub-Study will 
be used for population PK analysis. 
7.1.8.5. 
Analytical Method 
Plasma samples will be analyzed for PTC857, riluzole, edaravone, and/or sodium 
phenylbutyrate/taurursodiol concentration using validated liquid chromatography with tandem 
mass spectrometry (LC-MS/MS) methods. Similarly, CSF samples will be analyzed for PTC857 
using a validated LC-MS/MS method. 
7.1.8.6. 
Timing for Sampling 
The PK blood and CSF sampling for PK timepoints are presented in the Schedule of 
Assessments for each part of the study (Table 1 and Table 2). 
7.1.8.7. 
Procedures for Sampling 
Approximately 4.0 mL of blood for the PK samples will be collected via venipuncture or via an 
intravenous catheter placed in a vein in the arm following local standard procedures. 
Approximately 0.5 mL of CSF will be collected via lumbar puncture following standard 
procedures. Information on equipment and further details on the procedures of the sampling will 
be documented in a separate PK instruction in the laboratory manual. 
7.1.8.8. 
Labeling 
PK blood and plasma tubes will be pre-labeled prior to sample collection. Detailed information 
regarding collection, processing, handling, and storage will be given in a separate PK instruction 
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7.1.8.9. 
Shipping Procedures 
The clinical site staff will take care of the shipment of the samples. Details on the procedures on 
the sample shipment will be documented in a separate PK instruction in the laboratory manual. 
7.2. 
Safety Assessments 
Safety will be monitored through assessment of the incidence and severity of TEAEs (AEs that 
begin after start of study drug), TESAEs, vital signs, weight and height measurements, physical 
examination findings, C-SSRS, 12-lead ECG, and results of clinical laboratory tests. 
Refer to the Schedule of Assessments (Table 1, Table 2, and Table 3) for the timing of each 
safety assessment. 
7.2.1. 
Vital Signs 
Vital sign measurements will be collected after the subject has been resting for 5 minutes. 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate will be 
measured. Additional vital signs may be taken at any other times if deemed necessary. 
Blood pressure and heart rate measurements will be performed with subjects in a supine position, 
except when they semi-reclined because of study procedures and/or AEs (eg, nausea, dizziness) 
or if deemed necessary by the principal investigator (PI) or designee. 
7.2.2. 
Weight and Height 
The subject’s body weight will be measured using a calibrated balance. Body weight will be 
recorded with 1 decimal. The subject’s height is measured without wearing shoes. The BMI will 
be calculated from the weight and height recorded during the Screening Period (based on the 
following formula): 
BMI (kg/m2)=weight (kg)/height2 (m2). 
7.2.3. 
Physical Examination 
A complete physical examination will be performed at Screening Period, and a targeted physical 
examination will be performed in the remainder of the visits. Clinically relevant findings that are 
observed prior to the Screening Period assessment must be recorded on the relevant Medical 
History eCRF section. Clinically relevant findings found after study drug initiation and meeting 
the definition of an AE (new AE or worsening of previously existing condition) must be 
recorded on the AE section of the eCRF. 
7.2.4. 
12-Lead Electrocardiogram 
The predose 12-lead ECG assessment will be performed prior to administration of the study drug 
at the clinic visit. In subjects in the PK Sub-Study, an additional 12-lead ECG will be taken at 
approximately 4 and 8 hours after administration of study drug. Additional ECGs may be taken 
at any other times if deemed necessary by the PI or designee. Subjects should be resting for at 
least 5 minutes in supine position prior to ECG procedures. 


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All ECG tracings will be reviewed by the PI or designee. ECGs will be evaluated and classified 
as normal/abnormal. In case of “abnormal,” the abnormality must be described and its relevance 
in terms of clinical significance documented. 
7.2.5. 
Clinical Laboratory Assessments 
Blood samples will be taken under fasted conditions. Subjects will not be allowed to eat for a 
period of 8 hours prior to blood sampling or drink (except water) for a period of 4 hours prior to 
blood sampling. 
All clinical laboratory tests listed in Table 5 will be performed as outlined in the Schedule of 
Assessments (Table 1 and Table 2). In addition, laboratory safety tests may be performed at 
various unscheduled timepoints if deemed necessary by the PI or designee. 
Clinically significant laboratory abnormalities must be reported by the investigator as an AE or 
SAE as appropriate. 
The results of all laboratory tests will be provided to the investigator in order for the 
investigation to make an assessment of clinical significance, with the exception of the lipid 
(cholesterol [total], low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglycerides, 
apolipoprotein A, apolipoprotein B), amylase, and lipase values. The lipid, amylase, and lipase 
values (both individual subjects and study level) will be monitored regularly for the entirety of 
the study by the DSMB. 
Table 5: 
Summary of Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Others 
Hemoglobin 
Hematocrit 
RBC count 
Reticulocytes 
Platelet count 
WBC count 
Neutrophils 
Eosinophils 
Monocytes 
Basophils 
Lymphocytes 
Mean corpuscular volume 
Urea 
Creatinine 
Fasting glucose 
Sodium 
Potassium 
ALT 
AST 
GGT 
Bilirubin (total, direct/indirect) 
Alkaline phosphatase 
Albumin 
Cholesterol (total) 
LDL 
HDL 
Triglycerides 
LDH 
Amylase 
Lipase 
Apolipoprotein A 
Apolipoprotein B 
Urobilinogen 
Nitrite 
pH 
Glucose 
Total protein 
Erythrocytes 
Leukocytes 
Ketones 
Microscopya 
Specific gravity 
Bilirubin 
Serum/urine 
pregnancy test 
(β-HCG)b 
FSH 
Coagulation (PT 
[sec], PT [INR], 
aPTT) 
Abbreviations: β-HCG, beta human chorionic gonadotropin; ALT, alanine aminotransferase; aPTT, activated partial 
thromboplastin time; AST, aspartate aminotransferase; FSH, follicle-stimulating hormone; 
GGT, gamma-glutamyltransferase; HDL, high-density lipoprotein; INR, international normalized ratio; LDH, lactate 
dehydrogenase; LDL, low-density lipoprotein; PCR, polymerase chain reaction; PT, prothrombin time; RBC, red blood 
cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WBC, white blood cell 
a Urine sediment examination will only be performed if there is an abnormality in urinalysis in accordance with clinical 
laboratory standard procedures. 
b Required for all female subjects.  


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Note: Nasal and throat mucosal cell samples will be collected according to work instructions detailed in the site-
specific manual. The samples will be tested for SARS‑CoV-2 virus using PCR tests. 
7.2.6. 
Pregnancy Test 
Serum pregnancy tests (beta human chorionic gonadotropin [β-HCG]) will be performed at 
Screening. Urine pregnancy tests will be used for all other scheduled visits. If a urine pregnancy 
test is positive, a serum pregnancy test will be conducted for confirmation and dosing should be 
immediately suspended and evaluated for continued study participation based upon the result of 
the serum pregnancy test and in discussion with the medical monitor. Urine pregnancy test 
results should be available immediately to site. The results must be available prior to dosing 
(Table 1, Table 2, and Table 3 ). 
7.2.7. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and suicidal 
behavior. The C-SSRS, which uses a semi-structured interview to probe subject responses, will 
be administered by an individual who has received training and certification in its administration. 
During the Screening Visit (Day -56), the “baseline” version of the C-SSRS will be 
administered. This version assesses suicidal ideation and suicidal behavior during the subject’s 
lifetime and during a predefined period. At all subsequent visits, the “since last visit” version 
will be administered. 
7.2.8. 
Breast Cancer Imaging Surveillance 
Mammograms will be performed for female subjects only. If clinically indicated, an ultrasound 
or MRI may also be conducted for breast cancer imaging, per the investigator’s discretion. 
7.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
7.3.1. 
Definition of Adverse Events 
An AE is an untoward medical occurrence associated with the use of a study intervention in 
humans, whether or not it is considered related to the study intervention. An AE can therefore be 
any unfavorable and unintended sign (for example, an abnormal laboratory findings), symptom, 
or disease in a study subject who is administered with study intervention in this study. 
Below are the criteria for the events that meet and do NOT meet the definition of an AE: 
Events Meeting the Adverse Event Definition 
• All AEs during the course of treatment with study intervention. 
• All AEs resulting from medication misuse, abuse, withdrawal, or overdose of study 
intervention. 
• All AEs resulting from medication errors such as dispensing or administration error 
outside of what is described in the protocol. 
• Apparent unrelated illnesses, including worsening of a preexisting illness. 
• Injury or accidents. Note that if a medical condition is known to have caused the 
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and the accident (fall) should be reported as 2 separate AEs. The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
• Laboratory or ECG abnormalities that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event.  
Events NOT Meeting the Adverse Event Definition 
• Laboratory abnormalities associated with a clinical event should be captured in the 
source documents. Laboratory abnormalities not requiring clinical intervention or 
further investigation will be captured as part of overall laboratory monitoring and 
should not be reported as AEs. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studies, unless more severe than expected for the subject’s 
conditions (see Section 7.3.11). 
• Preexisting conditions (eg, allergic rhinitis) must be noted in the eCRF at Screening 
but should not be reported as AEs unless the medical condition worsens, or episodes 
increase in frequency during the AE reporting period.  
• Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, 
should not be reported as AEs unless the medical condition for which the procedure 
was performed meets the definition of an AE. For example, an acute appendicitis that 
occurs during treatment with the study drug should be reported as the AE, and the 
resulting appendectomy should be recorded in the source documents and eCRF. If a 
surgical procedure was planned prior to entry into the study, and the surgery is not 
performed because of a worsening of a baseline condition, this should not be reported 
as an AE. Note that, as described in Section 7.3.2, any hospitalization occurring as the 
consequence of an AE during the study period should be reported as an SAE. 
Each AE is to be classified as serious or nonserious by the investigator using medical and 
scientific judgment. 
7.3.2. 
Definition of Serious Adverse Event 
An SAE is an untoward medical occurrence or effect at any dose, regardless of whether it is 
related to the study intervention, which results in one of the following: 
• Results in death. This includes all deaths on treatment or within 30 days after last 
study intervention administration, including deaths due to disease progression. Any 
death occurring later than 30 days following the last dose need not be reported as an 
SAE unless it is a result of an event that started within the period covered by the on-
study definition. The reported AE should be the event that caused the death. In 
addition, any AE resulting in death that occurs post the AE reporting period and that 


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the investigator assesses as possibly related to the study intervention should also be 
reported as serious. 
• Is life-threatening. This refers to an event in which the subject was at risk of death at 
the time of the event. It does not include an event that, had it occurred in a more 
severe form, hypothetically might have caused death. 
• Requires hospitalization or prolongation of existing hospitalization (excluding 
hospitalizations for administration of the study intervention, procedures required by 
the study protocol, or treatment-related diagnostic procedures; other planned 
hospitalizations; or hospitalizations related only to progression of disease). 
Emergency room visits that do not require admission to the hospital do not fall into 
this category, but the event may be serious due to another seriousness criterion. 
• Results in persistent or significant disability or incapacity or substantial disruption of 
the ability to conduct normal life functions. 
• Any other medically important event that the investigator or PTC judges to be serious 
or which is defined as serious by the regulatory agency in the local country. These are 
AEs that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. Medical judgment should be 
exercised in deciding whether an AE is serious based on the above definition. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
• A pregnancy resulting in spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly (including that in an aborted fetus). 
Note: Hospitalization for social circumstances without any other accompanying SAE should not 
be reported as an SAE. 
7.3.3. 
Adverse Events Reporting 
AEs will be reported by the subjects (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue and 
obtain adequate information both to determine the outcome and to assess whether the event 
meets the criteria for classification as an SAE or caused the subject to discontinue the study 
intervention (see Section 6.1). 
Each subject/parent(s)/legal guardian will be questioned about the occurrence of AEs in a 
nonleading manner. 
In addition, the investigator may be requested by the PTC Pharmacovigilance Department to 
obtain specific follow-up information in an expedited fashion. 
All AEs are to be recorded in the source documents and on the eCRF using concise medical 
terminology; whenever possible, terms contained in the Medical Dictionary for Regulatory 


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Activities (MedDRA) should be employed. In addition, the following information should be 
recorded: 
• Indication of whether the event is serious or nonserious (see Section 7.3.2) 
• Relationship to study intervention (see Section 7.3.5) 
• Severity of the event (see Section 7.3.5) 
• Onset date  
• Resolution date, or date of death 
• Action taken 
• Outcome of the event 
Table 6 below summarizes the investigator site requirements for recording AEs on the eCRF and 
for reporting SAEs, adverse events of special interest (AESI) on the SAE Report Form to the 
PTC Pharmacovigilance Department. 
Table 6: 
Investigator Site Requirements for Recording/Reporting Adverse Events 
Event 
Recorded on the eCRF 
Reported to the PTC 
Pharmacovigilance Department 
Within 24 Hours of Awareness 
Serious AE 
All 
All 
Nonserious AE 
All 
None 
Other, eg, exposure to the study 
intervention during pregnancy or 
breastfeeding 
All (regardless of 
whether associated with 
an AE) 
All 
(regardless of whether associated with 
an AE) 
AESI 
Not applicable 
Not applicable 
Abbreviations: AE, adverse event, AESI, adverse event of special interest, eCRF, electronic care report form 
7.3.4. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
The AE (both serious and nonserious) collection and reporting period begins with the signing of 
the ICF and continues until 30 days after the last dose of study medication. All AEs during this 
time period must be recorded, whether or not the event is considered drug related. 
For subjects who are screen failures, the active collection period for AEs ends when screen 
failure status is determined. Any SAEs occurring during screening procedures, should have the 
appropriate completed causality assessment (ie, “not related” to study intervention) section of the 
SAE Report Form completed. 
If the subject withdraws from the study and also withdraws consent for the collection of future 
information, the active collection period for AEs ends when consent is withdrawn. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly notify PTC 
Pharmacovigilance Department via the SAE Report Form. 


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7.3.4.1. 
Serious Adverse Event Reporting 
All SAEs (both initial and follow-up) should be reported via the SAE Report Form to the PTC 
Pharmacovigilance Department immediately and under no circumstance should this exceed 
24 hours from awareness. In addition, the AE portion of the eCRF must also be completed. 
The SAE Report Form must be signed by the investigator; however, if the investigator is unable 
to sign at the time of the event or within 24 hours, the form should be signed by the clinical staff 
member reporting the SAE (eg, the study coordinator). The SAE Report Form must be faxed or 
emailed to the PTC Pharmacovigilance Department and to the site IRB/IEC (if required by local 
regulations) within 24 hours. The investigator’s signature must be obtained as soon as possible 
after the report is submitted and the report revised if necessary, and submitted to the PTC 
Pharmacovigilance Department. The investigator will maintain a copy of the SAE Report Form 
on file at the study site. 
Follow-up information to the SAE should be clearly documented as “follow-up” in the SAE 
Report Form and must also be faxed or emailed to the same party within the same timelines. All 
follow-up SAE Report Forms for the event must be signed by the investigator as per instructions 
above. Any source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test 
results, discharge summaries) provided to the PTC Pharmacovigilance Department should be 
redacted so that the subject’s name, address, and other personal identity information are 
obscured. Only the subject’s study number and initials are to be provided (in regions where the 
provision of such information is permitted). The information in the AE portion of the eCRF and 
the SAE Report Form(s) must match or be reconciled. Where the same data are collected, the 
forms must be completed in a consistent manner. For example, the same AE term should be used 
on both forms. 
The PTC Pharmacovigilance Department contact information for reporting SAEs is provided 
below. This information is also provided in the SAE Report Form: 
PTC Pharmacovigilance Department  
Email: Pharmacovigilance@ptcbio.com 
SAE FAX Line: +1-908-325-0355 
7.3.5. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
7.3.5.1. 
Assessments of Severity of Adverse Events 
The severity of AEs will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. For each episode, the highest severity grade attained should be reported. 
The investigator will make an assessment of severity for each AE and SAE reported during the 
study and assign it to 1 of the following categories (Table 7). 


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Table 7: 
Grading of Adverse Events 
Grade 
Adjective  
Description  
1  
Mild  
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2  
Moderate  
Minimal, local, or noninvasive intervention indicated, limiting 
age appropriate instrumental Activities of Daily Living (ADL). 
Instrumental ADL refers to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
3  
Severe  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL. Self-care ADL refers to bathing, dressing, and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
4  
Life-threatening 
Sign or symptom results in urgent intervention.  
5  
Fatal  
Sign or symptom results in death.  
7.3.5.2. 
Describing Adverse Event Relationship to Study Intervention 
The investigator should provide an assessment of the relationship of the AE/SAE to the study 
intervention and each occurrence of each AE/SAE outlined in Table 8. The investigator will use 
clinical judgment to determine the relationship. 
The investigator will also consult the IB and/or product information, for marketed products, in 
his/her assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations in which an AE/SAE has occurred, and the investigator has minimal 
information to include in the initial SAE Report Form to the PTC Pharmacovigilance 
Department. However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE Report Form to the PTC 
Pharmacovigilance Department. 
The investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. 
• If no valid reason exists for suggesting a relationship, then the AE should be 
classified as “unrelated.” If a relationship cannot be excluded but there is a clear 
alternate cause that is more likely to have caused the AE than the study intervention, 
the AE should be considered “unlikely related.” 
• If there is any valid reason, even if undetermined, for suspecting a possible 
cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “possibly or probably related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable,” the event will be considered related to the investigational product for 
the purposes of expedited regulatory reporting. An assessment of “unlikely related” will be 
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The investigator may change his/her opinion of causality in light of follow-up information and 
must send an SAE follow-up report with the updated causality assessment.  
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements (Table 8). 
Table 8: 
Relationship of Study Intervention to Adverse Event 
Relationship 
Description  
Probably 
A clinical event in which a relationship to the study drug seems probable because of 
such factors as consistency with known effects of the drug; a clear temporal 
association with the use of the drug; improvement upon withdrawal of the drug; 
recurrence upon rechallenge with the drug; lack of alternative explanations for the 
event.  
Possible  
A clinical event occurring coincident with administration of the study intervention, and 
which may or may not be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal or rechallenge may be lacking.  
Unlikely  
A clinical event with a temporal relationship to the study intervention exposure that 
does not preclude causality but for which there is a clear alternate cause that is more 
likely to have caused the adverse event than the study intervention. Such alternatives 
include a concomitantly administered drug, the subject’s disease state, other medical 
conditions, or environmental factors.  
Unrelated  
A clinical event for which a relationship to the study intervention seems improbable 
because of factors such as inconsistency with known effects of the study intervention, 
lack of a temporal association with study drug administration, lack of association of the 
event with study intervention withdrawal or rechallenge, and/or presence of alternative 
explanations for the event. Alternative explanations might include a known relationship 
of the adverse event to a concomitant drug, medical history of a similar event, the 
subject’s disease state, other medical conditions, or environmental factors.  
7.3.6. 
Treatment of Adverse Events and Serious Adverse Events 
Treatment of AEs and SAEs will be symptom-based and at the discretion of the investigator. 
7.3.7. 
Follow-Up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 6.3). 
All AEs should be followed up by the investigator until they are resolved or the investigator 
assesses them as chronic or stable. The investigator should consider protocol guidelines and use 
his/her discretion in ordering additional tests as necessary to monitor the resolution of such 
events. In the event of additional investigations, the PTC Pharmacovigilance Department should 
be informed via email or fax. 
A subject withdrawn from the study because of an AE must be followed by the investigator until 
clinical recovery is complete and laboratory results have returned to normal, or until progression 
has been stabilized. Follow-up may need to continue after the subject has discontinued from the 
study, and additional investigations may be requested by the medical monitoring team. 
The investigator must submit any updated SAE information to the PTC Pharmacovigilance Department 
within 24 hours of receipt of the information. 


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7.3.8. 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the investigator to PTC of an SAE is essential so that legal obligations 
and ethical responsibilities toward the safety of subjects and the safety of a study intervention 
under clinical investigation are met. 
As the sponsor of the study, PTC has a legal responsibility to notify the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. PTC will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/independent ethics 
committees (IECs), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives SUSAR or other safety-specific information (eg, summary or 
listing of SAEs) from PTC will review and then file it along with the reference document and 
will notify the IRB/IEC, if appropriate according to local requirements. 
7.3.9. 
PTC Expedited Reporting of SUSARs to EudraVigilance 
In the EU, as per requirements of EU Clinical Trials Regulation No. 536/2014 of the European 
Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for 
Human Use, and Repealing Directive 2001/20/EC, SUSARs should be submitted to the 
EudraVigilance database. Additional direct submissions from the Sponsor to Ethics Committees 
and National Competent Authorities are not required. 
As per the EU Clinical Trials Regulation, the Sponsor shall notify the Member States concerned 
of all findings which affect the benefit-risk balance of the medicinal product or clinical trial, and 
any urgent safety measures (USMs) taken. The Sponsor will submit findings that affect the 
benefit-risk balance or any USM via the Clinical Trials Information System (CTIS). 
7.3.10. 
Exposure During Pregnancy or Breastfeeding 
Exposure to the study intervention under study during pregnancy or breastfeeding are reportable 
to the PTC Pharmacovigilance Department within 24 hours of investigator awareness. 
7.3.10.1. Exposure During Pregnancy 
PTC Pharmacovigilance Department must be notified in the event that a female subject in the 
study, or a female partner of a male subject in the study, becomes pregnant on-study or within 
90 days of the last dose of the study intervention on an Investigational and Marketed Products 
Pregnancy Report Form (hereafter referred to as Pregnancy Report Form) (see study manual for 
details). This must be reported whether or not an AE has occurred and within 24 hours of 
awareness of the pregnancy. The information submitted should include the anticipated date of 
birth or pregnancy termination. 
Written consent is required prior to collecting and reporting any information on a female partner 
of a male subject in the study. 


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In any of the 4 situations listed below, the subject will be provided with a Pregnancy/Pregnant 
Partner Data Release Form to request their consent to follow the progress of the pregnancy and 
the birth and the health of their child. 
• Subject becomes pregnant while participating in the study. 
• Female partner of a male subject participating in the study becomes pregnant. 
• Subject becomes pregnant up to 30 days after completion of the study. 
• Female partner of a male subject participating in the study becomes pregnant up to 
90 days after the partner completed the study. 
Because the risk to an unborn child is unknown, the subject should be asked to sign the 
Pregnancy/Pregnant Partner Release Form. However, signing this form is voluntary; it is up to 
the subjects to decide whether to agree to the collection of this information or not. Upon signing, 
the subject’s and the child’s medical records relating to the pregnancy and delivery, and the 
health of the child, will be reviewed for up to 1 year of age. 
If possible, the investigator should follow the subject, or the pregnant female partner of a male 
subject, until completion of the pregnancy and notify the PTC medical monitor of the outcome 
within 5 days or as specified below. The investigator must provide this information as a follow-
up to the initial Pregnancy Report Form via the Pregnancy Outcome Section (see the study 
manual for details). 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus]), the investigator should follow the procedures for reporting SAEs (ie, report the 
event to PTC Pharmacovigilance Department and follow-up by completion of appropriate AE 
eCRFs and submission of the SAE Report Form). 
All information collected with regard to the pregnancy, delivery of the child, and the health of 
the child is confidential to the limit allowed by law. These data will be coded to hide the 
subject’s identity and the identity of the child. In particular, the subject’s name and the child’s 
name will not be reproduced on any other paper or electronic document. These data will not be 
disclosed voluntarily by PTC. However, regulatory agencies may have to examine these data to 
ensure that the study is done properly. 
Of note, if the pregnant female partner of a male study subject participating in the study does not 
wish to provide such information, this will not prevent the partner from continuing with the 
study. 
Any female subject who becomes pregnant while participating in the study will discontinue 
study intervention/withdrawn or be excluded from the study (see Section 4.3). 
7.3.10.2. Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 
• A female subject is found to be breastfeeding while receiving or up to 30 days after 
discontinuing study intervention. 


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• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact. 
The investigator must report exposure during breastfeeding to the PTC Pharmacovigilance 
Department within 24 hours of the investigator’s awareness, irrespective of whether an SAE has 
occurred. The information must be reported using the Pregnancy Report Form. When exposure 
during breastfeeding occurs in the setting of environmental exposure, the exposure information 
does not pertain to the subject enrolled in the study, so the information is not recorded on an 
eCRF. However, a copy of the completed Pregnancy Report Form is maintained in the 
investigator site file. An exposure during breastfeeding report is not created when a PTC drug 
specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accordance with authorized use. However, if the infant experiences an SAE associated with such 
a drug, the SAE is reported together with the exposure during breastfeeding via SAE Report 
Form. 
7.3.11. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
7.3.11.1. Progression of Underlying Disease 
If the progression of the underlying disease is greater than that which would normally be 
expected, or if the investigator considers that there may be a causal relationship between the 
investigational medicinal product or protocol design/procedures and the disease progression, 
then it must be reported to the PTC Pharmacovigilance Department within 24 hours of 
awareness. 
7.3.11.2. Abnormal Findings Associated with the Disease Being Studied 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen following the start 
of the study will be reported as AEs or SAEs. However, clinically significant abnormal 
laboratory findings or other abnormal assessments that are associated with the disease being 
studied, unless judged by the investigator as more severe than expected for the subject’s 
condition, or that are present or detected at the start of the study and do not worsen, should not 
be reported as AEs or SAEs. 
7.3.12. 
Contraceptive Guidance  
7.3.12.1. Male Participant Reproductive Inclusion Criteria 
Male subjects are eligible to participate if they agree to the following requirements during the 
intervention period and for at least 90 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study intervention(s): 
• Refrain from donating sperm. 


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PLUS, either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR 
• Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male subjects (refer to the list of highly effective 
methods below in Section 7.3.12.4). 
7.3.12.2. Female Participant Reproductive Inclusion Criteria 
A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least1 of 
the following conditions applies: 
• Is not a woman of childbearing potential (WOCBP) (see definitions below in 
Section 7.3.12.3). 
OR 
• Is a WOCBP and using an acceptable contraceptive method as described below 
during the intervention period (for a minimum of 90 days after the last dose of study 
intervention). The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention. The investigator is 
responsible for review of medical history, menstrual history, and recent sexual 
activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
7.3.12.3. Women of Childbearing Potential 
Women of childbearing potential includes any female who is fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
Postmenopausal is defined as no menses ≥12 months with or without an alternative medical 
cause. In addition, a high follicle-stimulating hormone level in the postmenopausal range must 
be used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. 
7.3.12.4. 
Contraception Methods 
Below are the general contraceptive methods (which are both highly and non-highly effective) 
use by men or women should be consistent with local availability/regulations regarding the use 
of contraceptive methods for those participating in clinical trials. 
1. Intrauterine device. 
2. Intrauterine hormone-releasing system. 


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3. Bilateral tubal occlusion. 
4. Vasectomized partner: 
• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. The spermatogenesis cycle is approximately 90 days. 
5. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral 
• Intravaginal 
• Transdermal 
6. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral 
• Injectable 
• Implantable 
7. Sexual abstinence: 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
subject 
7.3.13. 
Adverse Events of Special Interest 
There are currently no identified AESI for PTC857. 
7.3.14. 
Medication Errors 
Medication errors may result from the administration or consumption of the study intervention 
by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Table 9: 
Investigator Site Requirements for Recording/Reporting Medication Errors 
Event 
Recorded on the eCRF 
Reported to the PTC 
Pharmacovigilance Department 
Within 24 Hours of Awareness 
Medication errors 
All (regardless of whether associated 
with an AE) 
Only if associated with an SAE 
Abbreviations: AE, adverse event; eCRF, electronic case report form; SAE, serious adverse event 
Medication errors include the following: 
• Medication errors involving subject exposure to the study intervention 


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• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study subject 
• The administration of expired study intervention 
• The administration of an incorrect study intervention 
• The administration of an incorrect dosage 
• The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by PTC that the study 
intervention under question is acceptable for use. 
Such medication errors occurring to a study subject are to be captured in source and eCRF as 
applicable. 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, 
the medication error is recorded on source and, if applicable, any associated AE(s), serious and 
nonserious, are recorded on the AE page of the eCRF. Medication errors should be reported to 
the PTC Pharmacovigilance Department within 24 hours on a SAE Report Form only when 
associated with an SAE. 
7.3.15. 
Safety Oversight 
An independent DSMB will be utilized during the study. The DSMB will closely monitor 
potential emerging safety signals in all subjects in the study throughout their study participation, 
including the planned transition without interruption in treatment from Part A to Part B of the 
study. 


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8. 
STATISTICAL CONSIDERATOINS 
A Statistical Analysis Plan (SAP) will be prepared before database lock. 
8.1. 
Statistical Hypotheses 
For the primary efficacy endpoint, the null hypothesis of this study is that the subject ranks based 
on the composite survival and change from baseline in ALSFRS-R after the 24-week Treatment 
Period are the same in the PTC857 group and in the placebo group versus the alternative that 
they are different. 
The primary efficacy endpoint will be analyzed on the ITT1 Analysis Set at the significance 
level of 0.05 (2-sided). If p<0.05, then the study will be declared positive. 
8.2. 
Sample Size Determination 
For the primary efficacy endpoint, the combined assessment of ALSFRS-R and survival after 
24 weeks of treatment, 307 subjects in the ITT1 Analysis Set (205 in the PTC857 group and 102 
in the placebo group, based on a 2:1 randomization ratio) will provide approximately 85% power 
to detect a treatment difference of 2.5 points with a standard deviation of 5.3, based on a 2-sided 
0.05 level Joint Rank Test, and assuming 24-week survival rates of 96.5% and 95% in the 
PTC857 and placebo groups, respectively. Data from the 2 recently concluded clinical studies in 
ALS reported overall death rates of 5% and 0% (Edaravone (MCl-186) ALS 19 Study Writing 
Group 2017, Paganoni 2020). In addition, the edaravone study reported a standard deviation of 
5.3 points for the ALSFRS-R score at Week 24, among treated subjects. Assuming 
approximately 10% of randomized subjects will not meet the ITT1 Analysis Set definition, then 
approximately 340 subjects will be randomized to ensure that 307 subjects are randomized into 
the ITT1 Analysis Set. Given that the primary analysis incorporates deaths as a combined 
endpoint, and a fully imputed analysis dataset is utilized in the analysis, additional sampling for 
missing data is not planned. 
8.3. 
Population for Analyses 
Intent-to-Treat 1 Analysis Set: All subjects who are randomized after the Screening Period and 
take at least 1 dose of double-blind study drug in the Treatment Period and who have a decrease 
in the ALSFRS-R score of ≤4 points during the Screening Period will be included in the ITT1 
Analysis Set. Subjects will be analyzed according to their randomized treatment. The ITT1 
Analysis Set will be used for analysis of the primary endpoint. 
Intent-to-Treat 2 Analysis Set: All subjects who are randomized after the Screening Period and 
take at least 1 dose of double-blind study drug in the Treatment Period will be included in the 
ITT2 Analysis Set. Subjects will be analyzed according to their randomized treatment. 
Per Protocol Analysis Set: All subjects in the ITT1 Analysis Set who have no major protocol 
deviations that affect the validity of the efficacy measurements will be included in the PP 
Analysis Set. The PP Analysis Set will be used for sensitivity analysis of the efficacy endpoint. 
The criteria for inclusion in the PP Analysis Set will be finalized prior to study unblinding and 
detailed in the SAP. 


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Safety Analysis Set: All subjects in the ITT2 Analysis Set who receive at least 1 dose of study 
drug will be included in the Safety Analysis Set. Subjects will be analyzed according to the 
actual treatment received. 
PK Analysis Set: All subjects in the ITT2 Analysis Set who have at least 1 measurable plasma 
or CSF PTC857 concentration will be included in the PK Analysis Set. 
8.4. 
Statistical Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in the SAP. The analysis of the data for the Treatment Period (Part A) (ie, up to 
the Week 24 Visit) will be produced after the lock of database for Part A. The LTE Period 
(Part B) of the study will continue for all subjects participating in that part, and results from Part 
B will be reported separately. The Continued LTE Period (Part C) of the study will continue for 
all subjects participating in that part, and the results from Part C will also be reported separately. 
8.4.1. 
Primary Efficacy Endpoint 
For the primary efficacy endpoint, subject ranks based on the combined assessment of function 
and survival (CAFS) ranking method, will be analyzed when all subjects in the ITT1 Analysis 
Set finish the Treatment Period (Part A). This analysis will be performed using an analysis of 
covariance (ANCOVA) model following multiple imputation. Subjects who discontinue from the 
study prior to Week 24 will have their Week 24 ALSFRS-R score imputed using multiple 
imputation. The ANCOVA model will include the following covariates: treatment arm (PTC857 
and placebo), baseline ALSFRS-R score, the amount of change in the subject’s ALSFRS-R score 
during the Screening Period (<1, 1-2, and 3-4 points total loss), and standard-of-care exposure 
with rank scores as the response variable. A p value for the difference will be presented. 
The analysis of the primary efficacy endpoint will occur when the Part A database is locked. 
Sensitivity and subgroup analyses of the primary efficacy endpoint will be described in the SAP. 
8.4.2. 
Secondary Efficacy Endpoints (Part A) 
Change from baseline in ALSFRS-R at Week 24 will be evaluated by means of a mixed model 
repeated measures analysis using all available ALSFRS-R scores up to Week 24. The model will 
include fixed effects for treatment (PTC857 and placebo), baseline ALSFRS-R value, time of 
collection (actual week at the visit as a categorical variable), time-by-treatment interaction, 
time-by-baseline ALSFRS-R interaction, the amount of change in the subject’s ALSFRS-R score 
during the Screening Period (<1, 1-2, and 3-4 points total loss), standard-of-care exposure, 
TRICALS risk profile, and TRICALS risk profile by time interaction as covariates. The 
unstructured covariance matrix (UN) will be used in the model. Other types of covariance 
matrices will be explored in the case of non-convergence of the UN. Subjects with no 
post-baseline results for the outcome variable will be excluded. This analysis will be performed 
for the ITT1 and ITT2 analysis sets. 
Analysis of other secondary endpoints and sensitivity analyses will be specified in the SAP. 
8.4.3. 
Long-Term Extension Period Efficacy Endpoints (Part B) 
The analysis details for the LTE Period will be included in the SAP. 


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8.4.4. 
Continued Long-Term Extension Period Efficacy Endpoints (Part C) 
The analysis details for the Continued LTE Period will be included in the SAP. 
8.4.5. 
Safety Analyses 
Safety is measured by the severity and number of TEAEs and TESAEs, change from baseline in 
clinical laboratory tests, physical examination, vital signs, and 12-lead ECGs during the 
Treatment Period. 
Baseline is defined as the last value measured prior to first dose intake (vital signs, 12-lead ECG, 
laboratory parameters, C-SSRS), unless otherwise specified. 
The following have been defined as parameters regarding safety and tolerability: 
• Change from baseline to each scheduled timepoint up to EOS for vital signs 
• Change from baseline to each scheduled timepoint up to EOS for 12-lead ECG 
parameters 
• Change from baseline to each scheduled timepoint up to EOS for clinical laboratory 
tests 
• Changes from baseline in C-SSRS scores 
• Treatment-emergent AEs up to EOS 
• Treatment-emergent AEs leading to premature discontinuation of study drug 
• Treatment-emergent SAEs up to EOS 
All safety data will be populated in the individual eCRFs. Safety data, including dosing dates and 
times, will be listed by subject. 
All AEs and SAEs will be coded using the most current version of MedDRA available at PTC 
and summarized by treatment for the number of subjects reporting the TEAEs/TESAEs and the 
number of TEAEs reported. 
The TEAEs/TESAEs are tabulated by System Organ Class (SOC) and individual Preferred 
Terms within each SOC by treatment group. The number and percentage of subjects who 
experienced AEs coded with the same Preferred Term and SOC will be summarized by treatment 
group (in descending order according to the incidence in the investigational study drug group). 
Adverse events will also be tabulated by severity and by relationship to study drug. Summary 
tables will be accompanied by individual subject listings broken down by treatment group, 
including predose events. 
Reasons for death will only be listed. Reasons for premature discontinuation of study drug will 
be listed and summarized by frequency tables. 
Safety data, including 12-lead ECGs, vital signs assessments, and clinical laboratory results, will 
be summarized at each timepoint using mean, median, standard deviation, minimum, maximum, 
number of available observations, and change from baseline. Individual subject listings of 
12-lead ECG data, vital signs data, laboratory measurements, and C-SSRS scores will be 
provided. 


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Standard numeric laboratory parameters are presented in the units supplied. If needed, a 
conversion will be made to standard units. 
Quantitative safety data as well as the difference from baseline, when appropriate, will be 
summarized using the appropriate descriptive statistics. 
Concomitant medications will be listed by subject and coded using the most current version of 
World Health Organization (WHO) drug dictionary available at PTC. 
8.4.6. 
Pharmacokinetic Analyses 
The plasma PTC857, riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol 
concentrations, the PK parameters, and CSF exposure listed in Section 7.1.8.4 and 
Section 7.1.8.5 will be summarized using appropriate descriptive statistics, which will be fully 
outlined in the PK SAP. 
8.5. 
Interim Analysis 
No interim analysis is planned for this study. 


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9. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
In accordance with 21 Code of Federal Regulations Part 312.56 and/or relevant ICH guidelines, 
PTC or a designee will periodically inspect all eCRFs, study documents, research facilities, and 
clinical laboratory facilities associated with this study at mutually convenient times, before, 
during, and after completion of the study. As required by applicable regulations (FDA 2020), the 
monitoring visits provide PTC with the opportunity to evaluate the progress of the study; verify 
the accuracy and completeness of data in the eCRFs; ensure that all protocol requirements, 
relevant regulations, and investigator’s obligations are being fulfilled; and resolve any 
inconsistencies in the study records. This includes inspection of all documents and records 
required to be maintained by the investigator, including but not limited to medical records 
(office, clinic, or hospital) for the subjects in this study. The names and identities of all research 
subjects will be kept in strict confidence and will not appear on eCRFs or other records provided 
to or retained by PTC. The investigator/institution guarantees direct access to source documents 
by PTC or a designee and appropriate regulatory authorities. 
It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits, or inspections and that sufficient time is devoted to the 
process. 
9.1. 
Study Monitoring 
Before a potential investigational site can be selected to conduct the study, a representative of 
PTC or its designee will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence and the responsibilities of PTC or its representatives. This will 
be documented in a Clinical Study Agreement between PTC and the investigator 
During the study, a monitor from PTC or representative will have regular contacts with the 
investigational site for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice and other 
records relevant to the study. This will require direct access to all original records for 
each patient (eg, clinic charts) 
• Record and report any protocol deviations not previously sent to PTC 


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• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to PTC and those SAEs that met criteria for reporting 
have been forwarded to the IRB/IEC 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
9.2. 
Audits and Inspections 
PTC may conduct audits of clinical research activities in accordance with internal Standard 
Operating Procedures to evaluate compliance with the principles of Good Clinical Practice 
(GCP) and ICH-related guidelines. 
Health authorities may also wish to conduct an inspection (during the study or after its 
completion). Should an inspection be requested by health authorities, the investigator must 
inform PTC immediately that such request has been made. 
The investigator will permit such audits by PTC or health authorities and facilitate them by 
providing access to the relevant source documents. 


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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, PTC, 
PTC’s representatives, a regulatory authority, IEC, and/or IRB may conduct a quality assurance 
audit. Reasons for quality assurance audit may include, but are not limited to, random selection, 
geographic proximity, suspected GCP violation, high enrolling site, recurring protocol 
deviations, etc. The purpose of an audit or inspection by PTC is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. The 
investigator should contact PTC immediately if contacted by a regulatory agency about an 
inspection. 
10.1. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to, the following: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications that are specifically prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc (either the tests were not done, 
the incorrect tests were done, or the tests were not done within the time frame 
specified in the protocol) 
• Procedural deviations such as incorrect storage of study drug, failure to update the 
ICF when new risks become known, or failure to obtain IRB/IEC approvals for the 
protocol and ICF revisions 
Major deviations are any deviations that impact subject eligibility (ie, protocol 
inclusion/exclusion violations), subject safety, or a subject’s ability to continue in the study. 
At the outset of the study, a process for defining and handling protocol deviations will be 
established with the contract research organization (CRO). This will include determining which 
deviations will be designated major, thus requiring immediate notification to the medical monitor 
and PTC. Prospective deviations (eg, protocol waivers) are prohibited by PTC policy. The 
investigator is responsible for seeing that any known protocol deviations are recorded as agreed. 


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11. 
ETHICS 
11.1. 
Ethics Review 
The PI must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval and all 
materials approved by the IRB/IEC for this study, including the patient consent form and 
recruitment materials, must be maintained by the investigator and made available for inspection. 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The investigator must submit 
written approval to PTC before he or she can enroll any subject into the study. 
The PI is responsible for informing the IRB or IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit patients for the study. The protocol must be re-approved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. 
The PI is also responsible for providing the IRB or IEC with reports of any reportable serious 
adverse drug reactions from any other study conducted with the investigational product. PTC 
will provide this information to the PI. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
11.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory 
requirements, including EU Regulation No. 536/2014. 
11.3. 
Written Informed Consent 
By signing the protocol, the investigator assures that informed consent will be obtained from 
each subject/subject’s designee (legally authorized representative or caregiver) prior to study 
entry and that the informed consent will be obtained in accordance with current regulations. 
The investigator or sub-investigator will give each subject full and adequate verbal and written 
information regarding the objectives and procedures of the study and the possible risks involved. 
An informed consent document will be provided to each subject or designee in a language in 
which they are fluent. This information must be provided to the subject prior to undertaking any 
study-related procedure. Adequate time should be provided for the subject or designee to read 
the informed consent, to understand the risks and benefits of participating in the study, and to ask 
any questions that the subject may have about the study. The subject’s signature on the ICF 
should be obtained at the investigator site in the presence of the investigator or a qualified 
representative (eg, sub-investigator). 
The original signed ICFs will be retained by the investigator with the study records. The written 
subject information must not be changed without prior approval by PTC and the IRB/IEC. 
Due to the nature of ALS disease progression, it is anticipated that subjects who may not be able 
to provide ongoing written informed consent for the duration of the study, but could provide 
ongoing nonwritten informed consent, may be enrolled. Hence, nonwritten consent, which may 


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require the presence of a witness, may be provided in accordance with country-specific 
legislations as applicable.  
In addition, disease progression may make it difficult to attend on-site visits; hence, subjects may 
provide informed consent remotely, in accordance with site process and local 
requirements/regulations. The study site should provide the consent form in hard copy to the 
subject by post or delivered by a home healthcare professional. The subject’s written consent 
would be gathered on the consent form and collected by the home healthcare professional at a 
home visit. 


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12. 
DATA HANDLING AND RECORDKEEPING 
To enable evaluations and/or audits from regulatory authorities or PTC, the investigator agrees to 
keep accurate and complete records, including the identity of all participating subjects (sufficient 
information to link eCRFs and clinic records/source documents), all original signed ICFs, 
electronic copies (ie, CD-ROM, USB, etc) or paper copies of the data that have been captured in 
the EDC for each subject (eCRFs), and detailed records of study drug disposition. 
The investigator agrees to keep all information provided by PTC in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC. Study documents provided by 
PTC will be stored appropriately to ensure their confidentiality. The information provided by 
PTC to the investigator may not be disclosed to others without direct written authorization from 
PTC, except to the extent necessary to obtain informed consent from subjects who wish to 
participate in the study. 
All records and documents pertaining to the study will be maintained by the investigator until 
notification is received from PTC that the records no longer need to be retained. The investigator 
must obtain written permission from PTC before disposing of any records. The investigator will 
promptly notify PTC in the event of accidental loss or destruction of any study records. If the 
investigator relocates, retires, or for any reason withdraws from the study, the study records may 
be transferred to an acceptable designee, such as another investigator, another institution, or to 
PTC as applicable. 
12.1. 
Inspection of Records 
PTC will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, Drug Accountability Records, subject charts and study 
source documents, and other records relative to study conduct. 
12.2. 
Retention of Records 
The investigator will maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents will be 
classified into 2 different categories: investigator’s file and subject clinical source documents. 
The investigator’s file will contain the protocol/amendments, eCRFs, IEC/IRB and Health 
Authority approval with correspondence, informed consent, drug records, staff curriculum vitae 
and authorization forms, screening and enrollment logs, and other appropriate 
documents/correspondence as per ICH/GCP and local regulations. 
Subject clinical source documents include, but are not limited to, subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory, 12-lead ECG, pathology 
and special assessment reports, consultant letters, etc. 
These 2 categories of documents must be kept on file by the investigator for as long as needed to 
comply with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval or 25 years, whichever is longest). No study 
document should be destroyed without prior written approval from PTC. Should the investigator 
wish to assign the study records to another party, or move them to another location, PTC must be 
notified in advance. 


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When source documents are required for the continued care of the subject, appropriate copies 
should be made for storing outside of the site. 
The handling of personal data will comply with local regulations. 
12.3. 
Future Use of Stored Specimens and Data 
As part of the current study, blood, urine, and CSF will be collected. Sample processing will be 
performed by a laboratory under the direction of PTC. Processing, analysis, and storage will be 
performed at a secure laboratory facility to protect the validity of the data and maintain subject 
privacy. Samples will only be used for the purposes described in this protocol. Laboratories 
contracted to perform the analysis on behalf of PTC will not retain rights to the samples beyond 
those necessary to perform the specified analysis and will not transfer or sell those samples. PTC 
will not sell the samples to a third party.  
PTC may store biospecimen for up to 5 years after the end of the study, in accordance with local 
regulations, to achieve study objectives. Additionally, with the subject’s consent, samples may 
be used for further research by PTC to contribute to the understanding of ALS. A section within 
the ICF will address the use of remaining samples for optional exploratory research. 
Further research may include the biomarkers of neurodegeneration, synaptic function, 
inflammation, and metabolism/oxidative stress, if new assays are developed or validated and/or 
if more robust longitudinal and cross-sectional data are available. 
Subjects may request their samples be destroyed at any time. Samples collected while the subject 
was participating under consent of the study will be stored and analyzed, if necessary, in order to 
maintain the ability to analyze any samples if requested by a regulatory authority, or for any 
potential safety and/or efficacy reasons. 
At the end of the storage period, samples will be destroyed. Samples may be stored longer if a 
health authority (or medicinal product approval agency) has active questions about the study. In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed. No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with any of the biologic samples. All samples will be single coded. 
PTC will take steps to ensure that data are protected accordingly, and confidentiality is 
maintained as far as possible. 
Data from subjects enrolled in this study may be analyzed worldwide, regardless of location of 
collection. PTC and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research. These include the following: 
• CROs retained by PTC 
• IECs or IRBs that have responsibility for this research study 
• National regulatory authorities or equivalent government agencies 


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At the end of the analysis, results may be presented in a final report that can include part or all of 
the coded data in listing or summary format. Other publication (eg, in peer-reviewed scientific 
journals) or public presentation of the study results will only include summaries of the 
population in the study, and no identified individual results will be disclosed. Given the research 
nature of the laboratory analysis, it will not be possible to return individual data to subjects. The 
results that may be generated are not currently anticipated to have clinical relevance to the 
patients or their family members. Therefore, these results will not be disclosed to the patients or 
their physicians. 


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13. 
PUBLICATION POLICY 
The information developed during the conduct of this clinical study is considered confidential by 
PTC. This information may be disclosed as deemed necessary by PTC. 
PTC intends that the data from this study will be presented and published. The PTC staff under 
the direction of the PTC Chief Development Officer or designee in collaboration with the 
investigator will be responsible for writing presentations and manuscripts for publication. 
Investigators will not be allowed to publish or present the data from this study without prior 
agreement with PTC. 
The investigator is obliged to provide PTC with complete test results and all data derived by the 
investigator from the study. During the study, only PTC may make study information available 
to other study investigators or to regulatory agencies, except as required by law or regulation. 
Except as otherwise allowable in the Clinical Study Site Agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of PTC. 
PTC may publish any data and information from the study (including data and information 
generated by the investigator) jointly with the investigator. Manuscript authorship for any 
peer-reviewed publication will appropriately reflect contributions to the production and review 
of the document. All publications and presentations must be prepared in accordance with this 
section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
Data from all sites participating in the study will be pooled and analyzed by PTC or PTC’s 
designee. The first publication of the study results shall be made in conjunction with the results 
from other study sites as a multicenter publication. If a multicenter publication is not 
forthcoming within 24 months of completion of the study at all sites, the investigator may 
publish or present the results generated at his or her site. 
The investigator will provide PTC with a copy of any proposed publication or presentation for 
review and comment at least 60 days prior to such presentation or submission for publication. 
PTC shall inform the investigator in writing of any changes or deletions in such presentation or 
publication required to protect PTC’s confidential and proprietary technical information and to 
address inaccurate data or inappropriate interpretations in the context of any pooled multicenter 
results. At the expiration of such 60-day period, the investigator may proceed with the 
presentation or submission for publication unless PTC has notified the institution or the 
investigator in writing that such proposed publication or presentation discloses PTC’s 
confidential and proprietary technical information. Furthermore, upon the request of PTC, the 
investigator will delay the publication or presentation for an additional 90 days to permit PTC to 
take necessary actions to protect its intellectual property interests. 


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14. 
PROTOCOL AMENDMENT HISTORY 
Version 1.0: 19 January 2022 
Version 2.0: 14 March 2022 
Version 3.0: 13 July 2022 
Version 4.0: 31 October 2022 
Version 5.0: 08 September 2023 
Version 6.0: 14 June 2024 
14.1. 
Version 6.0: 14 June 2024 
The overall reason for Version 6.0 of the protocol was to revise the list of objectives and 
endpoints and update the statistical methodology for the study. 
Section # 
Description of Change 
Brief Rationale 
Protocol 
The version number and date were updated throughout. 
Editorial and administrative revisions (eg, typographical 
errors, punctuation, tenses, abbreviations) were 
incorporated to provide clarity.  
The synopsis, study design figure, and Schedule of 
Assessments were updated to be consistent with the 
changes in the protocol. 
The EU CT number was added and PTC’s address was 
updated throughout. 
Update 
Section 1.2 
Table 4  
Added details on the flavored formulation of PTC857. 
Update 
Section 1.4.1  
Added details on the completed embryo-fetal development 
and fertility and early embryonic development studies. 
Update 
Section 1.4.2 
Added details on the 3 additional completed Phase 1 
studies. 
Update 
Section 1.5.2 
Section 11.3  
Added details on nonwritten consent and remote consent. 
Update 
Section 2.1.2 
Section 2.1.3 
Section 2.2.2 
Section 2.2.3 
Section 2.2.4  
Neuropsychological function was moved to be an 
exploratory objective and endpoint rather than secondary. 
An objective for evaluating the efficacy in reducing disease 
progression in the population with any baseline rate of 
disease function was added. 
Revised the change from baseline in respiratory function to 
be change from baseline in slow vital capacity. 
Neurofilament light chain activity was added as a 
secondary objective and endpoint. 
Exposure-response relationships was added as an 
exploratory endpoint. 
Update 
Section 2.2.1  
The wording of the primary endpoint was updated to match 
the modified statistical analysis method. 
Update 
Table 1  
Table 2  
Added a note that for subjects who early terminate from the 
study and consent to continued follow-up, the investigator 
should continue to follow-up for vital status and conduct the 
ALSFRS-R assessment, as per local 
requirements/regulations. 
Update 


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Section # 
Description of Change 
Brief Rationale 
Specified that urine creatinine should be tested when urine 
p75NTR is sampled. 
Specified that visits indicated as in-person only may be 
conducted remotely following discussion and indicated the 
minimum required assessments at such visits. 
Added a note that the ALSFRS-R must be performed by a 
certified rater. 
Table 3  
Added a note that for subjects who early terminate from the 
study and consent to continued follow-up, the investigator 
should continue to follow-up for vital status and conduct the 
ALSFRS-R assessment, as per local 
requirements/regulations. 
Added weight and BMI, 12-lead ECG, vital signs, physical 
examinations, and clinical laboratory tests to the Schedule 
of Assessments for Part C. Reduced mammograms to 
occur yearly. 
Updated matching table footnotes. 
Specified that visits indicated as in-person only may be 
conducted remotely following discussion and indicated the 
minimum required assessments at such visits. 
Added a note that the ALSFRS-R must be performed by a 
certified rater. 
Update 
Section 3.3 
Section 3.4 
Section 8.2  
Update the sample size justification in accordance with the 
updated primary endpoint statistical methodology. 
Update 
Section 4.2 
Section 4.6  
Specified that if a subject is discontinued from standard-of-
care therapy due to removal of the product from the market, 
it will not be considered a protocol deviation. 
Update 
Section 7.1.7  
Removed CSF hydroxynonenal panel from biomarker 
assessments. 
Update 
Section 7.1.8.3  
Added to clarify that evaluation of PK in CSF samples will 
only be performed for PTC857. 
Update 
Section 7.2.1  
Removed the statement that vital signs will be performed 
within approximately 15 minutes of the scheduled timepoint. 
Update 
Section 7.3.9  
Added a section on PTC expedited reporting of SUSARs to 
EudraVigilance. 
Update 
Section 8.3  
Revised the definition of the ITT1 Analysis Set. 
Clarification 
Section 8.1 
Section 8.4.1  
Revised the primary efficacy endpoint analysis 
methodology. 
Update 
Section 8.4.2  
Added statistical methodology for the change from baseline 
in ALSFRS-R at Week 24. 
Update 
Section 11.2  
Added reference to EU Regulation No. 536/2014 
Update 
Section 12.3  
Clarified storage of samples to be “biospecimen.” 
Clarification 
14.2. 
Version 5.0: 08 September 2023 
The overall reason for Version 5.0 of the protocol was to include Part C of the study. 
Section # 
Description of Change 
Brief Rationale 
Protocol 
The version number and date were updated throughout. 
Editorial and administrative revisions (eg, typographical 
errors, punctuation, tenses, abbreviations) were 
incorporated to provide clarity.  
Update 


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Section # 
Description of Change 
Brief Rationale 
The synopsis, study design figure, and Schedule of 
Assessments were updated to be consistent with the 
changes in the protocol. 
Section 1.4.1  
Results of the in vivo phototoxicity study of PTC857 were 
added. Subsequently, measures to protect against sun and 
ultraviolet light are not necessary with PTC857 treatment, 
and these recommendations were removed. 
Update 
Section 1.4.2 
Section 16.1 
Results from the completed food effect and drug-drug 
interaction Phase 1 studies of PTC857 were added. 
Update 
Section 2.1.3 
Section 2.2.3 
Section 2.2.4 
Added objectives and endpoints for quality of life as 
assessed by EQ-5D-5L. 
Update 
Section 2.1.5 
Section 2.2.5 
Objectives and endpoints for Part C of the study were 
added. 
Update 
Section 2.2.4 
Endpoints for Part B of the study were modified to provide a 
concrete timepoint for analysis. 
Update 
Section 3.2 
Section 5.5 
Specified that the investigator must evaluated the individual 
subject’s standard-of-care therapy if they are not receiving 
any at the time of entering the Screening Period. 
Update 
Section 3.2 
Section 5.3.1 
Modified the phrasing of the stratification factors for 
simplicity. 
Update 
Section 3.1 
Section 3.2  
Table 3  
Section 3.5.1 
Section 3.5.3 
Table 4 
Section 5.3.1 
Section 5.3.2 
Section 6.4 
Section 8.4 
Section 8.4.4 
Added the study design and description of Part C. 
Update 
Table 1  
Added that Baseline Visit procedures may be performed 
within the 3 days before the day that study drug is first 
administered. 
Update 
Table 1  
Table 2 
Added that the ICF for Parts B and C should be presented 
to the subject prior to Day 169 of Part A and Day 365 of 
Part B, respectively, to ensure the subject has adequate 
time to make a decision on participation in Part B or Part C. 
Defined that the Day 169 and Day 365 visits are only 
considered the End of Treatment Visit if the subject does 
not choose to participate in Part B or Part C, respectively. 
Update 
Table 1 
Added a visit window for the collection of CSF samples. 
Update 
Section 3.5.4  
Added a window for the duration of the standard-of-care 
therapy must be stable for prior to enrollment in the study. 
Update 
Section 3.6 
Modified the end of study definition for clarity among Parts 
A, B, and C. 
Update 
Section 4.2 
Removed the body mass index inclusion criterion. 
Added a reference to the laboratory manual for inclusion 
criterion 4. 
Removed the inclusion criterion for willing and able to 
swallow study drug (oral solution) at randomization. 
Update 


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Section # 
Description of Change 
Brief Rationale 
Revised the inclusion criterion on concomitant medications 
to require medications be stable and unchanged from 14 
days prior to the start of the Screening Period, and moved 
the standard-of-care therapy requirements prior to the 
Screening Period to be a separate inclusion criterion. 
Section 4.3 
Removed language stating that lumbar punctures will only 
be performed at select clinical sites. 
Update 
Section 4.6 
Separated subject withdrawal criteria activities by 
discontinuation study treatment or completely from the 
study. 
Update 
Section 5.1.2 
Added specifications around administering PTC857 with a 
feeding tube. 
Update 
Section 6.4 
Added that PTC will continue to follow-up on long-term 
outcomes as per local regulations with the subject’s 
consent. 
Update 
Section 7.1.1 
Section 7.1.2 
Section 7.1.3 
Section 7.1.4 
Section 7.1.6 
Section 7.1.7 
Section 7.1.8 
Section 7.2 
Section 7.2.1 
Section 7.2.2 
Section 7.2.3 
Section 7.2.4 
Section 7.2.7 
Section 7.2.8  
Removed redundant references throughout the efficacy and 
safety assessments that referred to the Schedule of 
Assessments. 
Update 
Section 7.1.5  
Added a section for the EQ-5D-5L assessment. 
Update 
Section 7.2.5.1 
Section 7.2.5.2 
Section 7.2.5.3 
Sections on hematology, blood chemistry, and urinalysis 
were removed to reduce redundancy with that presented in 
Section 7.2.5 
Update 
Section 8.4.2 
Section 8.4.3 
Removed specification in SAP for Part A and Part B as 
there will be a single SAP inclusive of all parts of the study. 
Update 
Section 16.1 
Removed moderate inhibitors and inducers from Table 10 
and Table 11, respectively, based on the results of the 
Phase 1 clinical DDI study. 
Update 
14.3. 
Version 4.0: 31 October 2022 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to implement study design changes subsequent to 
agreement with health agencies and ethic committees and to incorporate changes to widen 
enrollment criteria for the study. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document formatting revisions 
Minor, therefore, have not 
been summarized 


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Section # 
Description of Change 
Brief Rationale 
The mITT and ITT analysis sets were renamed to ITT1 
and ITT2, respectively. 
Update 
Section 1.4.1 
Section 1.5.1  
Added results of the 9-month monkey toxicity study, 
nonclinical phototoxicity study, and dose-range finding 
embryo-fetal development nonclinical studies. 
Update 
Section 1.5.2 
Section 11.3  
Expanded on background information on ALS, as well 
as considerations for ongoing written informed 
consent. 
Update 
Section 1.5.3 
Added a summary of safety risks. 
Update 
Table 1 
Table 2 
Added a monthly urine pregnancy test. 
Added vital signs assessment on Days 29, 57, 113, 
141, 197, and 225. 
Added that the Day 113 and 141 Visits are in-home to 
assess vital signs. 
Added a mammogram assessment at the Early 
Termination Visit. 
Added coagulation to the list of clinical laboratory tests. 
Specified that a serum pregnancy test will be 
performed at Screening, then all other pregnancy tests 
will be via urine. 
Update 
Table 1 
Section 7.1.8.2 
Section 7.1.8.5 
Added blood sampling for edaravone and sodium 
phenylbutyrate/taurursodiol for those in the PK 
sub-study. 
Update 
Section 3.2 
Section 8.4.1 
Included additional stratification factors for use of 
edaravone and sodium phenylbutyrate/taurursodiol. 
Update 
Section 4.2 
Updated the upper limit of age for enrollment to be 
80 years. 
Updated the time frame for onset of the first symptoms 
leading to the diagnosis of ALS to be ≤24 months at 
the time of the initial Screening Visit. 
To widen enrollment criteria 
Section 4.3 
Specified the criteria for hepatic insufficiency. 
Added a note that subjects with a contraindication to 
lumbar punctures may still enroll but should not 
undergo the lumbar punctures as listed in the 
Schedule of Events. 
Modified exclusion criterion 11 to state that the 
combination of edaravone and sodium 
phenylbutyrate/taurusodiol will be excluded. 
Added an exclusion criterion prohibiting the use of a 
non-approved form of sodium phenylbutyrate and/or 
taurursodiol for the treatment of ALS. 
Update 
Section 5.1.2 
Added that subjects should be advised to limit sun and 
ultraviolet light exposure. 
To prevent the potential for 
phototoxicity. 
Section 5.2.2 
Updated the storage of study drug. 
Update 
Section 5.3 
Added criteria for emergency unblinding of study 
information. 
Update 
Section 5.5 
Section 16.1 
Added clarifications surrounding allowance of 
standard-of-care therapies. 
Update 
Section 7.1.7 
Updated the biomarkers planned to be evaluated. 
Update 
Section 7.2.6 
Specified that a serum pregnancy test will be 
performed at Screening and all other pregnancy tests 
will be via urine. 
Update 


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Section # 
Description of Change 
Brief Rationale 
Section 7.3 
Updated the entirety of the Adverse Events, Serious 
Adverse Events, and Other Safety Reporting section. 
For consistency with 
updated safety reporting 
language and to align with 
the new PTC protocol 
template 
pharmacovigilance 
language. 
Section 12.3  
Modified the duration and future use of stored 
specimens to be stored for up to 5 years are the end of 
the study, in accordance with local regulations. 
Samples may be used for future research with 
subject’s consent. 
Update 
NA 
The acceptable birth control methods appendix was 
deleted as the content was moved to Section 7.3.11.4. 
Update 
14.4. 
Version 3.0: 13 July 2022 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to include additional inclusion/exclusion criteria and 
assessments to ensure the safety of enrolled subjects. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document formatting revisions 
Minor, therefore, have not 
been summarized 
Section 1.4.1 
Section 1.5.1 
Section 3.5.2  
Additional text was added to provide information from 
the 6-month rat toxicology study. 
Update 
Section 3.2  
Specified that subjects in Part B will remain blinded to 
their original treatment from Part A. 
Clarification 
Table 1 
Table 2 
Section 7.2.8 
Added breast cancer imaging assessments for female 
subjects at Screening and approximately every 6 
months during the Treatment and Long-Term 
Extension periods. 
Additional assessment 
included for continued 
safety monitoring of 
subjects. 
Added that subjects may go to the site for an in-person 
visit if an in-home visit is not possible. 
Clarification 
Clarified language surround lumbar puncture 
requirements at the selected clinical sites. 
Clarification 
Section 4.2  
Specified that subjects or their designee must provide 
written informed consent. 
To allow flexibility in 
consent 
Added that female subjects must have a negative 
breast cancer screening status within 6 months of the 
Screening Visit or during the Screening Period. 
To ensure the safety of 
enrolled subjects 
Section 4.3  
Added that female subjects or female subjects with a 
first degree relative with a past medical history of 
breast cancer will be excluded from the study. 
To ensure the safety of 
enrolled subjects 
Section 7.2.5 
Table 5  
Added amylase, lipase, apolipoprotein A, and 
apolipoprotein B to the chemistry panel and specified 
these will be blinded to the investigator. 
For continued safety 
monitoring of enrolled 
subjects 


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Section # 
Description of Change 
Brief Rationale 
Section 8.4.1  
Specified that sensitivity and subgroup analyses of the 
primary efficacy endpoint will be provided in the SAP. 
Clarification 
14.5. 
Version 2.0: 14 March 2022 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to change the formulation of study drug utilized in 
this study from capsules to oral solution. 
Section # 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document formatting revisions 
Minor, therefore, have not 
been summarized. 
Throughout 
Assessment of urine biomarkers was added 
throughout the protocol. 
Update as p75NTR 
fragment will be evaluated 
through urine, not CSF. 
Section 1.2, 
Section 5.1, 
Section 5.2 
Updates were done throughout to switch from the use 
of a capsule formulation of the study drug to an oral 
solution formulation. 
To address the swallowing 
concerns in this subject 
population 
Section 2.2.2, 
Section 2.2.4, 
Table 1, 
Table 2, 
Section 7, 
Section 7.1.1  
Modified language as PFTs encompass the tests 
performed during this study, including SNIP. In 
addition, clarified that several tests will not be 
performed as part of PFTs. 
Clarification 
Section 3.2, 
Section 8.4, 
Section 8.4.1, 
Section 8.4.2, 
Section 8.4.3  
Added language related to Part A and Part B being 
reported separately. 
Clarification 
Section 3.2, 
Table 1, 
Section 7.1.8.2  
Removed language stating that subjects participating 
in the PK Sub-Study will sign an additional ICF. 
The PK Sub-Study will not 
have a separate ICF. 
Section 4.2  
Revised criteria for ALS definition and minimum 
ALSFRS-R score for enrollment. 
To broaden the enrollable 
patient population and ease 
site burden in identifying 
eligible patients 
Revised the time period prior to the start of Screening 
Period for concomitant medication use. 
Section 4.3  
Revised the time period prior to the start of Screening 
Period for surgery. 
To broaden the enrollable 
patient population and ease 
site burden in identifying 
eligible patients 
Clarified edaravone treatment, where applicable. 
Clarification as edaravone 
is not approved for the 
treatment of ALS in some 
countries where this study 
is planned to be conducted 
Table 1, 
Table 2 
Day 14 and Day 183 visits were added for evaluation 
of clinical laboratory tests. 
Visit added to incorporate 
FDA feedback to assess 
lipid profiles 14 days after 
initial dosing with PTC857. 
Several footnotes were added or modified for clarity. 
Clarification 
Section 6.4, 
Section 12.3 
Modified language surrounding storage and 
destruction of biological samples. 
Clarification 


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Section # 
Description of Change 
Brief Rationale 
Section 7.2.5  
Added language for which test results will be provided 
to the investigator. 
Clarification 
Section 8.5  
Added section to clarify that no interim analysis is 
planned. 
Clarification 


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15. 
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Ferrante, RJ, Browne, SE, Shinobu, LA, Bowling, AC, Baik, MJ, MacGarvey, U, et al. Evidence 
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Riederer, P, Sofic, E, Rausch, WD, Schmidt, B, Reynolds, GP, Jellinger, K and Youdim, MB. 
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Weiduschat, N, Mao, X, Hupf, J, Armstrong, N, Kang, G, Lange, DJ, et al. Motor cortex 
glutathione deficit in ALS measured in vivo with the J-editing technique. Neurosci Lett 
2014;570:102-107. 
Wenzel, SE, Tyurina, YY, Zhao, J, St Croix, CM, Dar, HH, Mao, G, et al. PEBP1 Wardens 
Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 2017;171(3):628-
641 e626. 
Ye, LF and Stockwell, BR. Transforming Lipoxygenases: PE-Specific Enzymes in Disguise. 
Cell 2017;171(3):501-502. 


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16. 
APPENDICES 
16.1. 
Prohibited Medications During the Course of the Study 
The results of an in vitro study indicated that multiple CYP enzymes (1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, and 3A4) may be involved in PTC857 metabolism. Since multiple CYPs are 
involved in the metabolism of PTC857, inhibition/induction of any single enzyme may not have 
significant effect. 
Hence, the strong and moderate inhibitors/inducers of the putative CYP enzymes that metabolize 
PTC857 listed in Table 10 and Table 11 may be used per the treating physician’s discretion (ie, 
are not prohibited). If the use of any of these medicines is necessary, greater attention should be 
exercised for monitoring subject safety. If any SAEs are observed, an ad hoc PK sample(s) may 
be collected, if possible, to measure the levels of PTC857, riluzole, edaravone, and/or sodium 
phenylbutyrate/taurursodiol to determine the causality. 
The results of a clinical drug-drug interaction study evaluating the effect of PTC857 on 
CYP1A2, CYP2B6, and CYP3A4 substrates (PTC857-DDI-101-HV) indicated mild to moderate 
changes in exposure of the respective substrates, hence, no dose adjustments are necessary when 
drugs metabolized by these enzymes are co-administered with PTC857. 
The combination of edaravone plus sodium phenylbutyrate/taurursodiol is not permitted for 
enrollment to this study. Furthermore, the use of any non-approved form of sodium 
phenylbutyrate and/or taurursodiol for the treatment of ALS is also excluded from this study. 
Subjects may not begin standard-of-care therapy (riluzole, edaravone, or sodium 
phenylbutyrate/taurursodiol) for ALS during the placebo-controlled Treatment Period (Part A). 
Upon entry to the LTE Period, participants may continue their established standard-of-care 
treatment and/or initiate treatment with standard-of-care therapy based on their treating 
physician’s discretion where applicable or available without restriction to the number or 
combination of therapies. 


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Table 10: 
Strong/Moderate Inhibitors of CYP Enzymes 
CYP Enzymes 
Strong Inhibitors 
Moderate Inhibitors 
CYP1A2 
Ciprofloxacin, enoxacin, fluvoxamine 
- 
CYP2B6 
- 
- 
CYP2C8 
Gemfibrozil 
Clopidogrel, deferasirox, teriflunomide 
CYP2C9 
- 
Amiodarone, fluconazole, miconazole, 
piperine 
CYP2C19 
Fluconazole, fluoxetine, fluvoxamine, 
ticlopidine 
Felbamate 
CYP2D6 
Bupropion, fluoxetine, paroxetine, 
quinidine, terbinafine 
Abiraterone, cinacalcet, duloxetine, 
lorcaserin, mirabegron 
CYP3A4 
Boceprevir, cobicistat, danoprevir and 
ritonavir, elvitegravir and ritonavir, 
grapefruit juice, indinavir and ritonavir, 
itraconazole, ketoconazole, lopinavir and 
ritonavir, paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir), 
posaconazole, ritonavir, saquinavir and 
ritonavir, telaprevir, tipranavir and 
ritonavir, telithromycin, troleandomycin, 
voriconazole, clarithromycin, idelalisib, 
nefazodone, nelfinavir 
- 
Abbreviations: AUC, area under the concentration-time curve; CYP, cytochrome P450; DDI, drug-drug interaction 
Note: Inhibitors predictably inhibit metabolism via a given pathway and are commonly used in prospective clinical DDI 
studies. Strong and moderate inhibitors are drugs that increase the AUC of sensitive substrates of a given metabolic 
pathway ≥5-fold and ≥2 to <5-fold, respectively. 
Table 11: 
Strong/Moderate Inducers of CYP Enzymes 
CYP Enzymes 
Strong Inducers 
Moderate Inducers 
CYP1A2 
- 
- 
CYP2B6 
Carbamazepine 
- 
CYP2C8 
- 
Rifampin 
CYP2C9 
- 
Enzalutamide, rifampin 
CYP2C19 
Rifampin 
Apalutamide, efavirenz enzalutamide, 
phenytoin 
CYP3A4 
Apalutamide, carbamazepine, 
enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s wort 
- 
Abbreviations: AUC, area under the concentration-time curve; CYP, cytochrome P450; DDI, drug-drug interaction 
Note: Inducers predictably induce metabolism via a given pathway and are commonly used in prospective clinical DDI 
studies. Strong and moderate index inducers are drugs that decreases the AUC of sensitive substrates of a given 
metabolic pathway by ≥80% and ≥50% to <80%, respectively. 

SAP_001.pdf: 
V2.0 
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Page 1 of 62 
STATISTICAL ANALYSIS PLAN 
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) 
FOR THE 
DOUBLE-BLINDED TREATMENT PERIOD (PART A) OF 
PTC857-CNS-001-ALS 
VERSION 2.0 
DATE OF PLAN: 25 SEPTEMBER 2024 
STUDY DRUG: UTRELOXASTAT 
PROTOCOL NUMBER:  PTC857-CNS-001-ALS 
PTC THERAPEUTICS, INC.  
500 WARREN CORPORATE CENTER DRIVE 
WARREN, NJ 07059 USA  
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach of this 
obligation, PTC Therapeutics, Inc. should be notified promptly.
NCT #: NCT05349721


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PTC THERAPEUTICS STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES  
 
Author: 
 
 
 
 
 
 
 
 
  
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
Approver (Biostatistics): 
 
 
 
 
 
 
 
 
 
 
 
  
PTC Therapeutics, Inc. 
 
Date 
 
 
 
Approver (Clinical): 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PTC THERAPEUTICS STATISTICAL ANALYSIS PLAN APPROVAL 
SIGNATURES .............................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION AND OVERVIEW ........................................................................8 
1.1. 
Study Design .................................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives .................................................................................................10 
1.2.3. 
Exploratory Objectives ...............................................................................................10 
1.3. 
Study Endpoints ..........................................................................................................10 
1.3.1. 
Primary Endpoints ......................................................................................................10 
1.3.2. 
Secondary Endpoints ..................................................................................................10 
1.3.3. 
Exploratory Endpoints ................................................................................................11 
1.4. 
Subject Selection ........................................................................................................11 
1.4.1. 
Inclusion Criteria ........................................................................................................11 
1.4.2. 
Exclusion Criteria .......................................................................................................12 
1.5. 
Sample Size ................................................................................................................13 
1.6. 
Randomization and Blinding ......................................................................................14 
2. 
ANALYSIS SETS ......................................................................................................15 
2.1. 
All Enrolled Set ..........................................................................................................15 
2.2. 
Intent-to-Treat (ITT) Analysis Sets ............................................................................15 
2.3. 
Safety Set ....................................................................................................................15 
2.4. 
Per Protocol Set ..........................................................................................................15 
2.5. 
Pharmacokinetic Analysis Set ....................................................................................16 
2.6. 
Protocol Deviations ....................................................................................................16 
3. 
GENERAL CONSIDERATIONS ..............................................................................18 
3.1. 
General Considerations ...............................................................................................18 
3.2. 
Data Definitions and Analysis Issues .........................................................................18 
3.2.1. 
Study/Onset Day .........................................................................................................18 
3.2.2. 
Baseline Definition and Change from Baseline ..........................................................18 
3.2.3. 
Duration of Event .......................................................................................................18 


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3.2.4. 
Retest and Unscheduled Visits ...................................................................................19 
3.2.5. 
Treatment Periods .......................................................................................................19 
3.2.6. 
Coding Dictionary ......................................................................................................19 
3.2.7. 
ALS Functional Rating Scale - Revised (ALSFRS-R) score .....................................19 
3.2.8. 
Pulmonary Function Tests ..........................................................................................20 
3.2.9. 
Modified Norris Scale .................................................................................................20 
3.2.10. 
ALS Cognitive Behavioral Screen ..............................................................................20 
3.2.11. 
ALSAQ-40 Assessment ..............................................................................................20 
3.2.12. 
EuroQol EQ-5D-5L ....................................................................................................20 
3.2.13. 
Survival .......................................................................................................................21 
3.2.14. 
Combined Assessment of Function and Survival (CAFS) .........................................21 
3.3. 
Estimands ....................................................................................................................21 
3.3.1. 
Estimand for Primary Efficacy (Combined Assessment of Function and 
Survival) .....................................................................................................................21 
3.3.2. 
Estimands for Change from Baseline in ALSFRS-R at Week 24 ..............................22 
3.3.3. 
Estimands for Survival Time ......................................................................................23 
3.3.3.1. 
Respiratory-Support free survival time - A supportive estimand for the 
survival time ...............................................................................................................24 
3.4. 
Interim Analysis ..........................................................................................................25 
3.5. 
Changes to Protocol Specified Analysis .....................................................................25 
4. 
SUBJECT DATA .......................................................................................................26 
4.1. 
Subject Disposition .....................................................................................................26 
4.2. 
Demographics and Baseline Characteristics ...............................................................26 
4.3. 
Disease Characteristics ...............................................................................................26 
4.4. 
Medical History ..........................................................................................................27 
4.5. 
Prior Medications/Procedures and Concomitant Medications/Procedures .................27 
4.6. 
Multiplicity .................................................................................................................28 
4.7. 
Missing Data ...............................................................................................................28 
4.8. 
Treatment Compliance ................................................................................................28 
4.9. 
Visit Windows for The Early Termination Visit and Unscheduled Visits .................29 
5. 
EFFICACY ANALYSIS ............................................................................................30 
5.1. 
Analysis of the Primary Efficacy Endpoint ................................................................30 
5.2. 
Sensitivity Analysis – Unstratified Analysis ..............................................................30 


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5.3. 
Sensitivity Analysis – Actual Stratification ................................................................30 
5.4. 
Per protocol Analysis Set ............................................................................................31 
5.5. 
Analysis of Secondary Efficacy Endpoints ................................................................31 
5.5.1. 
Change from Baseline in ALSFRS-R .........................................................................31 
5.5.1.1. 
Mixed Model Repeated Measures (MMRM) .............................................................31 
5.5.1.2. 
Analysis of Covariance Model (ANCOVA) with Multiple Imputation: ....................31 
5.5.1.3. 
Pattern Mixture Model - Missing not at random assumption: ....................................32 
5.5.2. 
Analysis of Other Continuous Secondary Endpoints .................................................32 
5.6. 
Subgroup Analyses for Efficacy .................................................................................33 
5.7. 
Overall Survival ..........................................................................................................34 
5.8. 
Exploratory Endpoints ................................................................................................34 
6. 
SAFETY ANALYSES ...............................................................................................35 
6.1. 
Extent of Exposure .....................................................................................................35 
6.2. 
Adverse Events ...........................................................................................................35 
6.2.1. 
Exposure Adjusted incidence rates (EAIR) ................................................................36 
6.2.2. 
Adverse Events Indicative of ALS Disease Progression ............................................37 
6.2.3. 
Disproportionate rate of Disease Progression by Treatment Received ......................37 
6.3. 
Laboratory Values ......................................................................................................38 
6.4. 
Vital Signs ..................................................................................................................38 
6.5. 
12-Lead Electrocardiogram ........................................................................................39 
6.6. 
Physical Examination .................................................................................................39 
6.7. 
Columbia-Suicide Severity Rating Scale ....................................................................39 
6.8. 
Other Safety: Body Weight, BMI, Breast Imaging and Pregnancies .........................41 
6.9. 
Subgroup Analyses for Safety ....................................................................................41 
7. 
PHARMACOKINETIC OUTCOMES .......................................................................43 
8. 
REFERENCES ...........................................................................................................44 
9. 
PROGRAMMING CONSIDERATIONS ..................................................................46 
10. 
MOCK TABLES, LISTINGS, AND GRAPHS .........................................................48 
11. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS ....................................................49 
12. 
APPENDIX 2: MISSING DATE AND MISSING ALSFRS-R 
PROCEDURE .............................................................................................................53 
13. 
APPENDIX 3: TRICALS RISK PROFILE CALCULATOR ....................................55 
14. 
APPENDIX 4: SAS CODE ........................................................................................56 


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15. 
APPENDIX 5. MAPPING ALSFRS-R TO KING’S STAGE ...................................59 
16. 
REVISION HISTORY ...............................................................................................60 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
AE 
Adverse Event 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
ALS Functional Rating Scale - Revised 
ALS CBS 
ALS Cognitive Behavioral Screen 
ATC 
Anatomical Therapeutic Chemical  
BDRM 
Blinded Data Review Meeting 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CAFS 
Combined Assessment of Function and Survival 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DB 
Double-Blind 
eGFR 
Estimated Glomular Filtration Rate 
ENR 
All Enrolled  
ICF 
Informed Consent 
ITT 
Intention to Treat 
LFT 
Liver Function Test 
LTE 
Long-term extension 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
NfL 
Neurofilament light chain 
PAV 
Permanent Assisted Ventilation 
PFT 
Pulmonary Function Test 
PK 
Pharmacokinetics 
PMM 
Pattern-Mixture Model 
PP 
Per Protocol 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SNIP 
Sniff Nasal Inspiratory Pressure 
SoC 
Standard of Care 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TRICALS 
TRICALS is the largest European research initiative to find a cure for ALS 
ULN 
Upper Limit if Normal 
WHO DD 
World Health Organization Drug Dictionary 


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1. 
INTRODUCTION AND OVERVIEW  
The purpose of this statistical analysis plan (SAP) is to provide a description of the statistical 
methods and procedures to be implemented for the analysis of data from PTC857-CNS-001-ALS 
study, also referred to as The Cardinals Study. This document details the statistical methods to be 
used in the analyses and presentation of the data collected during the double-blind treatment 
period (Part A) of the study. The primary efficacy endpoint of the study is assessed during this 
period. 
The statistical methods to be used for the data collected during the entire study including the 
open-label long-term extension periods (Parts B and C) will be described in a separate SAP. 
This document is based on the final protocol amendment version 6.0, dated 14 JUNE 2024, and 
has been developed, reviewed, and approved prior to the database lock of the double-blind 
Treatment Period (Part A). Any changes from the planned analysis as described in the protocol 
for Study PTC857-CNS-001-ALS and its amendments (as applicable) are detailed here, and any 
differences described here supersede the analysis presented in the protocol. Any additional 
analyses conducted to supplement the planned analyses and any deviations from the planned 
analyses described in this SAP will be documented in the Clinical Study Report (CSR).  
1.1. 
Study Design  
Brief description of the Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to assess 
the effects of PTC857 (also known as utreloxastat) in adult male and female subjects diagnosed 
with ALS. Eligible male and female subjects aged between 18 and 80 years will be enrolled in 
this study. The study consists of 5 periods: Screening, Treatment (Part A), LTE (Part B), 
Continued LTE (Part C), and Follow Up as illustrated in Figure 1 below. 
Approximately 340 subjects who meet the inclusion and exclusion criteria will be randomized in 
a 2:1 ratio to receive PTC857 (250 mg BID) or matching placebo with 2 stratification factors:  
1. Amount of change in ALSFRS-R score during the 8-week Screening Period by points 
total loss: 
a. <1, 
b. 1-2, 
c.  3-4, or 
d. >4 points total loss  
2. Use of edaravone, sodium phenylbutyrate/taurursodiol, or neither for the treatment of 
ALS at Screening as standard-of-care therapy: 
e. Edaravone  
f. Sodium phenylbutyrate/taurursodiol 
g. Neither edaravone nor sodium phenylbutyrate/taurursodiol 
Before protocol amendment version 4.0, dated 31 OCTOBER 2022, the second stratification 
factor above (treatment for ALS at baseline) was based on use of riluzole alone (with two levels: 
on riluzole and not on riluzole). Protocol amendment 4.0 opened the study to allow for 


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randomization of subjects who were taking other treatments for ALS, if approved in their region 
of participation, specifically edaravone or sodium phenylbutyrate/taurursodiol if their treatment 
was considered stable. In protocol amendment 4.0, the original riluzole stratification groups (on 
riluzole vs. not on riluzole) would be amalgamated, and randomization would be based on 
edaravone, sodium phenylbutyrate/taurursodiol, and Neither treatment status, as indicated above.  
After completion of the 24-week double-blind treatment phase, all subjects will be offered the 
opportunity to enter the optional 28 weeks long-term extension (LTE) Period of the study. Those 
who choose to enter the LTE Period will sign an additional informed consent form (ICF) and 
start open-label treatment with PTC857 250 mg BID. Those who choose not to enter the LTE 
Period will stop treatment, and a telephone follow-up visit will be conducted 4 weeks (±3 days) 
after the last dose of study treatment. At the end of the LTE Period, those who choose not to 
enter the Continued LTE Period will stop treatment, and a Telephone Follow-Up Visit will be 
conducted 4 weeks (±3 days) after the last dose of study treatment. Subjects who enter the 
Continued LTE Period (Part C) will continue treatment for an optional additional 108 weeks. All 
subjects will be treated with open-label PTC857 (250 mg BID) during the Continued LTE 
Period. Subjects will remain blinded to their original treatment from the Treatment Period (Part 
A). At the end of this period, a Telephone Follow-Up Visit will be conducted 4 weeks (±3 days) 
after the last dose of study treatment. Results from the Treatment Period (Part A), the LTE 
Period (Part B), and the Continued LTE Period (Part C) will be reported separately. The 
scheduled study visit assessments for the double-blind treatment period are presented in Section 
11 (Appendix 1). 
Total duration of the individual participation will be approximately 172 weeks, including a 
screening period of 8 weeks mandatory in duration, a double-blind treatment period of 24 weeks, 
a long-term open-label extension period of 28 weeks, a continued long-term extension period of 
108 weeks, and a follow up period of 4 weeks. A subset of approximately 36 subjects from select 
sites participating in the PK sub-study will participate in serial blood sampling to characterize the 
PK of PTC857 in subjects with ALS. The study schema is shown below. 
Figure 1: Study Design 
 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives  
The primary objective of this study is to evaluate the efficacy of PTC857 in reducing disease 
progression in subjects with amyotrophic lateral sclerosis (ALS). 


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1.2.2. 
Secondary Objectives  
The secondary efficacy objectives of this study are to assess the following in subjects with ALS: 
• Safety and tolerability of PTC857 
• Respiratory function in subjects randomized to PTC857 versus placebo 
• Motor/limb and bulbar function in subjects randomized to PTC857 versus placebo 
• Survival in subjects randomized to PTC857 versus placebo 
• Quality of life via 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire 
(ALSAQ-40) in subjects randomized to PTC857 versus placebo 
• Evaluate the efficacy of PTC857 in reducing disease progression in subjects with ALS 
with any baseline rate of functional decline 
• Effects on plasma neurofilament light chain (NfL) activity in subjects randomized to 
PTC857 versus placebo 
• Pharmacokinetics (PK) of PTC857 
1.2.3. 
Exploratory Objectives  
The exploratory objectives of the study are to assess the following in subjects with ALS: 
• Neuropsychological function in subjects randomized to PTC857 versus placebo 
• Effects on mechanistic and clinically based biomarker activity in subjects randomized to 
PTC857 versus placebo 
• Quality of life via the five-level European quality of life five-dimensional questionnaire 
(EQ-5D-5L) in subjects randomized to PTC857 versus placebo 
• Exposure-response relationships 
1.3. 
Study Endpoints  
1.3.1. 
Primary Endpoints  
The primary endpoint is subject ranks based on the combined assessment of ALS Functional 
Rating Scale-Revised and survival (CAFS) after 24 weeks of treatment in the Intent-to-Treat 1 
(ITT1) Analysis Set. 
1.3.2. 
Secondary Endpoints  
The secondary efficacy endpoints are: 
• Subject ranks based on the combined assessment of ALSFRS-R and survival (CAFS) 
after 24 weeks of treatment in the Intent-to-Treat 2 (ITT2) Analysis Set 
• Change from baseline in ALSFRS-R in the ITT1 Analysis Set after 24 weeks of 
treatment. 
• Change from baseline in ALSFRS-R in the ITT2 Analysis Set after 24 weeks of 
treatment. 


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• Safety and tolerability of PTC857 as measured by the severity and number of treatment-
emergent adverse events (TEAEs) and treatment-emergent serious adverse events 
(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 double-blind Treatment Period (Part A) 
• Change from baseline in slow vital capacity as assessed by pulmonary function tests 
(PFTs) after 24 weeks of treatment 
• Change from baseline in motor/limb and bulbar function as assessed by the Modified 
Norris Scale after 24 weeks of treatment 
• Survival as assessed by rate of and length of time to death 
• Quality of life as assessed by ALSAQ-40 after 24 weeks of treatment 
• Change from baseline in plasma NfL activity after 24 weeks of treatment 
• Plasma PK and cerebrospinal fluid (CSF) exposure of PTC857 
1.3.3. 
Exploratory Endpoints  
The exploratory endpoints of the study are the following: 
• Change from baseline in neuropsychological function as assessed by the ALS Cognitive 
Behavioral Screen (ALS CBS) after 24 weeks of treatment 
• Change from baseline in blood, urine, and CSF biomarker activity after 24 weeks of 
treatment 
• Quality of life as assessed by the EQ-5D-5L after 24 weeks of treatment 
• Exposure-response relationships after 24 weeks of treatment 
1.4. 
Subject Selection  
The study’s inclusion and exclusion criteria are detailed in the study protocol. 
1.4.1. 
Inclusion Criteria  
Individuals eligible to participate in this study include those who meet all the inclusion criteria at 
both the Screening Visit and the Baseline Visit, unless otherwise stated: 
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: 
- 
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 
3. A total ALSFRS-R score of at least 34 at the start of the Screening Period 


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4. No significant respiratory compromise as evidenced by slow vital capacity ≥60% at the 
start of the Screening Period 
5. Subjects or their designee (i.e., legal authorized representative or caregiver) must 
understand the nature of the study and must provide signed and dated written informed 
consent prior to conducting any study-related procedures. 
6. Females must be either postmenopausal for ≥1 year (cessation of menses for 12 
consecutive months) or surgically sterile (having undergone tubal ligation, hysterectomy, 
or bilateral oophorectomy) for at least 6 months or, if of childbearing potential and not 
abstinent, willing to use a highly effective method of contraception from the start of the 
Screening Period through 90 days after the last dose of study drug. Females who are 
abstinent will not be required to use a contraceptive method unless they become sexually 
active. 
7. Females must refrain from ova (egg cell) donation from the start of the Screening Period 
through 90 days after the last dose of study drug. 
8. Males, if not surgically sterilized, with female partners of childbearing potential must 
agree to use barrier contraceptive (i.e., condom) and their female partners must use a 
highly effective method of contraception from the start of the Screening Period through 
90 days after the last dose of study drug. 
9. Males must refrain from sperm donations from the start of the Screening Period through 
90 days after the last dose of study drug. 
10. Willing and able to comply with all protocol procedures. 
11. Willing and able to swallow study drug (oral solution) at randomization. 
12. All concomitant medications (both prescription and over the counter [OTC]), including 
standard-of-care therapy riluzole, edaravone, or sodium phenylbutyrate/taurursodiol, and 
non-pharmacologic therapy regimens should be stable and unchanged from at least 30 
days prior to the start of the Screening Period and intend to remain stable and unchanged 
throughout the course of the study. 
13. 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 
1.4.2. 
Exclusion Criteria  
Individuals are not eligible to participate in this study if they have met or meet any of the 
following exclusion criteria at either the Screening Visit or the Baseline Visit, unless otherwise 
stated: 
1. History of allergies or adverse reactions to any of the excipients in the study drug 
formulation 
2. Females who are pregnant or nursing or plan to become pregnant during the study. 
3. Subjects with clinically significant gastrointestinal, renal, hepatic, neurologic, 
hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or 


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CV/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. 
4. 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. 
Note: Lumbar punctures will be performed but may be skipped for an individual subject 
if the investigator deems it appropriate, and after discussion with the medical monitor. 
Subjects with a contraindication to lumbar punctures, such as but not limited to space-
occupying lesion with mass effect, increase of intracranial pressure due to increased CSF 
pressure, posterior fossa mass, Arnold-Chiari malformation, anticoagulation medication 
use, coagulopathy, uncorrected bleeding diathesis, congenital spine abnormality, previous 
adverse event associated with a lumbar puncture or skin infection at the puncture site, 
should not undergo the lumbar punctures as listed in the Schedule of Events. These 
subjects may still enroll in the study and should undergo all other study procedures. 
5. Hepatic insufficiency, defined as liver function tests (LFTs) (i.e., AST and/or ALT) ≥3× 
the upper limit of normal (ULN), or bilirubin ≥1.5× the ULN (except in the case of 
Gilbert’s disease) 
6. Moderate or worse renal insufficiency, defined as an estimated glomerular filtration rate 
(eGFR) of <60 mL/min. 
7. 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. 
8. History of alcohol or drug abuse within the last 6 months prior to the start of the 
Screening Period or current evidence of substance dependence 
9. Any surgery within 30 days prior to the start of the Screening Period that may affect the 
subject’s ability to complete all study procedures. 
10. Subject has previously received PTC857. 
11. Subject is receiving a combination of edaravone and sodium phenylbutyrate/taurursodiol 
treatment, where applicable, within 30 days prior to the start of the Screening Period 
12. For female subjects, any past medical history of breast cancer, regardless of remission 
status, or any first degree relative with history of breast cancer  
13. Subjects is taking a non-approved form of sodium phenylbutyrate and/or taurursodiol for 
the treatment of ALS. 
1.5. 
Sample Size  
For the primary efficacy endpoint, the combined assessment of ALSFRS-R and survival after 24 
weeks of treatment, 307 subjects in the ITT1 Analysis Set (205 in the PTC857 group and 102 in 
the placebo group, based on a 2:1 randomization ratio) will provide approximately 85% power to 
detect a treatment difference of 2 points with a standard deviation of 5.3, based on a 2-sided 0.05 
level Joint Rank Test, and assuming 24-week survival rates of 96.5% and 95% in the PTC857 
and placebo groups, respectively. These assumptions took into consideration data from 2 clinical 


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studies in ALS which reached statistical significance for their primary endpoints that reported 
overall death rates of 0% and 5% (Edaravone (MCl-186) ALS 19 Study Writing Group 2017 and 
Paganoni, 2020) A standard deviation of 5.3 points for the ALSFRS-R score at Week 24, among 
treated subjects was reported for the edaravone study (Edaravone (MCl-186) ALS 19 Study 
Writing Group 2017). 
Assuming approximately 10% of randomized subjects will not meet the ITT1 Analysis Set 
definition, then approximately 340 subjects will be randomized to ensure that 307 subjects are 
randomized into the ITT1 Analysis Set. Given that the primary analysis incorporates deaths as a 
combined endpoint, and a fully imputed analysis dataset is utilized in the analysis, additional 
enrollment and randomization to make up for discontinued subjects is not planned. This 
document clarifies a typographical error in the study protocol that incorrectly indicated a 
treatment difference of 2.5 points instead of 2 points, is of interest.  
1.6. 
Randomization and Blinding  
Double-Blind 24-Week Treatment Period (Part A): 
Subjects who satisfy all the inclusion and none of the exclusion criteria will be randomly 
assigned in a 2:1 ratio to receive one of the following two treatment arms during the 24-week 
treatment phase according to a study randomization scheme: 
• Arm 1: PTC857 (250 mg) administered orally BID for 24 weeks. 
• Arm 2: Matching placebo administered orally BID for 24 weeks. 
Investigators and site staff will be blinded to treatment assignments during the entire study 
period. Biostatistics staff who are directly involved in the analysis of the study results and 
members of the clinical study team will remain blinded to the treatment assignment throughout 
the conduct of Part A and will be unblinded after database lock for Part A.  
 


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2. 
ANALYSIS SETS  
2.1. 
All Enrolled Set  
The All-Enrolled set will contain all subjects who signed an informed consent for this study. This 
analysis set will be used to summarize subject disposition. 
2.2. 
Intent-to-Treat (ITT) Analysis Sets  
Intent-to-Treat 1 Analysis Set (ITT1) 
All subjects who are randomized after the Screening Period and take at least 1 dose of double-
blind study drug in the Treatment Period and who have a decrease in the ALSFRS-R score of ≤4 
points during the Screening Period will be included in the ITT1 Analysis Set. The ITT1 Analysis 
Set will be used for analysis of the primary endpoint. Subjects will be analyzed according to their 
randomized treatment. 
Intent-to-Treat 2 Analysis Set (ITT2) 
All subjects who are randomized after the Screening Period and take at least 1 dose of double-
blind study drug in the Treatment Period will be included in the ITT2 Analysis Set. Subjects will 
be analyzed according to their randomized treatment assignment. ITT2 analysis set will be used 
as supportive analysis population. 
2.3. 
Safety Set  
All subjects in the ITT2 Analysis Set who receive at least 1 dose of study drug will be included 
in the Safety Analysis Set. Subjects will be analyzed according to the actual treatment received.  
2.4. 
Per Protocol Set  
All subjects in the ITT1 Analysis Set who have no major protocol deviations that affect the 
validity of the efficacy measurements will be included in the PP Analysis Set. The PP Analysis 
Set will be used for sensitivity analysis of the efficacy endpoint. Classification of whether 
protocol deviations require exclusion from the ITT1 set will be assessed at a Blinded Data 
Review Meeting (BDRM) prior to database lock. Subjects who meet the following criteria will 
be excluded from the ITT1 population hereby forming the per-protocol analysis set:   
(1) Received a protocol prohibited concomitant medication during the double-blind period.  
a. Received edaravone and sodium phenylbutyrate/taurursodiol in combination,  
b. Received a non-approved form of sodium phenylbutyrate/taurursodiol, 
c. Initiated a new approved ALS therapy during the double-blind period. 
(2) Received study treatment different from the randomized treatment throughout the double-
blind period  
(3) Significant non-compliance to study drug  
(4) Had significant inclusion or exclusion criteria violations  
(5) Had protocol deviations which may confound results of study treatment effectiveness  
(6) ALSFRS-R assessment on day -56, day 1 or day 169 performed by a non-certified rater.  


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This population will be to analyze the primary efficacy endpoint as supportive efficacy analysis. 
A separate document listing subjects excluded from the ITT1 population and reasons for 
exclusion will be finalized prior to treatment unblinding. 
2.5. 
Pharmacokinetic Analysis Set  
All subjects in the ITT2 Analysis Set who have at least 1 measurable post-baseline plasma or 
CSF PTC857 concentration will be included in the PK Analysis Set. Subjects with protocol 
violations that could affect the PK parameters will be assessed by the pharmacokineticist for 
inclusion into the PK analysis set. The pharmacokineticist may also exclude subjects or specific 
concentrations from the PK parameter calculation if required, for example if doses were missed 
or if samples were collected out of the allowed assessment windows. PK summaries and analyses 
will be conducted using the PK analysis set. The PK analysis set will be based on the actual 
treatment received. 
2.6. 
Protocol Deviations  
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to, the following: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications that are specifically prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. (either the tests were not done, 
the incorrect tests were done, or the tests were not done within the time frame 
specified in the protocol) 
• Procedural deviations such as incorrect storage of study drug, failure to update the 
ICF when new risks become known, or failure to obtain IRB/IEC approvals for the 
protocol and ICF revisions 
Major protocol deviations are defined in the study’s Protocol Deviation Handling Plan and 
include quality issues that have a high likelihood to significantly impact a subject’s rights, safety 
or well-being, or have a potentially significant impact on data integrity. 
Protocol deviations will be documented separately in a stand-alone file before database lock 
which include deviation category (e.g., violation of inclusion and exclusion criteria at screening, 
use of excluded concomitant medications, received the wrong treatment or incorrect dose), 
deviation description, severity (minor/major), visit/time point for each deviation. .  
Protocol deviations pertaining to the effects of the COVID-19 pandemic and related measures 
may be seen on this trial, and there may be an increase in the number of deviations seen due to 
the pandemic. All discussions pertaining to the COVID-19 pandemic and related protocol 


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deviations affecting inclusion/exclusion of analysis sets, and any adjustments to data handling 
and/or analysis of data will be documented in the blinded data review meeting (BDRM) Report. 
Both the BDRM Report and this document (SAP) will be finalized before database lock. A by-
subject listing of major and minor protocol deviations will be provided for the safety analysis set. 


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3. 
GENERAL CONSIDERATIONS  
3.1. 
General Considerations  
Continuous data will be summarized using number of observations (n), arithmetic mean (mean), 
standard deviation (SD), median, minimum value (min) and maximum value (max) by treatment 
group. Additionally, for biomarker data, the summaries will include geometric means and 
standard deviations, as appropriate. Categorical variables will be summarized using the 
frequency count (n) and percentage (%) by treatment group. An overall/total group (i.e., sum of 
all treatment groups) will generally be presented additionally for summaries of disposition, 
demography, and baseline characteristics.  
For all percentage calculations, the denominator will be the number of subjects in the analysis set 
for the treatment group, unless otherwise stated. 
Only data from protocol scheduled visits will be included in the summary tables.  Data from 
unscheduled visits will not be included in the summary tables but will be included in the by-
subject listings. Descriptive summaries by visit and treatment will be provided for all the primary 
and secondary efficacy endpoints.   
3.2. 
Data Definitions and Analysis Issues  
3.2.1. 
Study/Onset Day  
The study/onset day will be defined as the number of days since the first dose of study drug, 
which is assigned as Day 1 for analysis purposes.  Study/onset day is calculated using the 
formula below: 
Assessment Date Relative to First Dose of Study Drug Study Day Calculation 
Assessment/Event date prior to date of first dose 
Date of assessment – Date of first dose of 
study drug 
Assessment/Event date on or after Date of first dose 
(Date of assessment – Date of first dose of 
study drug) +1 
3.2.2. 
Baseline Definition and Change from Baseline  
The Baseline Visit will be defined as Day 1 of the study. Unless otherwise stated, for each 
subject, baseline value of a parameter is defined as the last non-missing measurement taken at 
most one week prior to the first dose of study drug (including unscheduled assessments). If the 
last non-missing measurement and the date of first dose of study drug coincide, that 
measurement will be considered baseline, but AEs and medications commencing on the date of 
first dose of study drug will be considered post-baseline.  
For the purposes of calculating summary statistics of the outcome measures, change from 
baseline will be derived as follows: 
• Change from baseline = Post-baseline value – Baseline value 
3.2.3. 
Duration of Event  
Where the duration of an event is to be calculated, it will be derived as:  
Duration (days) = (Event stop/end date – Event start date) + 1. 


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Duration (months) = Duration (days) / 30.4375 
3.2.4. 
Retest and Unscheduled Visits  
Unscheduled measurements and retests will not be included in by-visit summaries but will 
contribute to incidence of significant abnormality tables, where applicable. 
In the case of a retest (same visit number assigned), the last available measurement for that visit 
will be used for by-visit summaries. Data listings will include all assessments, both scheduled 
and unscheduled.  
3.2.5. 
Treatment Periods  
Period 
Definition  
Pre-treatment 
Date of Screening through one day prior Date of first dose 
Double-blind 
Treatment Period 
Date of first dose through to Date of last dose during Part A  
or   
Date of first dose through to one day prior first dose during open-label treatment 
period 
3.2.6. 
Coding Dictionary  
Where applicable, safety data will be coded using the following coding dictionaries:
Dictionary 
Version 
Medical Dictionary for Regulatory Activities (MedDRA) 
25 or higher 
World Health Organization Drug Dictionary (WHODrug Global) 
WHODrug-Global-B3 Sep 2021 or 
later 
3.2.7. 
ALS Functional Rating Scale - Revised (ALSFRS-R) score  
The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the 
subjects’ capability and independence in 12 functional activities across 4 subdomains of bodily 
function (bulbar, gross motor, fine motor, and respiratory) relevant in ALS. Each activity is 
recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 
4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating less 
functional impairment (Cedarbaum 1999). 
The score change from baseline will be calculated as the post baseline score minus the baseline 
score, so that a positive score for change from baseline would indicate improvement in function 
relative to baseline, while a negative score indicates worsened disease relative to baseline.  
Subdomains 
Items 
Bulbar 
Speech, Salivation and Swallowing 
Fine Motor 
Handwriting, Cutting Food/Handling Utensils and Dressing Hygiene 
Gross Motor 
Turning in Bed, Walking and Climbing Stairs 
Respiratory 
Dyspnea, Orthopnea and Respiratory Insufficiency 
Scores for each item range from 0 to 4 (0 representing the worst/lowest functional rating and 4 the best 
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3.2.8. 
Pulmonary Function Tests  
Pulmonary function tests are used to assess respiratory function. Pulmonary function tests (PFTs) 
will assess SVC and SNIP. Forced vital capacity, vital capacity, forced expiratory volume, and 
maximum inspiratory pressure will not be measured. Oxygen saturation (SpO2), respiratory rate, 
and heart rate will be assessed in both upright and supine positions. The SNIP test will assess 
nasal pressure in each unilaterally occluded nostril during a maximal sniff to assess inspiratory 
muscle strength. 
3.2.9. 
Modified Norris Scale  
Modified Norris scale is used to assess the motor/limb and bulbar function. The Modified Norris 
Scale is a rating scale for ALS that consists of 2 parts: the Limb Norris Scale and the Norris 
Bulbar Scale. The Limb Norris Scale has 21 items to evaluate extremity function, and the Norris 
Bulbar Scale has 13 items to evaluate bulbar function. Each item is rated in 4 ordinal categories. 
The total score is calculated by summing all the scales (Norris 1974). 
3.2.10. 
ALS Cognitive Behavioral Screen  
The ALS CBS is a brief measure of cognition and behavior in patients with ALS. The ALS CBS 
is composed of 2 sections: cognitive and behavioral. The cognitive section includes commonly 
used elements of standard testing batteries, consisting of 8 tasks that assess attention, 
concentration, tracking/monitoring, and initiation and retrieval. Each subtest score ranges from 
0–5 and the total score ranges from 0–20. The behavioral section is composed of questions 
sensitive to organic brain changes. It consists of fifteen 3-point Likert items (total score ranges 
from 0–45) questioning caregivers on patients’ behavioral changes (3 = “no change”; 0 = “large 
change”) and 4 “yes/no” questions on anxiety and depression. 
3.2.11. 
ALSAQ-40 Assessment  
The ALSAQ-40 is a disease-specific measure of health-related quality of life for ALS (Jenkinson 
1999). It is specifically used to measure the subjective well-being of patients with ALS and 
provides scores for 5 scales: physical mobility (10 items: 1-10), activities of daily living and 
independence (10 items: 11-20), eating and drinking (3 items: 21-23), communication (7 items: 
24-30) and emotional reactions (10 items: 31-40).  If one of the question items of ALSAQ-40 is 
missing, the total score will be considered as a missing value. However, it may be included in the 
summary of the specific scales. Lower total scores for the ALSAQ-40 indicate better quality of 
life, with higher scores indicating poorer quality of life. Analyses will be performed on the total 
score. 
3.2.12. 
EuroQol EQ-5D-5L  
The EQ-5D-5L is a patient reported outcome measure (PROM) that determines a subject’s 
health-related quality of life (www.euroqol.org). EQ-5D-5L consists of 2 components: The 
health state descriptive system and the visual analogue scale (EQ-VAS).  
The health state descriptive system is a 5 Dimension (5-D) questionnaire covering 5 health 
related aspects: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. For 
each Dimension, the subject responds by selecting one of 5-levels (5L): 1=No problems; 
2=Slight Problems; 3=Moderate Problems; 4=Severe Problems and 5=Extreme Problems.  


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The visual analogue scale (EQ-VAS) is a 20 cm vertical graduated visual analogue scale with 
numbers ranging from 0 (=worst imaginable health) to 100 (=best imaginable health). Subjects 
rate their overall health by placing an X mark on the scale to indicate their perceived overall 
health. 
3.2.13. 
Survival  
The survival endpoint is defined as the time from the randomization date to the date of death 
from any cause.  
3.2.14. 
Combined Assessment of Function and Survival (CAFS)  
CAFS is a joint rank test developed for ALS that evaluates function while appropriately 
accounting for missing data due to deaths in ALS (Berry 2013). CAFS ranks each subject 
according to their outcome, with the worst subject’s clinical outcomes based on the survival time 
and the ALS Functional Rating Scale–Revised (ALSFRS-R) score at the timepoint of interest. 
Each subject’s outcome is compared to every other subject’s outcome, assigned a score, and the 
total scores are ranked. The mean rank score for each treatment group can then be calculated. A 
higher mean CAFS score indicates a better group outcome. 
CAFS scoring: Subject’s CAFS scores will be computed using the approach proposed by Berry 
(2013). Each subject is compared individually to all other subjects in the study. For each 
pairwise comparison of subjects, the participant who fares better earns a point (+1), and the one 
who fares worse loses a point (-1). In the case of a tie, no points are added or subtracted (0). The 
total score for each subject is the sum of the comparisons (+1, 0, -1) against all other subjects. 
The pairwise comparisons will be performed as follows: If both subjects die, the one surviving 
longer fared better; if only one survives then that subject fared better; and if both subjects 
survive, the one with the smaller decline (from baseline to 24 weeks) in ALSFRS-R fared better. 
If subjects discontinue prior to their week 24 assessment, comparison will be based on their 
imputed week-24 ALSFRS-R result (See Section 5.5.1.2 for multiple imputation details).   
CAFS ranking: The ranking has the following characteristics: 1) the first subject who dies will 
have the lowest score and is ranked the lowest; 2) the last to die is ranked above all others who 
die; 3) among survivors, the subject with the largest decline in ALSFRS-R score at week 24 is 
ranked just above the last subject who died; 4) the surviving subject with the smallest decline 
from baseline in ALSFRS-R score at week 24 is ranked highest. An average rank score can then 
be calculated for each treatment group. A higher mean rank score indicates that subjects in that 
treatment group, on average, fared better. 
3.3. 
Estimands  
3.3.1. 
Estimand for Primary Efficacy (Combined Assessment of Function and 
Survival)  
Research Question: What is the improvement in combined survival and activities of daily 
function between subjects treated with PTC857 versus Placebo after 24-weeks, in the population 
of patients with ALS as defined by the study’s inclusion exclusion criteria, regardless of whether 
subjects complete their assigned treatment during the 24-week treatment period, or underwent a 
tracheostomy, or had permanent assisted ventilation?  


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Patient Population: All subjects who are randomized to a treatment assignment and take at least 
1 dose of study drug during the double-blind treatment period, and who have a decrease in the 
ALSFRS-R score of ≤ 4 points during the Screening Period (ITT1 Population). 
Endpoint: CAFS rank at Week 24 
Population-level summary: Difference in the mean CAFS rank at Week 24 between PTC857 and 
Placebo. 
Treatment Condition: PTC857 compared to Placebo, in the setting where patients have the option 
(at screening), to take SOC treatments for ALS that are approved in their country; patients are 
allowed to take either edaravone or sodium phenylbutyrate/taurursodiol as monotherapy or in 
combination with riluzole but not in combination with each other. 
Intercurrent Event Strategy: 
1. The intercurrent event of death will be accounted for as part of the composite CAFS 
score. 
2. Treatment Discontinuation: Data collected after treatment discontinuation will be 
included and analyzed according to the treatment group to which the participant was 
randomized. (Treatment Policy). 
3. Initiation of new therapy for ALS: If subjects initiate new additional therapy for ALS 
after randomization their data will be analyzed according to the treatment group to which 
the participant was randomized, i.e., regardless of the initiation of new therapy for ALS. 
(Treatment Policy).  
4. Tracheostomy: Data collected after a Tracheostomy will be included and analyzed 
according to the treatment group to which the participant was randomized. (Treatment 
Policy). 
5. Permanent Assisted Ventilation (PAV): Data collected after a PAV will be included and 
analyzed according to the treatment group to which the participant was randomized. 
(Treatment Policy). 
The same estimand framework (above) will be used to analyze the primary endpoint for the ITT2 
population. 
3.3.2. 
Estimands for Change from Baseline in ALSFRS-R at Week 24  
Research Question: What is the difference in mean ALSFRS-R change from baseline between 
subjects treated with PTC857 versus Placebo after 24 weeks of treatment, in the population of 
patients with ALS as defined by the study’s inclusion exclusion criteria, regardless of whether 
subjects complete their assigned treatment during the 24-week treatment period, or underwent a 
tracheostomy, or had permanent assisted ventilation?  
Patient Population: All subjects who are randomized to a treatment assignment, take at least 1 
dose of study drug during the double-blind treatment period, and who have a decrease in the 
ALSFRS-R score of  ≤ 4 points during the Screening Period (ITT1 Population).  
Endpoint: Change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) at Week 
24 


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Population-level summary: Difference in the mean ALSFRS-R change from baseline to Week 24 
between PTC857 and Placebo. 
Treatment Condition: PTC857 compared to Placebo, in the setting where patients have the option 
(at screening), to take SoC treatments for ALS that are approved in their country; patients are 
allowed to take either edaravone or sodium phenylbutyrate/taurursodiol as monotherapy or in 
combination with riluzole but not in combination with each other. 
Intercurrent Event Strategy: 
1. Death: Missing data after death up to week 24 will be implicitly imputed by means of 
mixed model repeated measures analysis (MMRM) assuming MAR. Analysis will be 
carried out on all available data. (Hypothetical) 
2. Treatment Discontinuation: Data collected after treatment discontinuation will be 
included and analyzed according to the treatment group to which the participant was 
randomized. (Treatment Policy) 
3. Initiation of new therapy for ALS: If subjects initiate new additional therapy for ALS 
after randomization (for example a subject start taking edaravone at week 18 with or 
without discontinuing their baseline therapy), data collected from this point forward will 
be included and analyzed according to the treatment group to which the participant was 
randomized. (Treatment Policy)  
4. Tracheostomy: Data collected after a Tracheostomy will be included and analyzed 
according to the treatment group to which the participant was randomized. (Treatment 
Policy) 
5. Permanent Assisted Ventilation (PAV): Data collected after a PAV will be included and 
analyzed according to the treatment group to which the participant was randomized. 
(Treatment Policy) 
Other continuous endpoints will use a similar framework for the main estimand, with analysis 
via an MMRM model. This includes the Modified Norris Scale, ALS CBS, NfL and ALSAQ-40. 
This estimand framework will also be applied to the ITT2 population.  
3.3.3. 
Estimands for Survival Time  
The main estimand for survival time is as follows: 
Research Question: How does survival time compare between PTC857 treatment versus Placebo 
groups, in the population of patients with ALS as defined by the study’s inclusion exclusion 
criteria?  
Patient Population: All subjects who are randomized to a treatment assignment after the 
Screening Period, take at least 1 dose of study drug during the double-blind treatment period, and 
who have a decrease in the ALSFRS-R score of ≤ 4 points during the Screening Period (ITT1 
Population). 
Endpoint: Time to death  
Population-level summary: The hazard ratio between PTC857 and Placebo for the event of death. 
Treatment Condition: PTC857 compared to Placebo, in the setting where patients have the option 
(at screening), to take SOC treatments for ALS that are approved in their country; patients are 


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allowed to take either edaravone or sodium phenylbutyrate/taurursodiol as monotherapy or in 
combination with riluzole but not in combination with each other. 
Intercurrent Event Strategy: 
1. Treatment Discontinuation: Survival data after a treatment discontinuation will be 
included up through the date of death or last follow-up date and analyzed according to the 
treatment group to which the participant was randomized (Treatment Policy).   
2. Initiation of new therapy for ALS: If subjects initiate new additional therapy for ALS 
after randomization (for example a subject start taking edaravone at week18 without 
discontinuing their baseline therapy), survival data after this event will be included up 
through the date of death or last follow-up date and analyzed according to the treatment 
group to which the participant was randomized. (Treatment Policy). 
3. Tracheostomy: Survival data after a Tracheostomy will be included up through the date 
of death or last follow-up date and analyzed according to the treatment group to which 
the participant was randomized. (Treatment Policy).  
4. Permanent Assisted Ventilation (PAV): Survival data after a PAV will be included up 
through the date of death or last follow-up date and analyzed according to the treatment 
group to which the participant was randomized. (Treatment Policy).  
This estimand framework will also be applied to the ITT2 population. 
3.3.3.1. 
Respiratory-Support free survival time - A supportive estimand for the survival time  
Research Question: How does respiratory-support free survival time compare between PTC857 
treatment versus Placebo groups, in the population of patients with ALS as defined by the 
study’s inclusion exclusion criteria?  
Patient Population: All subjects who are randomized to a treatment assignment after the 
Screening Period, take at least 1 dose of study drug during the double-blind treatment period, and 
who have a decrease in the ALSFRS-R score of ≤ 4 points during the Screening Period (ITT1 
Population). 
Endpoint: Time to death or needing respiratory support (Tracheostomy and/or Permanent 
Assisted Ventilation [PAV]) 
Population-level summary: The hazard ratio between PTC857 and Placebo for the event of death 
or needing respiratory support/intubation. 
Treatment Condition: PTC857 compared to Placebo, in the setting where patients have the option 
(at screening), to take SOC treatments for ALS that are approved in their country; patients are 
allowed to take either edaravone or sodium phenylbutyrate/taurursodiol as monotherapy or in 
combination with riluzole but not in combination with each other. 
Intercurrent Event Strategy: 
1. Treatment Discontinuation: Survival data after a treatment discontinuation will be 
included up through the date of event (death/respiratory support) or last follow-up date 
and analyzed according to the treatment group to which the participant was randomized 
(Treatment Policy). 


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2. Initiation of new therapy for ALS: If subjects initiate new additional therapy for ALS 
after randomization (for example a subject start taking edaravone at week18 without 
discontinuing their baseline therapy), survival data after this event will be included up 
through the date of event (death/respiratory support) or last follow-up date and analyzed 
according to the treatment group to which the participant was randomized. (Treatment 
Policy). 
3. Tracheostomy: The intercurrent event of tracheostomy will be accounted for as part of 
the composite endpoint (death or needing respiratory support/intubation) (Composite). 
4. Permanent Assisted Ventilation (PAV): The intercurrent event of PAV will be accounted 
for as part of the composite endpoint (death or needing respiratory support/intubation). 
(Composite). 
This estimand framework will also be applied to the ITT2 population. 
3.4. 
Interim Analysis  
No formal interim analyses are planned for this study. 
The analysis of the data for the double-blind treatment period (Part A) as outlined in this SAP 
will be produced after the lock of database for Part A. 
3.5. 
Changes to Protocol Specified Analysis  
As described in Section 1.1, protocol amendment 4.0 allowed for randomization of subjects 
receiving edaravone or sodium phenylbutyrate/taurursodiol either in combination with riluzole or 
as monotherapy. It was anticipated that a significant number of subjects would opt for treatment 
with these therapies. As the study progressed and randomization continued, it became evident 
that the adoption rate of these treatments was markedly lower than anticipated. A vast majority 
of enrolled patients were only on riluzole as monotherapy with a small minority on either 
edaravone or sodium P/T as monotherapy or in combination with riluzole. To mitigate potential 
issues with statistical modeling arising from sparse strata, the protocol specified analyses 
described in Section 5, will use a binary form of the ALS treatment stratification factor, defined 
as the use of approved background ALS therapy at screening (Yes or No), rather than the 
original three-level stratification variable employed during randomization. Should modeling 
challenges due to sparse strata persist, a partially stratified analysis (excluding either one of the 
two stratification factors) or a fully unstratified analysis (exclusion of both factors) will be 
considered.  
Derivation of the binary stratification variable (use of approved background ALS therapy at 
screening) will be based on the stratum subjects were assigned to during randomization 
irrespective of stratification errors made by the sites. An example of such a stratification error is 
a subject on stable edaravone treatment being randomized out of the sodium 
phenylbutyrate/taurursodiol stratum.  
A list of all stratification errors including those related to the other stratification variable (decline 
in ALSFRS-R during the screening period), will be provided.  


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4. 
SUBJECT DATA  
4.1. 
Subject Disposition  
Subject disposition data will be listed and summarized. A summary table of subject disposition 
will be produced reflecting: 
• Screened (or enrolled) subjects. 
• Number of subjects in the ITT1, ITT2, Safety, Per-protocol and Pharmacokinetic 
analysis sets 
• Subjects who complete the study treatment 
• Subjects who early terminate the study treatment and reasons for early termination 
• Subjects who early terminate the study treatment but continue onto the survival 
follow-up 
• Subjects who early terminate the study and reasons for early termination 
Screen Failure subjects will be listed. 
For subjects who fail screening, the reasons for screen failure including details on which 
inclusion / exclusion criteria were not met will be listed. 
For the enrolled population, the number and percentage of participants in each analysis 
population will be presented.   
4.2. 
Demographics and Baseline Characteristics  
Subjects’ demographics and baseline characteristics will be summarized overall and by treatment 
group for the ITT1, ITT2, and Safety analysis sets.  
Continuous variables (e.g., age and weight) will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum). Qualitative variables (e.g., sex, 
race, and ethnicity) will be summarized with counts and percentages.  
The demographic parameters will include age category (<65 and ≥65 years), gender, race, and 
ethnicity. Age will also be summarized as a continuous variable. The baseline parameters 
include, height, body weight, BMI, ALSFRS-R score, amount of change in ALSFRS-R score 
during the screening period (<1, 1-2, 3-4, or >4 points total loss) use of standard of care (SoC) 
medications for ALS at baseline, and disease characteristics at screening. 
By-subject listings of demographic and other baseline characteristics will be provided for all 
randomized subjects. These listings will use flag variables to identify subjects in various analysis 
sets (ITT1, ITT2, safety and per-protocol).  
4.3. 
Disease Characteristics  
Subjects’ disease characteristics will be summarized overall and by treatment group for the ITT1, 
ITT2, and Safety analysis sets. By-subject listings of disease characteristics will also be 
provided. Duration of symptoms (months) and months since diagnosis will be summarized using 
descriptive statistics (n, mean, standard deviation, median, minimum, and maximum). The 
following disease characteristics will be summarized with counts and percentages (n (%)): 


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• Site of symptom onset 
• Family history 
• El Escorial criteria at screening 
• Pre-ALS impairment 
• Months since ALS symptom onset  
• Months since diagnosis 
• Site of onset 
• Diagnosis delay 
• Derived King’s Clinical Stage (Balendra 2014 also see Appendix 5) 
• TRICALS Risk Profile  
The TRICALS risk profile (van Eijk 2021) is based on the European-Network-to-Cure-ALS 
survival prediction model, a cross-validated model to predict the composite endpoint death or 
respiratory insufficiency based on data of 11,475 patients with ALS (Westeneng 2018). The 
TRICALS Risk Profile is a weighted average of seven pre-randomization patient characteristics, 
including: Percent predicted vital capacity, age at onset in years, diagnostic delay (months from 
symptom onset to diagnosis), presence of frontotemporal dementia, progression rate of the ALS 
functional rating scale (points per month), Bulbar onset of ALS, and an El Escorial criteria of 
clinical definite ALS at screening. The range of possible values for this summary predictor is 
from approximately −12.0 to 0.0 with higher scores indicating a poorer prognosis. Section 13 
(Appendix 3) provides details on its derivation.  
4.4. 
Medical History  
Medical history will be coded using a central coding dictionary, the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology.  
Medical history will be defined as any significant past medical conditions that ended before 
screening or current medical conditions that were ongoing at Screening. Medical history will be 
summarized separately by system organ class (SOC) and preferred term (PT) overall and for 
each treatment group for the safety analysis set. Summaries will be sorted alphabetically by 
SOC, and by descending order of frequency for PTs according to the total column. Subjects with 
more than one of the same PTs within an SOC will be counted only once. A summary of medical 
history by randomized treatment arm will be provided for the ITT1 and Safety analyses sets. In 
addition, a by-subject listing will also be provided for the safety analysis set. 
4.5. 
Prior Medications/Procedures and Concomitant Medications/Procedures  
Prior medications are medications which started and stopped before the first dose of study drug. 
Any changes to prior medications (dose, regimen, etc.) during the study will be considered a new 
concomitant medication.  
Concomitant medications/procedure are medications/procedures which started prior to or after 
the first dose of study drug and ended after the date of first dose of study drug or ongoing at the 


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end of the study. If a medication or procedure cannot be classified as “prior” or “concomitant” 
after applying imputation rules for missing/incomplete dates, it will be classified as concomitant. 
Prior and concomitant medications will be coded using the latest available version of the 
Anatomical Therapeutic Chemical (ATC) classification text from the World Health Organization 
Drug Dictionary (WHO DD) and summarized separately. The number and percentage of subjects 
taking a medication will be displayed by therapeutic class (ATC Level 3) and preferred name 
and treatment group. Summaries will be sorted alphabetically by ATC-Level 3, and by 
descending order of frequency for preferred name according to the total column. Subjects with 
more than one of the same preferred names within an ATC-Level 3 will be counted only once.  
Prior and concomitant procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. 
A by-subject listing of prior and concomitant medications will be provided for the safety analysis 
set. 
The count and percentage of subjects who have received prior and concomitant procedures will 
be summarized by treatment group, in addition, by-subject listing of prior and concomitant 
procedures will be provided for the safety analysis set. 
4.6. 
Multiplicity  
A fixed sequence testing procedure will be employed for selected efficacy endpoints. If the 
primary endpoint is statistically significant at a 2-sided 0.05 level, the secondary endpoints will 
then be tested sequentially in the order listed below, each at a 2-sided 0.05 alpha level. Testing 
within the specified sequence will stop if a null hypothesis in the sequence fails to be rejected. 
(1) Change from baseline in ALSFRS-R at Week 24 in the ITT1 analysis population 
(2) Change from baseline in ALSFRS-R at Week 24 in the ITT2 analysis population 
(3) Subject ranks based on the CAFS at Week 24 in the ITT2 analysis population 
(4) Change from baseline in total score of the Amyotrophic Lateral Sclerosis Assessment 
Questionnaire (ALSAQ-40) after 24 weeks of treatment, in the ITT1 analysis population 
(5) Change from baseline in log transformed plasma NfL, in the ITT1 analysis population 
There will be no interim analysis. 
4.7. 
Missing Data  
For the analysis of CAFS, missing ALFSRS-R data will be assumed to be missing at random 
(MAR) and will be imputed using multiple imputation. 
4.8. 
Treatment Compliance  
Percent compliance will be calculated as the amount of dose taken divided by the amount of dose 
that should have been taken multiplied by 100. The following formula will be used to calculate 
compliance. 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (%) = 100 × (2 × 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑)
2 × 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
 


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The extent of exposure to study medication (treatment duration) in days will be calculated as the 
last dose date minus the first dose date + 1.   
Exposure (number of days) and compliance will be summarized descriptively (number of doses 
taken / number of doses expected and percentage) for the ITT1, ITT2 and safety analysis sets. 
4.9. 
Visit Windows for The Early Termination Visit and Unscheduled Visits  
If a subject completely withdraws from the study prematurely, and unless consent is withdrawn, 
all efforts are made to collect efficacy and safety data and to complete the Early Termination 
Visit (ET). 
Follow-up efficacy data collected at the early termination visit will be incorporated into the study 
visit schedule using the visit windows, defined in Table 1 and Table 2. Similarly, follow-up 
efficacy data collected during unscheduled visits or make-up visits will also use the same visit 
windows. If a follow-up visit (ET) or unscheduled visit falls in the same visit window as a 
scheduled visit, then the scheduled visit data will be used. If an unscheduled visit and ET visit 
fall within the same window, then the visit closest to the target day will be used.  
Table 1: Visit Windows for Early Termination and Unscheduled Visits  
ALSFRS-R 
Visit 
Lower Bound 
Target Day 
Upper Bound 
Day 29 
15 
29 
42 
Day 57 
43 
57 
70 
Day 85 
71 
85 
98 
Day 113 
99 
113 
126 
Day 141 
127 
141 
154 
Day 169 
155 
169 
182 
 
Table 2: Visit Windows for Early Termination and Unscheduled Visits  
SVC, ALSAQ-40, Norris Scale, and plasma NfL 
Visit 
Lower Bound 
Target Day 
Upper Bound 
Day 85 
64 
85 
106 
Day 169 
148 
169 
190 
 


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5. 
EFFICACY ANALYSIS  
5.1. 
Analysis of the Primary Efficacy Endpoint  
The primary efficacy variable, subject ranks based on the combined assessment of function and 
survival (CAFS) after 24 weeks of treatment will be performed using an analysis of covariance 
model (ANCOVA) following multiple imputation. The estimand framework described in Section 
3.3.1 will be used. The ANCOVA model will contain the following main effects: treatment 
(PTC857 or placebo), the amount of change in the subject’s ALSFRS-R score during the 
Screening Period (<1, 1-2, or 3-4-points total loss), TRICALS risk profile (continuous), use of 
Approved Background Therapy for ALS (Yes [either riluzole, edaravone, or sodium 
phenylbutyrate/taurursodiol], No). Baseline ALSFRS-R score (continuous) and The TRICALS 
risk profile (continuous) will be included as covariates.  
Subjects who discontinue from the study prior to week 24 will have their week 24 ALSFRS-R 
score imputed using the same datasets described in Section 5.5.1.2. In each of the 100 imputed 
datasets, subjects who die will have their death day (study day) incorporated as part of the 
combined assessment of function and survival.  
The p-value for the treatment comparison (PTC857 versus Placebo) at week 24, estimate of 
LSMEANS for the treatment differences (PTC857 – Placebo), and the two-sided 95% 
confidence interval of the LSMEANS difference will be presented for the ITT1 analysis set 
(obtained from PROC MIANALYZE in SAS). If the p-value for the treatment arm comparisons 
at week 24 is less than 0.05, then the study will be declared as positive.  
This analysis will also be repeated for the ITT2 analysis set and a nominal p-value for treatment 
arm comparison at week 24 presented.  
In addition, averaged win probability (Rubin’s rule) and a win-odds, will also be presented. 
𝑊𝑊𝑊𝑊𝑊𝑊 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝(𝜃𝜃) = 0.5 + 𝑅𝑅ത𝑖𝑖−𝑅𝑅ത𝑗𝑗
𝑁𝑁𝑖𝑖+ 𝑁𝑁𝑗𝑗
 
 
Where: 
𝑅𝑅ത. =  𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑓𝑓𝑓𝑓𝑓𝑓 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔 𝑖𝑖,𝑗𝑗 
𝑁𝑁. = 𝑁𝑁𝑁𝑁. 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑖𝑖𝑖𝑖 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔 𝑖𝑖,𝑗𝑗 
𝑊𝑊𝑊𝑊𝑊𝑊 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜= 
𝜃𝜃
(1 − 𝜃𝜃) 
 
Given the difficulties in interpreting and quantifying the treatment effect from the CAFS 
analysis, results from the MMRM analysis in ALSFRS at week 24 (Section 5.5) will be used to 
describe the treatment effect in terms of loss of function). Similarly, survival differences will be 
described using results from the Survival analysis (Section 5.7)  
5.2. 
Sensitivity Analysis – Unstratified Analysis  
The primary efficacy analysis described in Section 5.1 will be repeated without including the two 
stratification factors (change in ALSFRS-R score during the 8-week Screening Period and 
standard of care therapy for ALS).   
5.3. 
Sensitivity Analysis – Actual Stratification  
A sensitivity analysis to determine the effect of any incorrect stratification during randomization 
on the primary analysis will also be performed. The primary analysis (Section 5.1) will be 


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repeated using the actual stratification, defined as the stratification level they should have been 
randomized from.  
5.4. 
Per protocol Analysis Set  
The primary efficacy analysis described in Section 5.1 will be repeated using the Per protocol 
analysis set described in Section 2.4. For this analysis the seed to be used in the MI model is 
587432 
5.5. 
Analysis of Secondary Efficacy Endpoints  
For all efficacy analyses described in this Section and in Sections 5.6 through 5.8, partially 
stratified analysis (excluding either one of the two stratification factors) or fully unstratified 
analyses (exclusion of both factors) may be considered should there be issues with statistical 
modeling arising from sparse strata.  
5.5.1. 
Change from Baseline in ALSFRS-R  
5.5.1.1. 
Mixed Model Repeated Measures (MMRM)  
Change from baseline in ALSFRS-R at Week 24 will be evaluated by means of a mixed model 
repeated measures analysis using all available ALSFRS-R scores up to Week 24. The estimand 
framework described in Section 3.3.2 will be used. The model will include fixed categorical 
effects of treatment (PTC857 or placebo), use of  approved background therapy for ALS (Yes vs 
No), the amount of change in the subject’s ALSFRS-R score during the Screening Period (<1, 1-
2 or 3-4 points total loss), time of collection (nominal week at the visit as a categorical variable), 
as well as the continuous, fixed covariates of baseline ALSFRS-R, and The TRICALS risk 
profile. In addition, the following interaction terms will be included: Time by treatment, time by 
baseline ALSFRS-R, and TRICALS risk profile by time. Subject will be included as a random 
effect. The Restricted Maximum Likelihood (REML) estimation approach will be used with the 
variance-covariance structure set as unstructured (UN). Other types of covariance matrices will 
be explored in the case of non-convergence of the UN. Subjects with no post baseline results for 
the outcome variable will be excluded. This analysis will be performed for both the ITT1 and 
ITT2 analysis sets. 
Observed and change-from-baseline values will also be summarized descriptively at each visit. 
In supplementary analyses, score changes from baseline at Week 24 for the ALSFRS-R 
subdomains will be analyzed under the same estimand framework where MMRM models will be 
used to implicitly impute missing data. Nominal P-values for the treatment arm comparison, 
estimate of LSMEANS for the treatment differences (PTC857 – Placebo) at Week 24, and the 
two-sided 95% confidence intervals of the LSMEANS difference will be presented. 
5.5.1.2. 
Analysis of Covariance Model (ANCOVA) with Multiple Imputation:  
An additional analysis to evaluate change from baseline in ALSFRS-R will be performed using 
an analysis of covariance model (ANCOVA) following multiple imputation (MAR assumption).  
Missing ALSFRS-R scores, (including those missing due to death) will be imputed using 
multiple imputation (MI), 100 imputations will be generated using PROC MI in SAS. The Fully 
Conditional Specification (FCS) model using the regression method will be used.  


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The ANCOVA model will contain the change from baseline in ALSFRS-R as the response 
variable and will include the following main effects: Treatment group (PTC857, or Placebo), the 
amount of change in the subject’s ALSFRS-R score during the Screening Period (<1 point, 1-2-
points or 3-4-points total loss), use of approved background therapy for ALS (Yes vs No). 
Baseline ALSFRS-R score (continuous) and The TRICALS Risk Profile (continuous) will be 
included as covariates.  
The seed to be used in the MI model is 20221219. 
For each imputed complete data set, the change from baseline in ALSFRS will be analyzed at 
week 24 using the ANCOVA analysis model.   
The 100 estimates and standard errors will then be combined using Rubin’s rule to produce a 
single estimate with standard error, confidence interval and nominal p-value using the PROC 
MIANALYZE procedure in SAS. 
5.5.1.3. 
Pattern Mixture Model - Missing not at random assumption:  
A sensitivity analysis for the primary efficacy endpoint, ALSFRS-R score change from baseline 
at Week 24, will handle missing efficacy data using the assumption that data are missing not at 
random using a control-based Pattern-Mixture Model (PMM). This method will assume that 
participants who discontinue from study treatment early will have an ALSFRS-R score that is 
similar to participants on placebo. For the PMM model, 100 imputations will be generated using 
PROC MI of SAS. The seed to be used for this analysis will be 1001. 
5.5.2. 
Analysis of Other Continuous Secondary Endpoints  
The following secondary (continuous) endpoints will be analyzed for both the ITT1 and ITT2 
analysis sets under the estimand framework described in Section 3.3.2, where an MMRM is used 
to implicitly impute missing data. The MMRM models will include fixed categorical effects of 
treatment (PTC857 or placebo), use of  approved background therapy for ALS (Yes vs No), the 
amount of change in the subject’s ALSFRS-R score during the Screening Period (<1, 1-2 or 3-4 
points total loss), time of collection (nominal week at the visit as a categorical variable), as well 
as the continuous, fixed covariates of baseline endpoint variable (e.g., ALSFRS-R, ALSAQ-40), 
and The TRICALS risk profile. In addition, the following interaction terms will be included: 
Time by treatment, time by baseline value of endpoint, and TRICALS risk profile by time. 
P-values for the treatment arm comparison at week 24, estimate of LSMEANS for the treatment 
differences (PTC857 – Placebo), and the two-sided 95% confidence intervals of the LSMEANS 
difference will be presented: 
• Change from baseline in ALSFRS-R in the Intent-to-Treat 2 (ITT2) Analysis Set after 
24 weeks of treatment. 
• Quality of life as assessed by Amyotrophic Lateral Sclerosis Assessment 
Questionnaire (ALSAQ-40) after 24 weeks of treatment, for ITT1 and ITT2 analysis 
sets. 
• Change from baseline in Modified Norris Scale total score, limbs score and bulbar 
score at Week 24, for ITT1 and ITT2 analysis sets. 


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• Change from baseline in slow vital capacity (SVC) as assessed by pulmonary 
function tests (PFTs) after 24 weeks of treatment for the ITT1 and ITT2 analysis sets.  
To assess the change from baseline in plasma NfL after 24 weeks of treatment, log 
transformation of the plasma NfL results will be performed. A MMRM analysis will be 
performed, this analysis will include fixed categorical effects of treatment (PTC857 or placebo), 
use of approved background therapy for ALS (Yes vs No), time of collection (nominal week at 
the visit as a categorical variable), as well as the continuous, fixed covariates of baseline log 
plasma NfL, and The TRICALS risk profile. In addition, the following interaction terms will be 
included: Time by treatment, time by baseline log plasma NfL, and TRICALS risk profile by 
time. Geometric means and mean ratios to baseline, as well as the difference in geometric mean 
ratios for those in the PTC875 arm to those in the Placebo arm will be reported, together with 
95% confidence intervals and p-values, for the ITT1 and ITT2 analysis sets. For this analysis 
values of plasma NfL that are BLQ will be set to half of LLOQ. 
5.6. 
Subgroup Analyses for Efficacy  
To explore the uniformity of the overall treatment effect in subgroups, change from baseline in 
ALSFRS-R at Week 24 for the subgroups listed below. This analysis will be performed using the 
MMRM analysis described in Section 5.2, with a treatment by subgroup interaction term added 
to the model. Subgroups with too few subjects resulting in model non-convergence will be 
summarized using descriptive summaries of the change from baseline in ALSFRS-R score at 
week 24.  
• Sex (male, female) 
• Race (white, non-white) 
• Geographic region (North America, Europe, South America, Asia) 
• Age at baseline (<65, ≥ 65 years) 
• Slow vital capacity at baseline (<80%, ≥ 80%) 
• Definite and probable ALS at screening  
• Duration of symptoms (<12 months, ≥ 12 months)  
• TRICALS Risk Profile (< -4, ≥ -4) 
• Kings’ Stage (1, 2, 3) 
• Plasma NfL at baseline (< median value, ≥ median value) 
• Decline in ALSFRS-R score during the 8-week screening period (1-2, 2-4, 1-4) 
• Use of approved background therapy for ALS (Yes, No) 
• Decline in ALSFRS-R score during the 8-week screening period (<4 vs >4) [*] 
• Site of ALS onset (limbs, bulbar, other) 
• Baseline ALSFRS-R (<41, >=41) 
• Family history of ALS (yes, no) 


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[*] ITT2 analysis set 
5.7. 
Overall Survival  
Overall survival (OS) is defined as the time in months from the date of first dose to the date of 
death from any cause or date last known alive for those who did not die. 
Specifically, 
OS = Date of death or date last known alive – Date of first dose + 1 
Subjects will be censored at the last date they are known to be alive. The last known alive date 
will be the last date of any subject record in the study database. The date may be the last visit 
date or last contact date that the subject is known to be alive. Subjects who only have baseline 
record will be censored at the first dose date. 
OS will be analyzed using KM methods. A summary table of the number of deaths, the number 
of censored subjects, and KM estimates (25th, 50th, 75th percentile of OS along with the 95% 
CI) will be presented. Kaplan-Meier survival curves will also be presented. 
A stratified Cox Proportional Hazards regression model will be used to estimate the hazard ratio 
of PTC857 compared to Placebo. The model will be stratified by the amount of change in the 
subject’s ALSFRS-R score during the Screening Period (<1, 1-2 and 3-4-points total loss), and 
use of approved background therapy for ALS (Yes vs No). In addition, baseline ALSFRS-R 
score and the TRICALS risk profile and ALSFRS-R score at baseline will be included in the 
model as covariates. Ties in survival time will be handled using the Breslow method. Hazard 
ratio between the treatment groups and the corresponding 95% confidence intervals will be 
presented. 
5.8. 
Exploratory Endpoints  
Exploratory endpoints will be summarized for both the ITT1 and ITT2 analysis sets. Summary 
statistics by nominal timepoint will be provided for all the exploratory endpoints, including ALS-
CBS, EQ5D-5L, and biomarkers (plasma hydroxyeicosatetraenoic acid [HETE], plasma ferritin, 
4-hydroxynonenal [4HNE], urine p75 neurotrophin receptor [p75NTR], and cerebrospinal fluid 
NfL). Values of biomarkers and CSF NfL that are BLQ will be set to half of LLOQ. 
ALS-CBS total score will be analyzed using the same methodology described for secondary 
(continuous) endpoints in Section 5.5.1.1. P-values for the treatment arm comparison at week 24, 
estimate of LSMEANS for the treatment differences (PTC857 – Placebo), and the two-sided 
95% confidence intervals of the LSMEANS difference will be presented.  


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6. 
SAFETY ANALYSES  
All analyses described in this section will be performed on the Safety Analysis set and will be 
presented by treatment group (actual treatment received PTC857 vs Placebo). The results will be 
descriptive in nature. There will be no statistical comparisons between the treatment groups for 
safety data, unless otherwise specified within the relevant section. All data will be summarized 
and listed.  
Safety  assessments will include adverse events, laboratory assessments, vital signs, 12-Lead 
electrocardiogram, physical examination, and Columbia-Suicide Severity Rating Scale (C-
SSRS). 
6.1. 
Extent of Exposure  
The extent of exposure to study drug will be summarized descriptively. The summaries will 
include mean, SD, median, minimum, and maximum values. 
The extent of study drug exposure for the double-blind treatment period (Part A) is defined as the 
difference between the dates of the last dose of study medication and the first dose study drug in 
the double-blind treatment period plus 1. 
6.2. 
Adverse Events  
Adverse events will be collected and recorded from the time subjects sign the informed consent 
form to the end of the follow-up period. All AEs will be classified by primary system organ class 
(SOC) and preferred term (PT) according to MedDRA coding dictionary. A treatment-emergent 
adverse event (TEAE) is an AE that begins after the first administration of study drug or any 
existing AEs that worsens after the first dose of study drug. All reported AEs will be listed, but 
only TEAEs will be summarized in tables. 
AEs with an onset from day 1 of the double-blind treatment period up to and including 30 days 
after the last dose of study drug in the double-blind treatment period (or up to and not including 
the start date of the LTE period whichever comes first) will be considered as occurring during 
the double-blind treatment period.  
An overall summary of TEAEs presenting number and percentage of subjects reporting at least 
one TEAE for the categories presented below: 
• Subjects with at least one TEAE 
• Subjects with at least one TEAE related to study drug 
• Subjects with at least one serious TEAE 
• Subjects with at least one non-serious TEAE 
• Subjects with at least one serious TEAE related to study drug 
• Subjects with at least one TEAE leading to premature discontinuation of study drug 
• Subjects with at least one TEAE leading to death 
• TEAEs by highest relationship to study drug 
• TEAEs by highest severity 


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The following summaries will be tabulated: 
• TEAEs overall and by SOC and PT 
• TEAEs occurring in ≥ 5% of subjects within a treatment group, by PT 
• TEAEs by PT 
• Study drug related TEAEs, overall and by SOC and PT 
• TEAEs by maximum severity, overall and by SOC and PT 
• Grade 3 or Higher TEAEs by SOC and PT 
• Grade 3 or higher related TEAE by SOC and PT 
• TEAEs by highest relationship to study drug 
• Serious TEAEs, overall and by SOC and PT 
• Serious TEAEs, overall and by severity grade, SOC and PT 
• Non-serious TEAEs, overall and by severity grade, SOC and PT 
• TEAEs leading to discontinuation of study drug, overall and by SOC and PT 
• TEAEs leading to death, overall and by SOC and PT 
TEAEs with “possibly related”, “probably related” or “related” to study drug based on the 
investigator assessment will be considered as drug related TEAEs. TEAEs with missing 
causality, if any, will be assumed as ‘Related AEs’. 
For summaries by SOC and PT, a subject will be counted only once at the SOC level and once at 
each PT within the SOC level, even if the subject experienced more than one AE within a 
specific SOC and PT. For summaries by SOC, PT, and maximum severity, a subject will be 
counted only once at the maximum severity level for which the event occurred at the SOC level 
and at the maximum severity level for which the event occurred for each unique PT within that 
SOC level. Therefore, subjects will contribute to only one severity level within a PT or SOC. 
Summaries presenting frequency of TEAEs by SOC and PT will be ordered by overall 
descending frequency of SOC and then, within a SOC, by overall descending frequency of PT. 
Summaries presenting TEAEs by PT only will be ordered by overall descending frequency of 
PT. 
Subject listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately. 
6.2.1. 
Exposure Adjusted incidence rates (EAIR)  
Exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs) will 
be presented by treatment group, MedDRA System Organ Class (SOC), and preferred term, as 
well as by treatment group and MedDRA preferred term. For each treatment group, the EAIR of 
a specific treatment-emergent event is defined as the number of subjects experiencing the event 
at least once, divided by the total exposure-adjusted follow-up time in person-years. EAIRs will 
be presented as incidence rates per person-years of follow-up.  


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For subjects who experience the event, the exposure-adjusted follow-up time will be calculated 
from the first exposure (to PTC857 or Placebo) until the first occurrence of the event. For 
subjects who do not experience the event (censored), the follow-up time will be calculated from 
the first dose until their last safety follow-up date while on Part A. This could either be the date 
of completion of Part A safety follow-up, the date of death if the subject died before 
experiencing the event, or the date of last on-treatment follow-up if the subject was lost to 
follow-up. 
Missing or partial AE onset dates will be imputed using the imputation rules described in Section 
12 (Appendix 2). 
6.2.2. 
Adverse Events Indicative of ALS Disease Progression  
TEAEs that are indicative of ALS disease progression will be tabulated by treatment arm. The 
following list of MedDRA preferred terms will be used to define TEAEs that are indicative of 
disease progression.  
• Acute respiratory failure 
• Increased bronchial secretion 
• Salivary hypersecretion 
• Affect lability 
• Increased upper airway 
secretion 
• Suicidal ideation 
• Amyotrophic lateral 
sclerosis 
• Muscle spasms 
• Upper respiratory tract infection 
• Asthenia 
• Muscle spasticity 
• Urge incontinence 
• Balance disorder 
• Muscular weakness 
• Urinary retention 
• Cardio-respiratory arrest 
• Musculoskeletal stiffness 
• Urinary tract infection in males 
• Death 
• Myalgia 
• Urinary tract inflammation in 
males 
• Dysgraphia 
• Neurogenic bladder 
• Viral upper respiratory tract 
infection 
• Dysphagia 
• Oral candidiasis 
• Vocal cord paralysis 
• Dyspnoea 
• Oral fungal infection 
• Weight decreased 
• Fall 
• Respiratory failure 
 
• Fatigue 
• Respiratory tract congestion 
 
• Hypotonia 
• Respiratory tract infection 
 
• Hypoxia 
• Respiratory tract infection viral  
6.2.3. 
Disproportionate rate of Disease Progression by Treatment Received  
To evaluate whether treatment with PTC857 may accelerate ALS disease progression, an 
analysis of participants with a disproportionate rate of disease progression by treatment 
assignment will be performed to further inform benefit-risk assessment. For this analysis the 
number and percent of subjects with declines in ALSFRS-R that are greater than or equal to 18 
points at the 24-week visit will be tabulated by treatment arm.  


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6.3. 
Laboratory Values  
All clinical laboratory analyses will be performed by the central laboratory. The clinical 
laboratory assessment of hematology, clinical chemistry, and urinalysis will be obtained at 
scheduled visits. The following parameters are collected during the double-blind period at the 
specified visits as per protocol: 
Parameter(s) 
Scheduled Visit(s) 
Hematology: Hemoglobin, Hematocrit, RBC count, 
Reticulocytes, Platelet count, WBC count, Neutrophils, 
Eosinophils, Monocytes, Basophils, Lymphocytes, Mean 
corpuscular volume 
Screening, Day 1, Day 29, Day 57, Day 
85, Day 169, Day 197, ET 
Clinical Chemistry: Urea, Creatinine, Fasting glucose, 
Sodium, Potassium, ALT, AST, GGT, Bilirubin (total, 
direct/indirect), Alkaline phosphatase, Albumin,  
Screening, Day 1, Day 29, Day 57, Day 
85, Day 169, Day 197ET 
Lipid Profiles: Cholesterol (total), LDL, HDL, Triglycerides, 
LDH 
Screening, Day 1, Day 14, Day 29, Day 
57, Day 85, Day 169, Day 183, Day 197,  
and ET 
Urinalysis: Urobilinogen, Nitrite, pH, Glucose, Total 
protein, Erythrocytes, Leukocytes, Ketones, Microscopy, 
Specific gravity, Bilirubin 
Screening, Day 1,  Day 85, Day 169, and 
ET 
Coagulation: PT [sec], PT [INR], aPTT 
Screening, Day 1, Day 29, Day 57, Day 
85, Day 169, Day 197, and ET 
Pregnancy Test: β-HCG, FSH 
Screening, Day 1, Day 29, Day 57, Day 
85, Day113, Day141, Day 169, Day 197, 
and ET 
Note: Follow-up Visit on Day 197 is only for subjects who choose not to enter the LTE Period (Part B). 
Separate summary tables and listings will be produced for each of the separate groups above 
(e.g., separate table for hematology and clinical chemistry etc.); however, urinalysis, and serum 
and urine pregnancy tests will be listed only. The International System of units (SI units)  will be 
used for all summary and data listing displays unless otherwise indicated.  
Laboratory data will be summarized descriptively by visit for each laboratory parameter by 
treatment group and overall. Both observed results and changes from baseline will be 
summarized for continuous variables. Laboratory values will be categorized as clinical grade 
(low/normal/high) according to normal ranges. Shifts from baseline to the last on-treatment 
grade and the worst on-treatment grade will be presented. For these shift summaries, for the last 
on-treatment summary only scheduled visits will be taken; for the worst on-treatment summaries 
unscheduled assessments will be included in the assessment of worst. Both worst low and worst 
high will be summarized.   
Laboratory values that are below the limit of quantification will be imputed as the lower-limit of 
quantification, similarly, values above the limit of quantification will be imputed as the upper-
limit of quantification for the summary statistics. But for listings, the values will be presented as 
recorded.  
By-subject listings of all the laboratory parameters will be presented that clearly indicate out of 
normal range values and possible abnormal values for the safety analysis set. 
6.4. 
Vital Signs  
Vital signs including systolic and diastolic blood pressure (mmHg), pulse rate (beats/min), body 
temperature (ºC), Oxygen saturation (SpO2), and respiratory rate (breaths/min) will be evaluated 


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at Screening, Day 1, Day 29, Day 57, Day 85, Day 113, Day 141, and Day 169, as well as the ET 
visit where applicable. 
For convenience, the conversion for temperature: Temperature (in °C) = (Temperature [in °F]-
32) x (5/9). 
Absolute results and changes from baseline will be summarized descriptively by visit for each 
parameter, by treatment group and overall. 
6.5. 
12-Lead Electrocardiogram  
The following 12-lead ECG will be performed at Screening, Day 1, Day 85, and Day 169, as 
well as the ET visit where applicable. 
• Heart rate (bpm) 
• QRS Interval (msec) 
• PR Interval (msec) 
• QT interval (msec) 
• QTcF Interval (msec) 
• Overall Interpretation 
Descriptive summaries will be presented for the ECG parameter values and change from baseline 
by visit for all quantitative measurements. Overall interpretation of ECG assessment will be 
summarized by counts and percentages. QT and QTcF will be categorized as follows, and the 
category based on actual value will be summarized by treatment group at each visit as well as the 
category at each post-baseline visit based on change from baseline per the following criteria: 
Type of Value 
Category 1 
Category 2 
Category 3 
Actual value 
> 450 ms 
> 480 ms 
>500 ms 
Change from Baseline 
> 30 ms 
>60 ms 
 
A by-subject listing of all ECG parameters will be provided. 
6.6. 
Physical Examination  
A detailed physical examination will be performed at Screening visit and targeted physical 
examination will be performed at Day 1, Day 85, and Day 169 as well as the ET visit where 
applicable. 
For the remaining visits, a symptom-driven physical examination will be performed as per the 
investigators’ discretion. Physical examination including details of clinically significant findings, 
will be listed. 
6.7. 
Columbia-Suicide Severity Rating Scale  
The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and suicidal behavior 
(Posner 2011). The C-SSRS, which uses a semi-structured interview to probe subject responses, 
is administered by an individual who has received training and certification in its administration. 
During the Screening Visit (Day -56), the “baseline” version of the C-SSRS is administered. This 


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version assesses suicidal ideation and suicidal behavior during the subject’s lifetime. At all 
subsequent visits, the “since last visit” version is administered. 
Counts and percentage of subjects who experience suicidal ideation, suicidal behavior or neither 
(no ideation or behavior) will be summarized by treatment group at baseline and double-blind 
treatment period.  
The C-SSR instrument consists of 11 Yes/No questions as shown in the table below and is 
grouped by type question, i.e., suicidal ideation questions and suicidal behavior questions. 
Within each type/group the questions are re-ordered by increasing severity. In addition, subjects 
are assessed for any self-injurious behavior without suicidal intent. 
 
C-SSRS Item 
Derivation 
Suicidal ideation 
A “yes” answer to any one of the following five questions. 
1. Wish to be dead. 
2. Non-specific active suicidal thoughts. 
3. Active suicidal ideation with any methods (not plan) without 
intent to act. 
4. Active suicidal ideation with some intent to act, without 
specific plan. 
5. Active suicidal ideation with specific plan and intent. 
Suicidal behavior 
A “yes” answer to any one of the following five questions. 
• 
Preparatory acts or behavior 
• 
Aborted attempt 
• 
Interrupted attempt 
• 
Actual attempt 
• 
Suicidal behavior 
• 
Completed suicide 
Self-injurious behavior without 
suicidal intent 
A “yes” answer to the following question from suicidal behavior 
section on the C-SSRS: Has subject engaged in Non-Suicidal 
Self-Injurious behavior? 
Suicidal Ideation Score 
Is defined as the maximum suicidal ideation category (1-5 on the 
C-SSRS) present at the assessment. A score of 0 is assigned if 
no ideation is present. 
For the overall assessment of suicidal ideation and behavior during the double-blind treatment 
period a subject’s worst finding during that period will be used. 
The following tables will be generated at the end of the Double-Blind Treatment Period: 
• Counts and Percentage of Subjects with Suicidal Ideation, Suicidal Behavior, and 
Self-Injurious Behavior without Suicidal Intent Based on the C-SSRS by Treatment 
group at baseline. 
• Counts and Percentage of Subjects with Suicidal Ideation, Suicidal Behavior, and 
Self-Injurious Behavior without Suicidal Intent Based on the C-SSRS by Treatment 
group during the double-blind treatment period. 


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• Counts and Percentage of Subjects with Suicide-Related Treatment Emergent Events 
Based on C-SSRS by Treatment group during the Double-Blind Treatment Period. 
• Shift table of changes in C-SSRS categories (ideation, behavior, or neither) from 
baseline to through Week 24. 
• Shift table in Changes in C-SSRS Suicidal Ideation scores from baseline to through 
Week 24 by Treatment. 
All C-SSRS assessments will be listed. 
6.8. 
Other Safety: Body Weight, BMI, Breast Imaging and Pregnancies  
 
Bodyweight  
Bodyweight is assessed at Screening, Day 1, Day 85, and Day 169, as well as the ET visit where 
applicable. Height is assessed once at the screening visit. 
The observed bodyweight and BMI values at each visit, along with the change from baseline to 
each post-baseline visit will be summarized descriptively as continuous variables by treatment 
group and overall. The following categorizations will additionally be summarized for body 
weight at each visit: 
Category 
Change from Baseline 
Category 1 
≥ 10% loss 
Category 2 
≥ 5 - 10% loss 
Category 3 
-5% < Weight change <+5% 
Category 4 
≥ 5 - 10% increase 
Category 5 
≥ 10% increase 
 
Breast Imaging and Pregnancies 
Breast imaging for female subjects is conducted at the screening visit and at the day 169 visit. 
Imaging is not required during the screening period if the subject has had a negative breast 
cancer imaging status (i.e., not considered clinically abnormal and/or requiring further 
evaluation/treatment) within 6 months prior to the screening visit. If clinically indicated, an 
ultrasound or MRI may also be conducted for breast cancer imaging, per the investigator’s 
discretion. Summary statistics will be used to describe the breast imaging results. 
6.9. 
Subgroup Analyses for Safety  
The count and percentage of subjects who report at least one TEAE will be summarized by 
treatment group and PT for the subgroups outlined below.  
• Sex (male, female) 
• Race (White, Non-white) 
• Age at baseline (<65, ≥ 65 years)  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Geographic region (North America, Europe, South America, Asia) 


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• Slow vital capacity (80%, ≥ 80%) 
• Use of approved background therapy for ALS (Y/N) 


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7. 
PHARMACOKINETIC OUTCOMES  
Approximately 36 subjects from selected sites will be enrolled in the PK sub-study.   
• Blood samples for riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol PK 
will be collected at Day -28 predose (prior to the first dose of riluzole, edaravone, 
and/or sodium phenylbutyrate/taurursodiol on Day -28) and 1 hour (±15 minutes) 
post-dose. 
• Blood samples for PTC857, riluzole, edaravone, and/or sodium 
phenylbutyrate/taurursodiol PK will be collected from those subjects taking part in 
the PK Sub-Study at predose (prior to the first dose of the day) and at 1, 2, 4, 5, 6, 8, 
and 12 hours (±15 minutes) (prior to the second dose) post-dose on Day 1 and Day 
29.  
• Blood samples for PTC857 PK only will be collected predose (prior to the first dose 
of the day) and at 1 hour (±15 minutes) and 4 hours (±1 hour) post-dose on Day 85, 
and predose only at all subsequent visits with blood PK sampling. 
• CSF samples will be collected predose (first dose of the day) on the Baseline Visit, 
Day 29 Visit, and the End of Treatment Visit.  
Summary statistics for plasma concentrations vs. time will be provided, in addition to by-subject 
listings.  
PK data collected from this study will be included in non-compartmental analysis and Population 
PK analysis. Separate PK analysis plan(s) and report(s) will be provided.  
   
 


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8. 
REFERENCES  
Group, WGEM-AS. Safety and efficacy of edaravone in well-defined patients with amyotrophic 
lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017; 
16(7): 505-512. 
Berry JD, Miller R, Moore DH, Cudkowicz ME, van den Berg LH, Kerr DA, Dong Y, Ingersoll 
EW, Archibald D. The Combined Assessment of Function and Survival (CAFS): a new endpoint 
for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Apr;14(3):162-8. 
doi: 10.3109/21678421.2012.762930. Epub 2013 Jan 17. PMID: 23323713. 
Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The 
ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory 
function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31;169(1-2):13-21. doi: 
10.1016/s0022-510x(99)00210-5. PMID: 10540002. 
Norris FH, Calanchini PR, Fallat RJ, Panchari S, and Jewett B. The administration of guanidine 
in amyotrophic lateral sclerosis. Neurology, Vol 24 | Number 8, August 01, 1974. 
Jenkinson C, Fitzpatrick R, Brennan C, Bromberg M, Swash M. Development and validation of 
a short measure of health status for individuals with amyotrophic lateral sclerosis/motor neurone 
disease: the ALSAQ-40. J Neurol. 1999 Nov;246 Suppl 3:III16-21. doi: 10.1007/BF03161085. 
PMID: 10631656. 
Garcia-Hernandex, A and Rizopoulos, D. %JM: A SAS Macro to Fit Jointly Generalized Mixed 
Models for Longitudinal Data and Time-to-Event Responses. Journal of Statistical Software. 
2018 Apr; 84(12), doi:10.18637/jss.v084.i12. 
Westeneng HJ, Debray TPA, Visser AE, et al. Prognosis for patients with amyotrophic lateral 
sclerosis: development and validation of a personalised prediction model. Lancet Neurol 
2018;17:423-433 
van Eijk RPA, Westeneng HJ, Nikolakopoulos S, et al. Refining eligibility criteria for 
amyotrophic lateral sclerosis clinical trials. Neurology 2019;92:451-460 
van Eijk RPA, Roes KCB, van den Berg LH, Lu Y. Joint modeling of endpoints can be used to 
answer various research questions in randomized clinical trials. J Clin Epidemiol. 2022 
Jul;147:32-39. doi: 10.1016/j.jclinepi.2022.03.009. Epub 2022 Mar 26. PMID: 35346783. 
TRICALS Eligibility, Standard Operating Procedure, version 1.0, 2020, 
https://tricals.shinyapps.io/risk-profile/ 
van Eijk RPA, et al. Innovating Clinical Trials for Amyotrophic Lateral Sclerosis. Challenging 
the Established Order, Neurology Sep 2021, 97 (11) 528-536; DOI: 
10.1212/WNL.0000000000012545 
Westeneng HJ, Debray TPA, Visser AE, et al. Prognosis for patients with amyotrophic lateral 
sclerosis: development and validation of a personalised prediction model. Lancet Neurol 
2018;17:423-433 
Rubika Balendra, Ashley Jones, Naheed Jivraj, Catherine Knights, Catherine M. Ellis, Rachel 
Burman, Martin R. Turner, P. Nigel Leigh, Christopher E. Shaw & Ammar Al- 


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Chalabi (2014) Estimating clinical stage of amyotrophic lateral sclerosis from the ALS 
Functional Rating Scale, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15:3-
4, 279-284, DOI: 10.3109/21678421.2014.897357 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity 
and internal consistency findings from three multisite studies with adolescents and adults. Am J 
Psychiatry. 2011 Dec;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704. PMID: 22193671; 
PMCID: PMC3893686. 
Paganoni S., et al.; N Engl J Med. 2020 Sep 3;383(10):919-930. doi: 10.1056/NEJMoa1916945.; 
Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. 
Writing Group; Edaravone (MCI-186) ALS 19 Study Group; Lancet Neurol.,2017 Jul;16(7):505-
512. doi: 10.1016/S1474-4422(17)30115-1.; Safety and efficacy of edaravone in well-defined 
patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. 
 


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9. 
PROGRAMMING CONSIDERATIONS  
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for 
Windows, Release 9.4 or higher (SAS Institute Inc., Cary, NC, USA). Computer-generated table, 
listing and figure output will adhere to the following specifications.  
1. One SAS program can create several outputs. 
2. Each output will be stored in a separate file. 
3. Output files will be delivered in Word format. 
4. The numbering of TFLs will follow ICH E3 guidance. 
5. All tables and listings will be produced in landscape orientation. Figures use the 
orientation that best facilitates interpretation of the data. 
6. All TFLs will be produced using the Courier New font, size 10. The smallest acceptable 
point size for the Regulatory Authorities is 8. 
7. Headers and footers for figures will be in Courier New font, size 8, which is the smallest 
acceptable point size for the Regulatory Authorities. 
8. TFLs will be in black and white (no color), unless otherwise specified. 
9. Specialized text styles, such as bolding, italics, borders, shading, and color are not used in 
the tables and listings, unless otherwise specified. Color may be used in figures 
containing multiple plotted lines as long as information is not lost when the figure is 
reproduced in monotone. 
10. A mixed case will be used for titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
11. For categorical parameters, all categories will be presented in the table, even if n=0 for all 
treatment groups in each category. For example, the frequency distribution for symptom 
severity would appear as: 
Severity Rating 
n 
Mild 
2 
Moderate 
5 
Severe 
0 
• An Unknown or Missing category will be added to each parameter for which 
information is not available for 1 or more subjects. 
• Unless otherwise specified, the estimated mean, median, Q1 and Q3 for a set of 
values will be printed out to 1 more significant digit than the original values, and 
standard deviations and standard errors will be printed out to 2 more significant digits 
than the original values. The minimum and maximum will report the same significant 
digits as the original values. 
• Confidence intervals are displayed within round brackets and separated by a comma. 
The lower limit is presented first, and the upper limit is presented second. The 
confidence interval is placed either beside or below the corresponding estimate. The 
estimate and the confidence limits are presented using the same degree of precision. 


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• P-values will be output in the format: ‘0.xxx’, where xxx is the value rounded to 3 
decimal places. Every p-value less than 0.001 will be presented as <0.001. If the p-
value is returned as >0.999, then present as >0.999. 
• Percentage values will be printed to one decimal place. Unless otherwise noted, for 
all percentages, the number of subjects in the analysis population for the treatment 
group who have an observation will be the denominator. Percentages after zero 
counts will not be displayed and percentages equating to 100% will be presented as 
100%, without decimal places.  
• Tabular display of data for medical history, prior/concomitant medications, and all 
tabular displays of adverse event data will be presented by the body system, treatment 
class, or SOC with the highest occurrence in the active treatment group in decreasing 
order, assuming all terms are coded. Within the body system, drug class and SOC, 
medical history (by preferred term), drugs (Medication class), and adverse events (by 
preferred term) will be displayed in decreasing order. If incidence for more than 1 
term is identical, they will then be sorted alphabetically.  
• Missing descriptive statistics or p-values which cannot be estimated will be reported 
as ‘-’ Missing values for numeric and character variables are displayed as blanks in 
data listings. 
• The percentage of subjects will normally be calculated as a proportion of the number 
of subjects assessed in the relevant treatment group (or overall) for the analysis 
population presented. However, careful consideration is required in many instances 
due to the complicated nature of selecting the denominator, usually the appropriate 
number of subjects exposed. Details will be described in footnotes or programming 
notes, as necessary.  
• If no relevant data are available at all for a display, then present “No data to Report”. 
 


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10. 
MOCK TABLES, LISTINGS, AND GRAPHS  
The study tables, listings and graphs shells will be provided in a separate document. 


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11. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS  
Schedule of Assessments for Screening and Double-Blind Treatment Period (Part A) 
  
 
 


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Schedule of Assessments for Long-Term Extension Period (Part B) 
 
 


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Schedule of Assessments for Continued Long-Term Extension Period (Part C) 
 
 


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12. 
APPENDIX 2: MISSING DATE AND MISSING ALSFRS-R PROCEDURE  
Prior/Concomitant Medications 
For the purpose of assessing whether a medication is prior or concomitant, if a medication has a 
completely missing start date it will be considered a prior medication, and if a medication has a 
completely missing stop date it will be considered a concomitant medication. If a partial start or 
stop date occurs, the following imputation process will be implemented: 
Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for 
Stop Date 
Day missing, month 
and year present 
• 
Month and/or year different to month and year of first 
study drug dose: Impute day with “01” 
• 
Month and/or year same as month and year of first 
study drug dose: Impute day with same day as first 
dose of study drug. 
Impute day with last 
day of the month 
Day and month 
missing, year 
present 
• 
Year different to year of first study drug dose: Impute 
day and month with “01JAN” 
• 
Year same as year of first study drug dose: Impute 
month and day with same month and day as first dose 
of study drug. 
Impute day and 
month with 
“31DEC” 
Month missing, day 
and year present 
• 
Year different to year of first study drug dose: Impute 
month with “JAN” 
• 
Year same as year of first study drug dose: Impute 
month with same month as first dose of study drug. 
Impute with “DEC” 
Caveats 
• 
If any imputed start date leads to a start date that is after the stop date, then 
the start date will be imputed with the date of the stop of medication. 
• 
No stop date will be imputed if the treatment is ongoing. 
Adverse Events 
For the purpose of assessing whether an AE is treatment emergent, if an AE has a completely 
missing start and stop date, it will be considered treatment emergent; if the stop date is not 
missing, but the start date is completely missing, it will be considered treatment emergent unless 
the stop date occurs prior to the first dose of study drug.  
For assessing treatment emergence or for calculation of duration of AE, if a partial start or stop 
date occurs, the following imputation process will be implemented: 
Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for Stop 
Date 
Day missing, month 
and year present 
• 
Month and/or year different to month and year of 
first study drug dose: Impute day with “01”. 
• 
Month and/or year same as month and year of first 
study drug dose: Impute day with same day as first 
dose of study drug. 
Impute day with last 
day of the month 
Day and month 
missing, year 
present 
• 
Year different to year of first study drug dose: 
Impute day and month with “01JAN”. 
• 
Year same as year of first study drug dose: Impute 
month and day with same month and day as first 
dose of study drug.  
Impute day and 
month with “31DEC” 


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Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for Stop 
Date 
Month missing, day 
and year present 
• 
Year different to year of first study drug dose: 
Impute month with “JAN”. 
• 
Year same as year of first study drug dose: Impute 
month with same month as first dose of study drug. 
Impute with “DEC” 
Caveats 
• 
If any imputed start date leads to a start date that is after the stop date, then 
the start date will be imputed with the date of the stop of AE. 
ALSFRS-R incomplete / missing data 
This section describes visit level imputations performed prior to the multiple imputation 
procedure.  
If 1 item is missing within a domain (e.g. Bulbar), then the domain item will be inputted using 
the following formula:  
Imputed domain score = mean of non-missing items multiplied by 3. 
If item 12 on the ALSFRS score is missing, and the patient is not reported as having received 
non-invasive ventilation at the time of the visit (concomitant procedures CRFs) then item 12 will 
be imputed as a 4. 
Total Score: 
If a whole domain is missing or two items are missing, then the total ALSFRS-R total score will 
be imputed from the remaining 3 domains as the mean of all answered item scores in the 3 
domains x 12. Total score will not be imputed if more than 1 domain has 2 or more missing 
items.  


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13. 
APPENDIX 3: TRICALS RISK PROFILE CALCULATOR  
TRICALS Risk Profile Calculator, v2.01 (2022-02-20), Source: https://tricals.shinyapps.io/risk-
profile/ 
The TRICALS Risk Profile is a prognostic summary value of seven patient characteristics and 
can be used for patient selection in clinical trials. The Risk Profile Calculator estimates the 
TRICALS Risk Profile. 
References 
1. Westeneng HJ, Debray TPA, Visser AE, et al. Prognosis for patients with amyotrophic 
lateral sclerosis: development and validation of a personalised prediction model. Lancet 
Neurol 2018;17:423-433 
2. van Eijk RPA, Westeneng HJ, Nikolakopoulos S, et al. Refining eligibility criteria for 
amyotrophic lateral sclerosis clinical trials. Neurology 2019;92:451-460 
3. van Eijk RPA, Nikolakopoulos S, Roes KCB et al. Innovating clinical trials for 
amyotrophic lateral sclerosis: challenging the established order. Neurology 2021 
Estimation of the TRICALS Risk Profile 
The TRICALS Risk Profile is based the ENCALS (European Network to Cure ALS) survival 
prediction model, a cross-validated model to predict the composite endpoint death or respiratory 
insufficiency based on data of 11,475 patients with ALS. Patient selection is based on the linear 
predictor of the model and not on the absolute risk predictions as (1) the baseline hazard 
significantly varies across countries, and (2) the ENCALS model estimates the absolute survival 
probability from disease onset rather than trial enrolment. The linear predictor of the model, 
hereafter stated as TRICALS Risk Profile, can be conceptualized as a relative summary of 
prognostic information. The risk profile indicates how patients compare to each other (i.e. who is 
faster or slower progressing than average) without estimating the absolute survival time or 
probability. 
The TRICALS Risk Profile is calculated as: 
𝑹𝑹𝑹𝑹𝑹𝑹𝑹𝑹 𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑= (0.474 × 𝑉𝑉𝑉𝑉𝑡𝑡) - (2.376 × 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑡𝑡) - (1.839 × ∆𝐹𝐹𝐹𝐹𝐹𝐹𝑡𝑡) – (0.264 × 𝐴𝐴𝐴𝐴𝐴𝐴𝑡𝑡) + 
(0.271 × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵) + (0.238 × 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷) + (0.415 × 𝐹𝐹𝐹𝐹𝐹𝐹)  
Where t represents the non-linear transformations for continuous variables, VC the vital capacity 
(in %predicted), Age is age at onset in years, diagnostic delay (DxDelay) in months, FTD the 
presence of frontotemporal dementia and ΔFRS (points per month) is the progression rate of the 
ALS functional rating scale (ALSFRS-R). 
𝐴𝐴𝐴𝐴𝐴𝐴𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡. = ቀ
𝐴𝐴𝐴𝐴𝐴𝐴 𝑎𝑎𝑎𝑎 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜
100
ቁ
−2
    
 
 
 
 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡. = ቀ
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
10
ቁ
− 1
2 + ln ቀ
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
10
ቁ 
∆𝐹𝐹𝐹𝐹𝐹𝐹𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡. = (∆𝐹𝐹𝐹𝐹𝐹𝐹+ 0.1)− 1
2  
 
 
 
𝑉𝑉𝑉𝑉𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡. = ቀ
𝑉𝑉𝑉𝑉
100ቁ
−1
+ ቀ
𝑉𝑉𝑉𝑉
100ቁ
− 1
2 
∆𝐹𝐹𝐹𝐹𝐹𝐹𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡= ൫48 −𝐹𝐹𝐹𝐹𝐹𝐹𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠൯÷ 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 


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14. 
APPENDIX 4: SAS CODE  
Mixed Model Repeated Measure 
The following is example SAS syntax for producing least squares estimates, for the MMRM 
analysis: 
proc mixed data=ALSFRS_LONG method=reml; 
class ID TRTRND(ref=”0”) STADCARE(ref=”3”) CHANGE(ref=”<1”) 
TIME(ref=”baseline”); 
model DELFRS = TIME VALUEBL CHANGE STADCARE TIME*TRTRND TIME*VALUEBL TRP 
TIME*TRP / ddfm=kr solution; 
repeated TIME / type=UN subject=id; 
lsmeans trtrnd*TIME /cl pdiff=control('0' '5')cl; 
run; 
where id is the subject identifier, trtrnd is the randomized treatment arm, stadcare is a 
factor variable for the SoC stratification group at baseline, change is the amount of change in 
the subject’s ALSFRS-R score during the Screening Period, time is the categorical variable for 
study visit, Valuebl is the baseline ALSFRS-R score, TRP represents the TRICALS risk profile 
at baseline, and the response variable DELFRS is the change from baseline in ALSFRS-R score.: 
ANCOVA with Multiple Imputation 
SAS code for the ALSFRS-R endpoint at 24 weeks: 
proc mi data = ALSFRS_DATA out = ALSFRS_DATA_OUT  
seed = 20221219 nimpute = 100 noprint; 
class trtrnd stadcare change sex; 
var trtrnd Valuebl change stadcare sex age trp  
ALSFRS_R_4 ALSFRS_R_8 ALSFRS_R_12 ALSFRS_R_16 ALSFRS_R_20 ALSFRS_R_24; 
fcs reg(ALSFRS_R_4 ALSFRS_R_8 ALSFRS_R_12 ALSFRS_R_16 ALSFRS_R_20 
ALSFRS_R_24); 
run; 
The next set of code performs the analyses for the ALSFRS-R 24-week endpoint: 
proc reg data=ALSFRS_DATA_OUT  utset=outreg covout noprint; 
model ALSFRS_24 = trtrnd Valuebl change stadcare TRP; 
by _Imputation_; 
run; 
This step will combine the results: 
proc mianalyze data=outreg; 
modeleffects Intercept trtrnd Valuebl change stadcare TRP; 
run; 
 
Pattern Mixture Model 
The strategy implemented to carry out the control-based PMM assumes that all other variables, 
except ALSFRS-R, with missing data are first imputed using the FCS approached outlined in the 
previous sensitivity analysis, with 100 imputation datasets. These data are stored in 
DATAIN_IMP0, which contains a variable _Imputation_ to distinguish between multiple copies 
of the original input data. In the next step missing ALSFRS-R at the first time point will be 
imputed (the first time-point that has some missing data). To use the control-based imputation 


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method, the starting dataset will be separated into two separate datasets: DATAIN_IMP1, 
containing all Placebo subjects and those subjects from the PTC875 arm that have values at time-
point 1 missing; and DATAIN_REST1, containing the remainder of the subjects from the 
PTC875 arm who have ALSFRS-R scores available at this time point.  
Create a variable VISIT1 where it is equal to 1 if ALSFRS-R is available at this visit and 0 if it is 
missing. 
Data DATAIN_IMP1 DATAIN_REST1;  
set DATAIN_IMP0;  
if trtrnd = 1 and VISIT1 = 1 then output DATAIN_REST1;  
else output DATAIN_IMP1;  
run;  
Next, use PROC MI to impute missing data at the first timepoint with missing data, based on the 
model estimated exclusively from control subjects with non-missing values at time-point 1. The 
following code assumes that Week 4 contains the first missing data from the ALSFRS-R 
outcome dataset.  
Proc mi data= DATAIN_IMP1 out=DATAIN_REG_IMP1 nimpute=1 seed=1001;  
class trtrnd stadcare change sex; 
by _Imputation_;  
var trtrnd Valuebl change stadcare sex age trp ALSFRS_R_4;  
monotone reg(ALSFRS_R_4);  
run;  
Next, combine all the data into one dataset.  
Data DATAIN_IMP1_COMB;  
set DATAIN _REST1 DATAIN_REG_IMP1;  
run;  
Repeat the above steps for the second timepoint with missing data for ALSFRS-R. Dataset 
DATAIN_IMP1_COMB will be used for input to the next PROC MI call, but first, separate it 
into two datasets: DATAIN _IMP2, containing all Placebo subjects and those subjects from the 
experimental arm that have values at second timepoint missing; and DATAIN_ REST2, 
containing the remainder of the subjects from the PTC875 arm. Create a variable VISIT2 where 
it is equal to 1 if ALSFRS-R is available at the second timepoint with missing data and 0 if it is 
missing. The below code assumes that this will be at Week 8. 
Data DATAIN_IMP2 DATAIN_REST2; set DATAIN_IMP1_COMB;  
if trtrnd = 1 and VISIT2 = 1 then output DATAIN_REST2;  
else output DATAIN_IMP2;  
run;  
Next use PROC MI to impute missing data at time-point 2 based on the model estimated 
exclusively from Placebo subjects with non-missing data at time-point 2.  
Proc sort data= DATAIN_IMP2; by _Imputation_; run;  
proc mi data=DATAIN_IMP2 out=DATAIN_REG_IMP2 nimpute=1 seed=1002;  
by _Imputation_;  
var trtrnd Valuebl change stadcare sex age trp ALSFRS_R_4 ALSFRS_R_8;  
monotone reg(ALSFRS_R_8);  
run; 
Re-assemble the data back into a single dataset containing all subjects:  
data DATAIN_IMP2_COMB;  


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set DATAIN_REST2 DATAIN_REG_IMP2;  
run;  
Repeat the same procedure until ALSFRS-R is imputed at all timepoints.  
The next set of code performs the analyses for the ALSFRS-R 24-week endpoint as for the FCS 
multiple-imputation approach, assuming that there were six timepoints at which there were 
missing data in the ALSFRS-R dataset: 
proc reg data= DATAIN_IMP6_COMB utset=outreg covout noprint; 
model ALSFRS_24 = trtrnd Valuebl change stadcare TRP; 
by _Imputation_; 
run; 
This step will combine the results: 
proc mianalyze data=outreg; 
modeleffects Intercept trtrnd Valuebl change stadcare TRP; 
run; 
 
Survival Analysis 
The following is sample code for producing a Kaplan-Meier survival plot: 
proc lifetest data=survdata plots=survival(cl cb=hw test atrisk); 
time time*status(0); 
strata trtrnd / test=logrand adjust=sidak; 
run; 
where time is the time of event or censoring, status is the variable indicating censored (1) or 
not censored (0), i.e., death observed, trtrnd is the treatment allocation variable. The 
following sample code runs a Cox regression model: 
 
proc phreg data=survdata atrisk plots(cl)=(survival cumhaz); 
class trtrnd stadcare TRP(ref=’B’);  
STRATA stadcare change;  
model time*status(0)= trtrnd Valuebl / ties=breslow rl; 
hazardratio trp;  
run; 
where time is the time of event or censoring, status is the variable indicating censored (1) or 
not censored (0), i.e., death observed, and trtrnd is the treatment allocation variable. 


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15. 
APPENDIX 5. MAPPING ALSFRS-R TO KING’S STAGE  
The King’s clinical staging criteria for ALS (Balendra 2014) is defined as a count of involved 
central nervous system (CNS) regions (Stage 1, 2 or 3), requirement for gastrostomy or 
noninvasive ventilation (Stage 4) and death (Stage 5) .  
Stage 
Definition 
1 
Functional involvement of one CNS region (symptom onset) 
2 
Functional involvement of two CNS regions 
3 
Functional involvement of three CNS regions 
4 
Need for gastrostomy (4A) or non-invasive ventilation (4B) 
5 
Death 
1. Bulbar region is involved: If the subject dropped any points on any of the three ALSFRS-
R questions regarding speech (question 1), salivation (question 2) or swallowing 
(question 3). 
2. Upper limb region is involved: If the subject dropped any points on either of the two 
ALSFRS-R questions regarding hand function, which are handwriting (question 4) and 
ability to cut food and handle utensils (question 5A). 
3. Lower limb region is involved: If the subject dropped any points on the ALSFRS-R 
question regarding ability to walk (question 8). 
4. Stage 4A attained: If question 5B is answered instead of question 5A, which is only 
answered by patients without a gastrostomy. 
5. Stage 4B reached: If a patient scored 0 points on question 10 or less than 4 points on 
question 12. 


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16. 
REVISION HISTORY  
The following list summarizes the major changes incorporated into Version 2.0 of the SAP from 
Version 1.0. 
Section 
Description of Change 
Brief Rationale 
SAP 
The version number and date were updated 
throughout.  
The intent of the SAP was changed from a 
description of all the analyses for the whole study (all 
Parts) to a description of the analyses pertaining to 
the double-blind treatment period (Part A). A 
description of all analyses for the long-term extension 
periods and entire study are now described in a 
separate SAP 
Editorial and administrative revisions (e.g., 
typographical errors, punctuation, tenses, 
abbreviations) were incorporated to provide clarity. 
Update 
1.2 
Objectives for the Long-Term Extension periods 
(Parts B and C) were removed 
Analyses of the Long-term 
extension periods are described 
in a separate SAP 
1.3.2 
Added 2 secondary endpoints 
Following Protocol amendment 
6.0 
1.3 
Long-Term Extension periods (Parts B and C) 
endpoints removed 
Analyses of the Long-term 
extension periods are described 
in a separate SAP 
1.5 
Description of sample-size updated following change 
in the primary endpoint as recommended by the FDA. 
Update 
1.6 
Removed extraneous unblinding details that are not 
necessary in the SAP, as they are described in the 
protocol 
Update 
2.4 
Criteria for removal of subjects from the ITT 
population, to form the per-protocol population is 
added. 
Update 
2.6 
Added more text with examples of major protocol 
deviations (PD), and definition of PDs 
Update 
3.2 
Treatment compliance section removed, because it’s 
described in Section 4.8 
Update 
3.3 
The whole section has been updated to reflect FDA 
feedback, to change the primary efficacy endpoint 
from change from baseline in ALSFRS-R to subject 
ranks based on the combined assessment of function 
and survival (CAFS).  
Text updated to provide more clarity 
Update 
4.8 
Treatment compliance is more clearly defined, and 
formula added. 
Extent of exposure is more clearly defined.  
Update 
4.9 
Visit Windows for The Early Termination Visit and 
Unscheduled Visits were added. 
 
5 
The whole section has been updated to reflect FDA 
feedback, to change the primary efficacy endpoint 
from change from baseline in ALSFRS-R to CAFS.  
Text updated to provide more clarity. 
T Joint Model (Shared parameter) analysis removed. 
Update 
 
Joint model requires making 
unknown assumptions regarding 
the change in function overtime. 
5.6 
Additional subgroup analyses of interest added 
Update 


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Section 
Description of Change 
Brief Rationale 
6.2.1 
Additional incidence rate analyses specified 
Update 
6.2.2 
Additional summaries to evaluate differences in AEs 
that are indicative of disease progression added 
Update 
6.2.3 
Additional summaries to evaluate disproportionate 
rate of disease progression by treatment  
Update 
6.8 
Weight change categories added 
Breast Imaging and Pregnancy summaries specified 
Update 
6.9 
Subgroup Analyses for Safety specified 
Update 
 
 
 


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ERRATUM  
 
STATISTICAL ANALYSIS PLAN 
FOR THE DOUBLE-BLINDED TREATMENT PERIOD 
(PART A) OF PTC857-CNS-001-ALS 
 
VERSION NUMBER: 2.0, DATED: 25 SEPTEMBER 2024 
 
 
     ISSUE DATE: 29 OCTOBER 2024 
 
 
The purpose of this erratum is to correct a typographical error in the Statistical Analysis Plan for 
Part A of Study PTC857-CNS-001-ALS, version 2.0, dated: 25 SEPTEMBER 2024.  
The first paragraph of Section 5.1 contains redundant text implying that the TRICALS variable 
would be incorporated into the model twice (as a covariate and as a main effect), instead of 
solely intended as a covariate. The following table displays the paragraph with the extraneous 
text marked in strikethrough font. 
The primary efficacy variable, subject ranks based on the combined assessment of function 
and survival (CAFS) after 24 weeks of treatment will be performed using an analysis of 
covariance model (ANCOVA) following multiple imputation. The estimand framework 
described in Section 3.3.1 will be used. The ANCOVA model will contain the following main 
effects: treatment (PTC857 or placebo), the amount of change in the subject’s ALSFRS-R 
score during the Screening Period (<1, 1-2, or 3-4-points total loss), TRICALS risk profile 
(continuous), use of Approved Background Therapy for ALS (Yes [either riluzole, edaravone, 
or sodium phenylbutyrate/taurursodiol], No). Baseline ALSFRS-R score (continuous) and The 
TRICALS risk profile (continuous) will be included as covariates. 
 
 


V1.0 
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STATISTICAL ANALYSIS PLAN 
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) 
FOR THE 
OPEN LABEL LONG-TERM EXTENSION PERIOD (PART B), 
CONTINUED LONG-TERM EXTENSION PERIOD (PART C) AND 
ENTIRE STUDY PERIOD (PARTS A, B AND C POOLED) OF 
PTC857-CNS-001-ALS 
VERSION 1.0 
DATE OF PLAN: 25 SEPTEMBER 2024 
STUDY DRUG: UTRELOXASTAT 
PROTOCOL NUMBER:  PTC857-CNS-001-ALS 
PTC Therapeutics, Inc.  
500 WARREN CORPORATE CENTER DRIVE 
WARREN, NJ 07059 USA  
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
NCT #: NCT05349721


 
 
V1.0 
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applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach of this 
obligation, PTC Therapeutics, Inc. should be notified promptly.


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PTC Therapeutics STATISTICAL ANALYSIS PLAN Approval Signatures 
Author: 
 
PTC Therapeutics, Inc. 
Date 
Approver (Biostatistics): 
 
PTC Therapeutics, Inc. 
Date 
Approver (Clinical): 
 
PTC Therapeutics, Inc. 
Date 


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Table of Contents  
PTC THERAPEUTICS STATISTICAL ANALYSIS PLAN APPROVAL 
SIGNATURES .............................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION AND OVERVIEW ........................................................................8 
1.1. 
Study Design .................................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Long-Term Extension Period Objectives (Part B) ........................................................9 
1.2.2. 
Continued Long-Term Extension Period Objectives (Part C) ....................................10 
1.3. 
Study Endpoints ..........................................................................................................10 
1.3.1. 
Long-Term Extension Period Endpoints (Part B) ......................................................10 
1.3.2. 
Continued Long-Term Extension Period Endpoints (Part C) .....................................10 
1.4. 
Randomization Blinding .............................................................................................11 
2. 
ANALYSIS SETS ......................................................................................................12 
2.1. 
All Enrolled Set ..........................................................................................................12 
2.2. 
Intent-to-Treat (ITT) Analysis Sets ............................................................................12 
2.3. 
Safety Analysis Set .....................................................................................................12 
2.4. 
Long-Term Extension Safety Analysis Set .................................................................12 
2.5. 
Per Protocol Set ..........................................................................................................12 
2.6. 
Pharmacokinetic Analysis Set ....................................................................................12 
2.7. 
Protocol Deviations ....................................................................................................13 
3. 
GENERAL CONSIDERATIONS ..............................................................................14 
3.1. 
General Considerations ...............................................................................................14 
3.2. 
Data Definitions and Analysis Issues .........................................................................14 
3.2.1. 
Study/Onset Day .........................................................................................................14 
3.2.2. 
Weeks Since Initial Dose of Investigational Product (PTC857) ................................14 
3.2.3. 
Study Baseline Definition and Change from Baseline ...............................................15 
3.2.3.1. 
Baseline Definition and Change from Baseline ..........................................................15 
3.2.4. 
Duration of Event .......................................................................................................15 
3.2.5. 
Retest and Unscheduled Visits ...................................................................................15 
3.2.6. 
Study Treatment Periods .............................................................................................15 
3.2.7. 
Coding Dictionary ......................................................................................................16 


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3.2.8. 
ALS Functional Rating Scale - Revised (ALSFRS-R) score .....................................16 
3.2.9. 
Pulmonary Function Tests ..........................................................................................16 
3.2.10. 
Modified Norris Scale .................................................................................................17 
3.2.11. 
ALS Cognitive Behavioral Screen ..............................................................................17 
3.2.12. 
ALSAQ-40 Assessment ..............................................................................................17 
3.2.13. 
EuroQol EQ-5D-5L ....................................................................................................17 
3.2.14. 
Survival .......................................................................................................................17 
3.3. 
Interim Analysis ..........................................................................................................18 
3.4. 
Changes to Protocol Specified Analysis .....................................................................18 
4. 
SUBJECTS DATA .....................................................................................................19 
4.1. 
Subject Disposition .....................................................................................................19 
4.1.1. 
Subject Disposition – Part B .......................................................................................19 
4.1.2. 
Subject Disposition – Part C ......................................................................................19 
4.2. 
Demographics and Baseline Characteristics ...............................................................19 
4.3. 
Disease Characteristics ...............................................................................................20 
4.4. 
Medical History ..........................................................................................................20 
4.5. 
Prior Medications and Concomitant Medications ......................................................21 
4.6. 
Multiplicity .................................................................................................................21 
4.7. 
Missing Data ...............................................................................................................21 
4.8. 
Treatment Compliance ................................................................................................21 
4.9. 
Visit Windows for The Early Termination Visit and Unscheduled Visits .................22 
5. 
EFFICACY ANALYSIS ............................................................................................24 
5.1. 
Primary Efficacy Analysis ..........................................................................................24 
5.2. 
Analysis of Efficacy Endpoints in the LTE Period ....................................................24 
5.2.1. 
Change from Baseline in ALSFRS-R .........................................................................24 
5.3. 
Analysis of Continuous Long Term Extension Endpoints .........................................24 
5.4. 
Overall Survival ..........................................................................................................25 
5.5. 
Analysis of Exploratory Endpoints in the LTE ..........................................................25 
6. 
SAFETY ANALYSES ...............................................................................................26 
6.1.1. 
Pooling of Safety Analyses .........................................................................................26 
6.2. 
Extent of Exposure .....................................................................................................26 
6.3. 
Adverse Events ...........................................................................................................26 
6.3.1. 
Reporting of Adverse Event Data ...............................................................................26 


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6.3.2. 
Exposure Adjusted incidence rates (EAIR) ................................................................28 
6.4. 
Laboratory Values ......................................................................................................28 
6.5. 
Vital Signs ..................................................................................................................29 
6.6. 
12-Lead Electrocardiogram ........................................................................................30 
6.7. 
Physical Examination .................................................................................................30 
6.8. 
Columbia-Suicide Severity Rating Scale ....................................................................30 
6.9. 
Body Weight, BMI, Breast Imaging and Pregnancies ................................................32 
6.10. 
Subgroup Analyses of Safety ......................................................................................32 
7. 
PHARMACOKINETIC OUTCOMES .......................................................................33 
8. 
REFERENCES ...........................................................................................................34 
9. 
PROGRAMMING CONSIDERATIONS ..................................................................36 
10. 
MOCK TABLES, LISTINGS, AND GRAPHS .........................................................38 
11. 
APPENDIX 1: SCHEDULE OF ASSESSMENT ......................................................39 
12. 
APPENDIX 2: MISSING DATE AND MISSING ALSFRS-R 
PROCEDURE .............................................................................................................43 
13. 
APPENDIX 3: TRICALS RISK PROFILE CALCULATOR ....................................45 
14. 
APPENDIX 4: SAS CODE ........................................................................................46 
15. 
APPENDIX 5. MAPPING ALSFRS-R TO KING’S STAGE ...................................48 
16. 
REVISION HISTORY ...............................................................................................49 


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List of Abbreviations  
Abbreviation 
Definition 
AE 
Adverse Event 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
ALS Functional Rating Scale - Revised 
ALS CBS 
ALS Cognitive Behavioral Screen 
ATC 
Anatomical Therapeutic Chemical  
BDRM 
Blinded Data Review Meeting 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CAFS 
Combined Assessment of Function and Survival 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DB 
Double-Blind 
eGFR 
Estimated Glomular Filtration Rate 
ENR 
All Enrolled  
ICF 
Informed Consent 
ITT 
Intention to Treat 
LFT 
Liver Function Test 
LTE 
Long-term extension 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
NfL 
Neurofilament light chain 
PAV 
Permanent Assisted Ventilation 
PFT 
Pulmonary Function Test 
PK 
Pharmacokinetics 
PMM 
Pattern-Mixture Model 
PP 
Per Protocol 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SNIP 
Sniff Nasal Inspiratory Pressure 
SoC 
Standard of Care 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TRICALS 
TRICALS is the largest European research initiative to find a cure for ALS 
ULN 
Upper Limit if Normal 
WHO DD 
World Health Organization Drug Dictionary 


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1. 
INTRODUCTION AND OVERVIEW  
The purpose of this statistical analysis plan (SAP) is to provide a description of the statistical 
methods and procedures to be implemented for data analysis of the open-label long-term 
extension periods (Parts B and C) and the entire study period (where applicable), for PTC857-
CNS-001-ALS, a Phase 2 randomized trial.  
This document is based on the final protocol amendment version 6.0, dated 14 JUNE 2024 and 
has been developed, reviewed and approved prior to the database lock. Any changes from the 
planned analysis as described in the protocol for PTC857-CNS-001-ALS and its amendments (as 
applicable) are detailed here, and any differences described here supersede the analysis presented 
in the protocol. Any additional analyses conducted to supplement the planned analyses and any 
deviations from the planned analyses described in this SAP will be documented in the Clinical 
Study Report (CSR).  
1.1. 
Study Design  
Brief description of the Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to assess 
the effects of PTC857 (also known as utreloxastat) in adult male and female subjects diagnosed 
with amyotrophic lateral sclerosis (ALS). Eligible male and female subjects aged between 18 and 
80 years will be enrolled in this study. The study consists of 5 periods: Screening, Treatment 
(Part A), LTE (Part B), Continued LTE (Part C), and Follow Up. During the open-label 
extension periods (Parts B and C), subjects remain blinded to the original treatment allocation in 
Part A. 
Approximately 340 subjects who meet the inclusion and exclusion criteria will be randomized in 
a 2:1 ratio to receive PTC857 (250 mg BID) or matching placebo using a central randomization 
process. The randomization will be stratified for the 2 stratification factors:  
1. Amount of change in ALSFRS-R score during the 8-week Screening Period by points 
total loss: 
a. <1, 
b. 1-2, 
c.  3-4,  
d. >4 points total loss  
2. Use of edaravone, sodium phenylbutyrate/taurursodiol, or neither for the treatment of 
ALS at Screening as standard-of-care therapy: 
a. Edaravone  
b. Sodium phenylbutyrate/taurursodiol  
c. Neither edaravone nor sodium phenylbutyrate/taurursodiol 
Before protocol amendment version 4.0, dated 31 OCTOBER 2022, the second stratification 
factor above (treatment for ALS at baseline) was based on use of riluzole alone (i.e., the 
following two levels: on riluzole therapy for ALS and not on riluzole therapy). Protocol 
amendment 4.0 opened the study to allow for randomization of subjects who were taking other 


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treatments for ALS if approved in their region of participation, specifically edaravone and 
sodium phenylbutyrate/taurursodiol if their treatment was considered stable at screening. In 
protocol amendment 4.0 the original riluzole stratification groups (on riluzole therapy vs. not on 
riluzole therapy) would be amalgamated, and randomization would be based on edaravone, 
sodium phenylbutyrate/taurursodiol, and neither, as indicated above.  
After completion of the 24-week double-blind treatment phase, all subjects will be offered the 
opportunity to enter the optional 28 weeks long-term extension (LTE) Period of the study. Those 
who choose to enter the LTE Period will sign an additional informed consent form (ICF) and 
start open-label treatment with PTC857 250 mg BID. Those who choose not to enter the LTE 
Period will stop treatment, and a telephone follow-up visit will be conducted 4 weeks (±3 days) 
after the last dose of study treatment. At the end of the LTE Period, those who choose not to 
enter the Continued LTE Period will stop treatment, and a Telephone Follow-Up Visit will be 
conducted 4 weeks (±3 days) after the last dose of study treatment. Subjects who enter the 
Continued LTE Period (Part C) will continue treatment for an optional additional 108 weeks. All 
subjects will be treated with open-label PTC857 (250 mg BID) during the Continued LTE 
Period. Subjects will remain blinded to their original treatment from the Treatment Period (Part 
A). At the end of this period, a Telephone Follow-Up Visit will be conducted 4 weeks (±3 days) 
after the last dose of study treatment. Results from the Treatment Period (Part A), the LTE 
Period (Part B), and the Continued LTE Period (Part C) will be reported separately. The 
scheduled study visit assessments are presented in Section 11 (Appendix 1). 
Total duration of the individual participation will be approximately 172 weeks, including a 
screening period of 8 weeks mandatory in duration, a double-blind treatment period of 24 weeks, 
a long-term open-label extension period of 28 weeks, a continued long-term extension period of 
108 weeks, and a follow up period of 4 weeks. A subset of approximately 36 subjects from select 
sites participating in the PK sub-study will participate in serial blood sampling to characterize the 
PK of PTC857 in subjects with ALS. The study schema is shown below. 
Figure 1: Study Design 
 
1.2. 
Study Objectives  
1.2.1. 
Long-Term Extension Period Objectives (Part B)  
The objectives of the Long-Term Extension (LTE) Period of this study are to assess the 
following in subjects with ALS: 


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• Disease progression, survival, neuropsychological function, respiratory function, 
motor/limb and bulbar function, and effects on biomarker activity upon long-term 
treatment with PTC857 
• Safety and tolerability upon long-term treatment with PTC857 
• Quality of life upon long-term treatment with PTC857 
• PK of PTC857 
1.2.2. 
Continued Long-Term Extension Period Objectives (Part C)  
• The objectives of the Continued LTE Period of the study are to assess the following 
in subjects with ALS: 
• Safety and tolerability upon continued long-term treatment with PTC857 
• Disease progression and survival upon continued long-term treatment with PTC857 
• Quality of life upon continued long-term treatment with PTC857 
1.3. 
Study Endpoints  
1.3.1. 
Long-Term Extension Period Endpoints (Part B)  
The LTE Period endpoints of this study are the following: 
• Severity and number of TEAEs and TESAEs, change in clinical laboratory tests, 
physical examination, vital signs, and 12-lead ECGs during the LTE Period 
• Change from baseline in ALSFRS-R after 52 weeks of treatment 
• Change from baseline in slow vital capacity as assessed by PFTs after 52 weeks of 
treatment 
• Change from baseline in motor/limb and bulbar function as assessed by the Modified 
Norris Scale after 52 weeks of treatment 
• Change from baseline in neuropsychological function as assessed by the ALS CBS 
after 52 weeks of treatment 
• Survival after 52 weeks of treatment 
• Quality of life as assessed by ALSAQ-40 after 52 weeks of treatment 
• Quality of life as assessed by EQ-5D-5L after 52 weeks of treatment 
• Change from baseline in blood and urine biomarker activity after 52 weeks of 
treatment 
• PK of PTC857 
1.3.2. 
Continued Long-Term Extension Period Endpoints (Part C)  
The Continued LTE Period endpoints of this study are the following: 
• Severity and number of TEAEs and TESAEs during the Continued LTE Period 


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• Change from baseline in ALSFRS-R after 160 weeks of treatment 
• Survival after 160 weeks of treatment 
• Quality of life as assessed by ALSAQ-40 after 160 weeks of treatment 
1.4. 
Randomization and Blinding  
Subjects who satisfy all the inclusion and none of the exclusion criteria will be randomly 
assigned in a 2:1 ratio to receive one of the following two treatment arms during the 24-week 
treatment phase according to a study randomization scheme: 
• Arm 1: PTC857 (250 mg) administered orally BID for 24 weeks. 
• Arm 2: Matching placebo administered orally BID for 24 weeks. 
Investigators, subjects and site staff will be blinded to treatment assignments during the entire 
study period. PTC biostatistics staff who are directly involved in the analysis of the study results 
and members of the clinical study team will remain blinded to the treatment assignment 
throughout the conduct of Part A and will be unblinded after the first database lock for Part A. 
Participation in the long-term extension periods does not involve randomization.  


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2. 
ANALYSIS SETS  
2.1. 
All Enrolled Set  
The All-Enrolled set will contain all subjects who signed an informed consent for this study. This 
analysis set will be used to summarize subject disposition. 
2.2. 
Intent-to-Treat (ITT) Analysis Sets  
Intent-to-Treat 1 Analysis Set (ITT1) 
All subjects who are randomized after the Screening Period and take at least 1 dose of double-
blind study drug in the Treatment Period and who have a decrease in the ALSFRS-R score of ≤4 
points during the Screening Period will be included in the ITT1 Analysis Set. Subjects will be 
analyzed according to their randomized treatment. 
Intent-to-Treat 2 Analysis Set (ITT2) 
All subjects who are randomized after the Screening Period and take at least 1 dose of double-
blind study drug in the Treatment Period will be included in the ITT2 Analysis Set. Subjects will 
be analyzed according to their randomized treatment assignment. ITT2 analysis set will be used 
as supportive analysis population. 
2.3. 
Safety Analysis Set  
All subjects in the ITT2 Analysis Set who receive at least 1 dose of study drug will be included 
in the Safety Analysis Set. Subjects will be analyzed according to the actual treatment received.  
2.4. 
Long-Term Extension Safety Analysis Set  
All subjects who receive at least one dose of the open-label study drug during the long-term 
extension periods will be included in the LTE Safety Analysis Set.  
2.5. 
Per Protocol Set  
All subjects in the ITT1 Analysis Set who have no major protocol deviations that affect the 
validity of the efficacy measurements will be included in the PP Analysis Set. The PP Analysis 
Set will be used for sensitivity analysis of the efficacy endpoint.  
2.6. 
Pharmacokinetic Analysis Set  
All subjects in the ITT2 Analysis Set who have at least 1 measurable post-baseline plasma or 
CSF PTC857 concentration will be included in the PK Analysis Set. Subjects with protocol 
violations that could affect the PK parameters will be assessed by the pharmacokineticist for 
inclusion into the PK analysis set. The pharmacokineticist may also exclude subjects or specific 
concentrations from the PK parameter calculation if required, for example if doses were missed 
or if samples were collected out of the allowed assessment windows. PK summaries and analyses 
will be conducted using the PK analysis set. The PK analysis set will be based on the actual 
treatment received. 


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2.7. 
Protocol Deviations  
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to, the following: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications that are specifically prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc (either the tests were not done, 
the incorrect tests were done, or the tests were not done within the time frame 
specified in the protocol) 
• Procedural deviations such as incorrect storage of study drug, failure to update the 
ICF when new risks become known, or failure to obtain IRB/IEC approvals for the 
protocol and ICF revisions 
Major protocol deviations are defined in the study’s Protocol Deviation Handling Plan and 
include quality issues that have a high likelihood to significantly impact a subject’s rights, safety 
or well-being, or have a potentially significant impact on data integrity. 
Protocol deviations will be documented separately in a stand-alone file before database lock 
which include deviation category (e.g., violation of inclusion and exclusion criteria at screening, 
use of excluded concomitant medications, received the wrong treatment or incorrect dose), 
deviation description, severity (minor/major), visit/time point for each deviation. 


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3. 
GENERAL CONSIDERATIONS  
3.1. 
General Considerations  
Continuous data will be summarized using number of observations (n), arithmetic mean (mean), 
standard deviation (SD), median, minimum value (min) and maximum value (max). 
Additionally, for biomarker data, the summaries will include geometric means and geometric 
standard deviations, as appropriate. Categorical variables will be summarized using the 
frequency count (n) and percentage (%).  
For all percentage calculations, the denominator will be the number of subjects in the analysis 
set, unless otherwise stated. 
Only data from protocol scheduled visits will be included in the summary tables. Data from 
unscheduled visits will not be included in the summary tables but will be included in the by-
subject listings. Descriptive summaries by visit will be provided for all the primary and 
secondary efficacy endpoints. 
3.2. 
Data Definitions and Analysis Issues  
3.2.1. 
Study/Onset Day  
The study/onset day will be defined as the number of days after the first dose of study drug, 
which is assigned as Day 1 for analysis purposes. Study/onset day is calculated using the formula 
below: 
Assessment Date Relative to First Dose of Study Drug Study Day Calculation 
Assessment/Event date prior to date of first dose 
Date of assessment – Date of first dose of 
study drug 
Assessment/Event date on or after Date of first dose 
(Date of assessment – Date of first dose of 
study drug) +1 
 
3.2.2. 
Weeks Since Initial Dose of Investigational Product (PTC857)  
Nominal visits for subjects initiating open-label PTC857 in Part B will be aligned with those 
who initiated PTC857 during the double-blind period (Part A). 
This alignment allows for the evaluation of changes from initial exposure for scheduled 
assessments (e.g., laboratory tests, and vital signs) for subjects initiating PTC857 at different 
periods of the study, i.e., those randomized to active drug in Part A at the randomization visit 
(Day 1) and those randomized to placebo and initiating active drug in Part B. The display below 
illustrates the matching of these two groups.  
 
Study Day 
LTE period 
Study Day  
Double-blind period 
Weeks since initial 
exposure to PTC857 
Day 169 
Day 1 
0 
Day 183 
Day 14 
2 
Day 197 
Day 29 
4 
Day 225 
Day 57 
8 
Day 253 
Day 85 
12 


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Day 365 
Day 113 
28 
Day 393 
Day 141 
32 
Day 449 
NA 
40 
Day 533 
NA 
52 
Day 617 
NA 
64 
Day 701 
NA 
76 
Day 785 
NA 
88 
Day 869 
NA 
100 
Day 953 
NA 
112 
Day 1037 
NA 
124 
Day 1121 
NA 
136 
Day 1149 
NA 
140 
  
3.2.3. 
Study Baseline Definition and Change from Baseline  
3.2.3.1. 
Baseline Definition and Change from Baseline  
The Baseline Visit will be defined as Day 1 of the study. Unless otherwise stated, for each 
subject, baseline value of a parameter is defined as the last non-missing measurement taken at 
most one week prior to the first dose of study drug (including unscheduled assessments). If the 
last non-missing measurement and the date of first dose of study drug coincide, that 
measurement will be considered baseline, but AEs and medications commencing on the date of 
first dose of study drug will be considered post-baseline.  
For the purposes of calculating summary statistics of the outcome measures, change from 
baseline will be derived as follows: 
• Change from baseline = Post-baseline value – Baseline value 
3.2.4. 
Duration of Event  
Where the duration of an event is to be calculated, it will be derived as:  
Duration (days) = (Event stop/end date – Event start date) + 1. 
Duration (months) = Duration (days) / 30.4375 
3.2.5. 
Retest and Unscheduled Visits  
Unscheduled measurements and retests will not be included in by-visit summaries but will 
contribute to incidence of significant abnormality tables, where applicable. 
In the case of a retest (same visit number assigned), the last available measurement for that visit 
will be used for by-visit summaries. 
3.2.6. 
Study Treatment Periods  
Period 
Definition  
Pre-treatment 
Period 
Date of Screening through one day prior Date of first dose 
Double-blind 
Date of first dose through one day after Date of last dose 


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Treatment Period 
OR  
Date of first dose through one day prior first dose during open-label treatment 
period 
Open label Long-
term Extension 
Periods  
Date of first dose during open-label LTE period (Part B) to Date of last dose 
during open-label LTE period (Part B or C) plus one 
OR 
Date of first dose during open-label LTE period (Part B) through one after Date of 
last dose during open-label continued-LTE period (Part C) 
3.2.7. 
Coding Dictionary  
Where applicable, safety data will be coded using the following coding dictionaries: 
Dictionary 
Version 
Medical Dictionary for Regulatory Activities (MedDRA) 
25 or higher 
World Health Organization Drug Dictionary (WHODrug Global) 
WHODrug-Global-B3 Sep 2021 or 
later 
3.2.8. 
ALS Functional Rating Scale - Revised (ALSFRS-R) score  
The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the 
subjects’ capability and independence in 12 functional activities across 4 subdomains of bodily 
function (bulbar, gross motor, fine motor, and respiratory) relevant in ALS. Each activity is 
recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 
4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating less 
functional impairment (Cedarbaum 1999). 
The score change from baseline will be calculated as the post baseline score minus the baseline 
score, so that a positive score for change from baseline would indicate improvement in function 
relative to baseline, while a negative score indicates worsened disease relative to baseline.  
Subdomains 
Items 
Bulbar 
Speech, Salivation and Swallowing 
Fine Motor 
Handwriting, Cutting Food/Handling Utensils and Dressing Hygiene 
Gross Motor 
Turning in Bed, Walking and Climbing Stairs 
Respiratory 
Dyspnea, Orthopnea and Respiratory Insufficiency 
3.2.9. 
Pulmonary Function Tests  
Pulmonary function tests are used to assess respiratory function. Pulmonary function tests (PFTs) 
will assess SVC and SNIP. Forced vital capacity, vital capacity, forced expiratory volume, and 
maximum inspiratory pressure will not be measured. Oxygen saturation (SpO2), respiratory rate, 
and heart rate will be assessed in both upright and supine positions. The SNIP test will assess 
nasal pressure in each unilaterally occluded nostril during a maximal sniff to assess inspiratory 
muscle strength. 


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3.2.10. 
Modified Norris Scale  
Modified Norris scale is used to assess the motor/limb and bulbar function. The Modified Norris 
Scale is a rating scale for ALS that consists of 2 parts: the Limb Norris Scale and the Norris 
Bulbar Scale. The Limb Norris Scale has 21 items to evaluate extremity function, and the Norris 
Bulbar Scale has 13 items to evaluate bulbar function. Each item is rated in 4 ordinal categories. 
The total score is calculated by summing all the scales (Norris 1974). 
3.2.11. 
ALS Cognitive Behavioral Screen  
The ALS CBS is a brief measure of cognition and behavior in patients with ALS. The ALS CBS 
is composed of 2 sections: cognitive and behavioral. The cognitive section includes commonly 
used elements of standard testing batteries, consisting of 8 tasks that assess attention, 
concentration, tracking/monitoring, and initiation and retrieval. Each subtest score ranges from 
0–5 and the total score ranges from 0–20. The behavioral section is composed of questions 
sensitive to organic brain changes. It consists of fifteen 3-point Likert items (total score ranges 
from 0–45) questioning caregivers on patients’ behavioral changes (3 = “no change”; 0 = “large 
change”) and 4 “yes/no” questions on anxiety and depression. 
3.2.12. 
ALSAQ-40 Assessment  
The ALSAQ-40 is a disease-specific measure of health-related quality of life for ALS (Jenkinson 
1999). It is specifically used to measure the subjective well-being of patients with ALS and 
provides scores for 5 scales: physical mobility (10 items: 1-10), activities of daily living and 
independence (10 items: 11-20), eating and drinking (3 items: 21-23), communication (7 items: 
24-30) and emotional reactions (10 items: 31-40). If one of the question items of ALSAQ-40 is 
missing, the total score will be considered as a missing value. However, it may be included in the 
summary of the specific scales. Lower total scores for the ALSAQ-40 indicate better quality of 
life, with higher scores indicating poorer quality of life. Analyses will be performed on the total 
score. 
3.2.13. 
EuroQol EQ-5D-5L  
The EQ-5D-5L is a patient reported outcome measure (PROM) that determines a subject’s 
health-related quality of life (www.euroqol.org). EQ-5D-5L consists of 2 components: The 
health state descriptive system and the visual analogue scale (EQ-VAS). The health state 
descriptive system is a 5 Dimension (5-D) questionnaire covering 5 health related aspects: 
Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. For each 
Dimension, the subject responds by selecting one of 5-levels (5L): 1=No problems; 2=Slight 
Problems; 3=Moderate Problems; 4=Severe Problems and 5=Extreme Problems.  
The visual analogue scale (EQ-VAS) is a 20 cm vertical graduated visual analogue scale with 
numbers ranging from 0 (=worst imaginable health) to 100 (=best imaginable health). Subjects 
rate their overall health by placing an X mark on the scale to indicate their perceived overall 
health. 
3.2.14. 
Survival  
The survival endpoint is defined as the time from the randomization date to the date of death 
from any cause.  


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3.3. 
Interim Analysis  
No formal interim analyses are planned for this study. However, At the time of the database lock 
of the double-blind treatment period (Part A) selected data from the open-label long term 
extension periods (combined Parts B and C) will be descriptively summarized and included in 
the interim clinical study report. This (select data) will include: 
• All available safety endpoints described in Section 6 
• All available survival data 
• All available ALSFRS-R data 
• All available ALSAQ-40 data 
3.4. 
Changes to Protocol Specified Analysis  
Safety data for Parts B and C will be combined, as the transition from Part B to Part C does not 
represent a clinically significant timepoint.  
 


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4. 
SUBJECTS DATA  
4.1. 
Subject Disposition  
Subject disposition data will be summarized. A summary table of subject disposition will be 
produced reflecting: 
4.1.1. 
Subject Disposition – Part B  
• Subjects completed in Part A  
• Subjects enrolled (or consented) in part B 
• Safety analysis set for Part B (Subjects received treatment in Part B) 
• Subjects completed in Part B 
• Subjects who early terminate the study treatment during part B and reasons for early 
termination 
• Subjects who early terminate the study in Part B and reasons for early termination 
4.1.2. 
Subject Disposition – Part C  
• Subjects completed in Part A  
• Subjects completed in Part B  
• Subjects enrolled (or consented) in part C 
• Subjects dosed in Part C 
• Subjects completed in Part C 
• Subjects who early terminate the study treatment during part C and reasons for early 
termination 
• Subjects who early terminate the study in Part C and reasons for early termination 
For the enrolled population in the LTE parts, the number and percentage of participants in each 
analysis population will be presented.  
4.2. 
Demographics and Baseline Characteristics  
Subjects’ demographics and baseline characteristics will be summarized overall and by treatment 
group for subjects in the safety analysis sets for Part B and C.  
Continuous variables (e.g., age and weight) will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum). Qualitative variables (e.g., sex, 
race, and ethnicity) will be summarized with counts and percentages.  
The demographic parameters will include age category (<65 and ≥65 years), gender, race, and 
ethnicity. Age will also be summarized as a continuous variable. The baseline parameters 
include, height, body weight, BMI, ALSFRS-R score, amount of change in ALSFRS-R score 
during the screening period (<1, 1-2, 3-4, or >4 points total loss) use of standard of care (SoC) 
medications for ALS at baseline and disease characteristics at screening. 


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By-subject listings of demographic and other baseline characteristics will be provided for all 
randomized subjects. In this listing flag variables will be used to identify subjects in various 
analysis sets. 
4.3. 
Disease Characteristics  
Subjects’ disease characteristics will be summarized for subjects in the Long-Term Extension 
Safety Analysis. By-subject listings of disease characteristics will also be provided. Duration of 
symptoms (months) and months since diagnosis will be summarized using descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum). The following disease 
characteristics will be summarized with counts and percentages (n (%)): 
• Site of symptom onset 
• Family history 
• El Escorial criteria at screening 
• Pre-ALS impairment 
• Months since ALS symptom onset  
• Months since diagnosis 
• Site of onset 
• Diagnosis delay 
• Derived King’s Clinical Stage (Balendra 2014 also see Appendix 5) 
• TRICALS Risk Profile  
The TRICALS risk profile (van Eijk 2021) is based on the European-Network-to-Cure-ALS 
survival prediction model, a cross-validated model to predict the composite endpoint death or 
respiratory insufficiency based on data of 11,475 subjects with ALS (Westeneng 2018). The 
TRICALS Risk Profile is a weighted average of seven pre-randomization subject characteristics, 
including: Percent predicted vital capacity, age at onset in years, diagnostic delay (months from 
symptom onset to diagnosis), presence of frontotemporal dementia, progression rate of the ALS 
functional rating scale (points per month), Bulbar onset of ALS, and an El Escorial criteria of 
clinically definite ALS at screening. The range of possible values for this summary predictor is 
from approximately -12.0 to 0.0 with higher scores indicating a poorer prognosis. Section 13 
(Appendix 3) provides details on its derivation.  
4.4. 
Medical History  
Medical and surgical history will be provided for subjects in the long-term extension safety set 
sets for Part B and C. Medical history will also be provided for all subjects who were exposed to 
the investigational product (PTC857). 
Medical and surgical history will be coded using a central coding dictionary, the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.  
Medical and surgical history will be defined as any significant past medical conditions that ended 
before screening or current medical conditions that were ongoing at Screening. Medical and 
surgical histories will be summarized separately by system organ class (SOC) and preferred term 


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(PT) overall and for each treatment group for the safety analysis set. Summaries will be sorted 
alphabetically by SOC, and by descending order of frequency for PTs according to the total 
column. Subjects with more than one of the same PTs within an SOC will be counted only once. 
A by-subject listing will be provided for the safety analysis set. 
4.5. 
Prior Medications and Concomitant Medications  
Prior medications are medications which started and stopped before the first dose of study drug. 
Any changes to prior medications (dose, regimen, etc.) during the study will be considered a new 
concomitant medication. In the analyses of subjects exposed to the investigational product 
(PTC857) prior medications will be defined as medications started and stopped before the first 
dose of PTC857.  
Concomitant’ medications/procedure are medications/procedures which started prior to or after 
the first dose of study drug and ended after the date of first dose of study drug or ongoing at the 
end of the study. If a medication or procedure cannot be classified as “prior” or “concomitant” 
after applying imputation rules for missing/incomplete dates, it will be classified as concomitant. 
Prior and concomitant medications will be coded using the latest available version of the 
Anatomical Therapeutic Chemical (ATC) classification text from the World Health Organization 
Drug Dictionary (WHO DD) and summarized separately. The number and percentage of subjects 
taking a medication will be displayed by therapeutic class (ATC Level 3) and preferred name. 
Summaries will be sorted alphabetically by ATC-Level 3, and by descending order of frequency 
for preferred name according to the total column. Subjects with more than one of the same 
preferred names within an ATC-Level 3 will be counted only once. Prior medications and 
concomitant medications will be summarized for subjects in the LTE safety analysis set and for 
the subjects exposed to PTC857. 
Prior and concomitant procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. 
The count and percentage of subjects who have undergone various prior and concomitant 
procedures will be summarized by treatment received.  
A by-subject listing of prior and concomitant medications will be provided for the safety analysis 
set. 
4.6. 
Multiplicity  
There will be no multiplicity consideration. 
4.7. 
Missing Data  
For the analysis of change from baseline in ALSFRS-R at weeks 52 and 160, missing outcome 
data will be assumed to be missing at random (MAR) and will be imputed implicitly using a 
mixed model repeated measures analysis. 
4.8. 
Treatment Compliance  
Percent compliance will be calculated as the amount of dose taken divided by the amount of dose 
that should have been taken multiplied by 100. The following formula will be used to calculate 
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𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (%) = 100 × (2 × 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑)
2 × 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑖𝑖𝑖𝑖 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
 
The extent of exposure to study medication (treatment duration) in days will be calculated as the 
last dose date minus the first dose date + 1.  
Exposure (number of days) and compliance will be summarized descriptively (number of doses 
taken / number of doses expected and percentage) for the LTE safety analysis set and for subjects 
exposed to PTC857. 
4.9. 
Visit Windows for The Early Termination Visit and Unscheduled Visits  
If a subject completely withdraws from the study prematurely, and unless consent is withdrawn, 
all efforts are made to collect efficacy and safety data and to complete the Early Termination 
Visit (ET). 
Follow-up efficacy data collected at the early termination visit will be incorporated into the study 
visit schedule using the visit windows, defined in Table 1, Table 2 and Table 3. Similarly, 
follow-up efficacy data collected during unscheduled visits or make-up visits will also use the 
same visit windows. If a follow-up visit (ET) or unscheduled visit falls in the same visit window 
as a scheduled visit, then the scheduled visit data will be used. If an unscheduled visit and ET 
visit fall within the same window, then the visit closest to the target day will be used.  
Table 1: Visit Windows for The Early Termination and Unscheduled Visits  
ALSFRS-R 
Visit 
Lower Bound 
Target Day 
Upper Bound 
Day 29 
15 
29 
42 
Day 57 
43 
57 
70 
Day 85 
71 
85 
98 
Day 113 
99 
113 
126 
Day 141 
127 
141 
154 
Day 169 
155 
169 
182 
Day 197 
183 
197 
210 
Day 225 
211 
225 
238 
Day 365 
351 
365 
378 
Day 449 
435 
449 
462 
Day 533 
519 
533 
546 
Day 617  
603 
617 
630 
Day 701 
687 
701 
714 
Day 785 
771 
785 
798 
Day 869  
855 
869 
882 
Day 953 
939 
953 
966 
Day 1037 
1023 
1037 
1050 
Day 1121 
1107 
1121 
1134 
 


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Table 2: Visit Windows for The Early Termination and Unscheduled Visits  
SVC, Norris Scale, and plasma NfL 
Visit 
Lower Bound 
Target Day 
Upper Bound 
Day 85 
64 
85 
106 
Day 169 
148 
169 
190 
Day 253 
232 
253 
274 
Day 365 
344 
365 
386 
 
 
 
Table 3: Visit Windows for The Early Termination and Unscheduled Visits  
ALSAQ-40 
Visit 
Lower Bound 
Target Day 
Upper Bound 
Day 85 
64 
85 
106 
Day 169 
148 
169 
190 
Day 253 
232 
253 
274 
Day 365 
344 
365 
386 
Day 449 
428 
449 
470 
Day 533 
512 
533 
554 
Day 617  
596 
617 
638 
Day 701 
680 
701 
722 
Day 785 
764 
785 
806 
Day 869  
848 
869 
890 
Day 953 
932 
953 
974 
Day 1037 
1016 
1037 
1058 
Day 1121 
1100 
1121 
1142 
 


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5. 
EFFICACY ANALYSIS  
5.1. 
Primary Efficacy Analysis  
Not applicable 
5.2. 
Analysis of Efficacy Endpoints in the LTE Period  
Analyses of the LTE efficacy endpoints will compare subjects randomized to PTC857 (early 
start of PTC857) against those randomized to Placebo (late start of PTC857). The two treatment 
groups will be labelled as utreloxastat/utreloxastat and Placebo/utreloxastat and will include all 
available efficacy results from the entire study period (parts A, B and C). 
Analyses will be performed for both the ITT1 and ITT2 analyses sets.  
5.2.1. 
Change from Baseline in ALSFRS-R  
Change from baseline in ALSFRS-R at Weeks 52 and 160 will be evaluated by means of a 
mixed model repeated measures analysis using all available ALSFRS-R scores up to Week 160.  
The model will include fixed categorical effects of treatment (PTC857 or placebo), use of 
approved background therapy for ALS at screening (Yes vs No), the amount of change in the 
subject’s ALSFRS-R score during the Screening Period (<1, 1-2 or 3-4 points total loss), time of 
collection (nominal week at the visit as a categorical variable), as well as the continuous, fixed 
covariates of baseline ALSFRS-R, and The TRICALS risk profile. In addition, the following 
interaction terms will be included: Time by treatment, time by baseline ALSFRS-R, and 
TRICALS risk profile by time. Subject will be included as a random effect. The Restricted 
Maximum Likelihood (REML) estimation approach will be used with the variance-covariance 
structure set as unstructured (UN). Other types of covariance matrices will be explored in the 
case of non-convergence of the UN. Subjects with no post baseline results for the outcome 
variable will be excluded. This analysis will be performed for both the ITT1 and ITT2 analysis 
sets. 
Observed and change-from-baseline values will also be summarized descriptively at each visit. 
In supplementary analyses, score changes from baseline at Weeks 52 and 160 for the ALSFRS-R 
subdomains will be analyzed under the same estimand framework where MMRM models will be 
used to implicitly impute missing data. Nominal P-values for the treatment arm comparison, 
estimate of LSMEANS for the treatment differences (PTC857 – Placebo) at Weeks 52 and 160, 
and the two-sided 95% confidence intervals of the LSMEANS difference will be presented. 
To determine if there is a reduction in the decline of ALSFRS-R scores in subjects randomized to 
placebo after starting open-label PTC857, graphical plots comparing the decline during the 
double-blind period and the open-label extension periods will be provided. Additionally, changes 
(in ALSFRS-R) from both the initial study baseline and the treatment baseline in Part B will be 
reported. 
5.3. 
Analysis of Continuous Long Term Extension Endpoints  
The following continuous long term extension endpoints will be analyzed for both the ITT1 and 
ITT2 analysis sets using a similar model as described in Section 5.2.1, p-values for the treatment 
arm comparison, estimate of LSMEANS for the treatment differences (PTC857 – Placebo), and 
the two-sided 95% confidence intervals of the LSMEANS difference will be presented: 


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• Quality of life as assessed by Amyotrophic Lateral Sclerosis Assessment 
Questionnaire (ALSAQ-40) at 52 and 160 weeks. 
• Change from baseline in Modified Norris Scale total score at 52 weeks. 
• Change from baseline in slow vital capacity (SVC) as assessed by pulmonary 
function tests (PFTs) at 52 weeks.  
• Change from baseline in neuropsychological function as assessed by the ALS CBS at 
52 weeks.  
• Change from baseline in log transformed NfL (plasma) at 52 weeks. Geometric 
means and mean ratios to baseline, as well as the difference in geometric mean ratio 
for those in the PTC875 arm to those in the Placebo arm will be reported, together 
with 95% confidence intervals and p-values. 
5.4. 
Overall Survival  
Overall survival (OS) is defined as the time in months from the date of first dose to the date of 
death from any cause or date last known alive for those who did not die. 
Specifically, 
OS = Date of death or date last known alive – Date of first dose + 1 
Subjects will be censored at the last date they are known to be alive. The last known alive date 
will be the last date of any subject record in the study database. The date may be the last visit 
date or last contact date that the subject is known to be alive. Subjects who only have baseline 
record will be censored at the first dose date. 
OS will be analyzed using KM methods. A summary table of the number of deaths, the number 
of censors, and KM estimates (25th, 50th, 75th percentile of OS along with the 95% CI). Kaplan-
Meier survival curves will also be presented. 
A stratified Cox Proportional Hazards regression model will be used to estimate the hazard ratio 
(and 95% CIs) of PTC857 compared to Placebo. The model will be stratified by the amount of 
change in the subject’s ALSFRS-R score during the Screening Period (<1, 1-2 and 3-4-points 
total loss), and use of approved background therapy for ALS at screening (Yes vs No). In 
addition, the TRICALS risk profile and ALSFRS-R score at baseline will be included in the 
model as covariates. Ties in survival time will be handled using the Breslow method.  
Kaplan-Meier survival curves will also be presented. 
5.5. 
Analysis of Exploratory Endpoints in the LTE  
Exploratory endpoints will be summarized for both the ITT1 and ITT2 analysis sets. Summary 
statistics by nominal timepoint will be provided for all the exploratory endpoints, including ALS-
CBS, EQ5D-5L, and urine p75 neurotrophin receptor (p75NTR). 
ALS-CBS total score will be analyzed using the same methodology described for secondary 
(continuous) endpoints in Section 5.3. P-values for the treatment arm comparison at week 52, 
estimate of LSMEANS for the treatment differences (PTC857 – Placebo), and the two-sided 
95% confidence intervals of the LSMEANS difference will be presented. 


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6. 
SAFETY ANALYSES  
Safety will be assessed based on exposure, and will include adverse events, laboratory 
assessments, vital signs, 12-Lead electrocardiogram, physical examination, and Columbia-
Suicide Severity Rating Scale (C-SSRS). The results will be descriptive in nature. All data will 
be summarized and listed. There will be no statistical comparisons between the treatment groups 
for safety data, unless otherwise specified within the relevant section. All data will be 
summarized and listed. 
6.1.1. 
Pooling of Safety Analyses  
Safety data will be reported for the pooled open-label long-term extension period (Parts B and C) 
as well as for the entire pooled study period (Parts A, B, and C).  
Safety summaries for the open long-term extension periods, (Parts B and C) will be based on The 
Long-Term Extension Safety Population (defined in Section 2.4). These summaries will be 
displayed by actual treatment received during the double-blind treatment period and long-term 
extension periods. Tabular outputs will have columns labeled as follows: 
• Placebo / Utreloxastat (subjects initially randomized to placebo) 
• Utreloxastat / Utreloxastat (subjects initially randomized to utreloxastat) 
• Total 
The safety summaries for the entire pooled study period (Parts A, B, and C) will be presented in 
a single total column and will be limited to the subset of the Safety Analysis Set consisting of 
subjects who received the actual investigational product (PTC857).  
6.2. 
Extent of Exposure  
The extent of exposure to study drug will be summarized descriptively. The summaries will 
include mean, SD, median, minimum, and maximum values. 
The extent of study drug exposure for the open label long-term extension period is defined as the 
difference between the last dose of study medication and the first dose study drug in the open 
label long-term extension period plus 1. 
Extent of exposure to PTC857 during the whole study period will also be summarized. Extent of 
exposure to PTC857 will be defined as the difference in time between first exposure to PTC857 
and the last dose of PTC857. 
6.3. 
Adverse Events  
6.3.1. 
Reporting of Adverse Event Data  
Adverse events will be collected and recorded from the time subjects sign the informed consent 
form to the end of the follow-up period. All AEs will be classified by primary system organ class 
(SOC) and preferred term (PT) according to the MedDRA coding dictionary. A treatment-
emergent adverse event (TEAE) is an AE that begins after the first administration of study drug 
or any existing AEs that worsens after the first dose of study drug. All reported AEs will be 
listed, but only TEAEs will be summarized in tables. 


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AEs with an onset from day 1 of the open label long-term extension periods up to and including 
30 days after the last dose of study drug in the open label long-term treatment periods (or up to 
and not including the start date of the Continued LTE period whichever comes first) will be 
considered as occurring during the LTE treatment period.  
An overall summary of TEAEs, including the number and percentage of subjects reporting at 
least one TEAE for the categories listed below, will be provided. 
• Subjects with at least one TEAE 
• Subjects with at least one TEAE related to study drug 
• Subjects with at least one serious TEAE 
• Subjects with at least one non-serious TEAE 
• Subjects with at least one serious TEAE related to study drug 
• Subjects with at least one TEAE leading to premature discontinuation of study drug 
• Subjects with at least one TEAE leading to death 
• TEAEs by highest relationship to study drug 
• TEAEs by highest severity 
The following summaries will be tabulated: 
• TEAEs overall and by SOC and PT 
• TEAEs occurring in ≥ 5% of subjects within a treatment group, by PT 
• TEAEs by PT 
• Study drug related TEAEs, overall and by SOC and PT 
• TEAEs by maximum severity, overall and by SOC and PT 
• Grade 3 or Higher TEAEs by SOC and PT 
• Grade 3 or higher related TEAE by SOC and PT 
• TEAEs by highest relationship to study drug 
• Serious TEAEs, overall and by SOC and PT 
• Serious TEAEs, overall and by severity grade, SOC and PT 
• Non-serious TEAEs, overall and by severity grade, SOC and PT 
• TEAEs leading to discontinuation of study drug, overall and by SOC and PT 
• TEAEs leading to death, overall and by SOC and PT 
TEAEs with “possibly related”, “probably related” or “related” to study drug based on the 
investigator assessment will be considered as drug related TEAEs. TEAEs with missing 
causality, if any, will be assumed as ‘Related AEs’. 
For summaries by SOC and PT, a subject will be counted only once at the SOC level and once at 
each PT within the SOC level, even if the subject experienced more than one AE within a 


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specific SOC and PT. For summaries by SOC, PT, and maximum severity, a subject will be 
counted only once at the maximum severity level for which the event occurred at the SOC level 
and at the maximum severity level for which the event occurred for each unique PT within that 
SOC level. Therefore, subjects will contribute to only one severity level within a PT or SOC. 
Summaries presenting frequency of TEAEs by SOC and PT will be ordered by overall 
descending frequency of SOC and then, within a SOC, by overall descending frequency of PT. 
Summaries presenting TEAEs by PT only will be ordered by overall descending frequency of 
PT. 
TEAE summaries for the LTE periods (Parts B and C) will be displayed by actual treatment 
received during the double-blind period and the long-term extension periods.  
TEAE summaries for the entire trial period (Parts A, B and C combined) will be presented with a 
total column only and will include subjects exposed to actual PTC857. 
Subject listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately. 
6.3.2. 
Exposure Adjusted incidence rates (EAIR)  
Exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs) will 
be presented by treatment group, MedDRA System Organ Class (SOC), and preferred term, as 
well as by treatment group and MedDRA preferred term.  
For each grouping of subjects (e.g., “All subjects” and “subjects on PTC857), the EAIR of a 
specific treatment-emergent event is defined as the number of subjects experiencing the event at 
least once, divided by the total exposure-adjusted follow-up time in person-years. 
For subjects who experience the event, the exposure-adjusted follow-up time will be calculated 
from the first exposure (to PTC857 in Part B) until the first occurrence of the event. For subjects 
who do not experience the event (censored), the follow-up time will be calculated from the first 
dose during the safety reporting period until their last safety follow-up for that period.  
EAIR will also be calculated for the subset of subjects exposed to the IP (PTC857), for those 
summaries, the start period of exposure will be defined at the date the subject first took PTC857.  
Missing or partial AE onset dates will be imputed using the imputation rules described in 
Appendix 2. 
6.4. 
Laboratory Values  
All clinical laboratory analyses will be performed by the central laboratory. The clinical 
laboratory assessment of hematology, clinical chemistry, and urinalysis will be obtained at 
scheduled visits. The following parameters are collected at the following visits per protocol: 
Parameter(s) 
Scheduled Visit(s) 
Hematology: Hemoglobin, Hematocrit, RBC count, 
Reticulocytes, Platelet count, WBC count, Neutrophils, 
Eosinophils, Monocytes, Basophils, Lymphocytes, Mean 
corpuscular volume 
Screening, Day 1, Day 29, Day 57, Day 
85, Day 169, Day 197, Day 225, Day 253,  
Day 365, Day 533, Day 701, Day 869, 
Day 1037, and ET 
Clinical Chemistry: Urea, Creatinine, Fasting glucose, 
Sodium, Potassium, ALT, AST, GGT, Bilirubin (total, 
direct/indirect), Alkaline phosphatase, Albumin,  
Screening, Day 1, Day 29, Day 57, Day 
85, Day 169, Day 197, Day 225, Day 253,  


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Parameter(s) 
Scheduled Visit(s) 
Day 365, Day 533, Day 701, Day 869, 
Day 1037, and ET 
Lipid Profiles: Cholesterol (total), LDL, HDL, Triglycerides, 
LDH 
Screening, Day 1, Day 14, Day 29, Day 
57, Day 85, Day 169, Day 183, Day 197,  
Day 225, Day 253, Day 365, and ET 
Urinalysis: Urobilinogen, Nitrite, pH, Glucose, Total 
protein, Erythrocytes, Leukocytes, Ketones, Microscopy, 
Specific gravity, Bilirubin 
Screening, Day 1, Day 85, Day 169, , Day 
253, Day 365, Day 533, Day 701, Day 
869, Day 1037 and ET 
Coagulation: PT [sec], PT [INR], aPTT 
Screening, Day 1, Day 29, Day 57, Day 
85, Day 169, Day 197, Day 225, Day 253,  
Day 365, Day 533, Day 701, Day 869, 
Day 1037, and ET 
Pregnancy Test: β-HCG, FSH 
Screening, Day 1, Day 29, Day 57, Day 
85, Day113, Day141, Day 169, Day 197, 
Day 225, Day 253, Day 281, Day 309, 
Day 337, Day 365, Days 393, 421, 449, 
477, 505, 533, 561, 589, 617, 645, 673, 
701, 729, 757, 785, 813, 841, 869, 897, 
925, 953, 981, 1009, 1037, 1065, 1093, 
and 1121 and ET 
Separate summary tables and listings will be produced for each of the separate groups above 
(e.g., separate table for hematology and clinical chemistry etc.); however, urinalysis, and serum 
and urine pregnancy tests will be listed only. The International System of units (SI units) will be 
used for all summary and data listing displays unless otherwise indicated.  
Laboratory data will be summarized descriptively by visit for each laboratory parameter. Both 
observed results and changes from baseline will be summarized for continuous variables. 
Laboratory values will be categorized as clinical grade (low/normal/high) according to normal 
ranges. Shifts from baseline to the last on-treatment value and the worst on-treatment value will 
be presented. For these shift summaries, for the last on-treatment summary only scheduled visits 
will be taken; for the worst on-treatment summaries unscheduled assessments will be included in 
the assessment of worst. Both worst low and worst high will be summarized.  
Laboratory values that are below the limit of quantification will be imputed as the lower-limit of 
quantification, similarly, values above the limit of quantification will be imputed as the upper-
limit of quantification for the summary statistics. But for listings, the values will be presented as 
recorded.  
By-subject listings of all the laboratory parameters will be presented that clearly indicate out of 
normal range values and possible abnormal values for the safety analysis set. 
6.5. 
Vital Signs  
Vital signs including systolic and diastolic blood pressure (mmHg), pulse rate (beats/min), body 
temperature (ºC), Oxygen saturation (SpO2), and respiratory rate (breaths/min) will be evaluated 
at Screening, Day 1, Day29, Day57, Day 85, Day 113, Day 141, Day 169, Day 197, Day 225, 
Day 253, Day 365, Day 533, Day 701, Day 869, and Day 1037 as well as the ET visit where 
applicable. 
For convenience, the conversion for temperature: Temperature (in °C) = (Temperature [in °F]-
32) x (5/9). 


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Absolute results and changes from baseline will be summarized descriptively by visit for each 
parameter, by treatment group and overall. 
6.6. 
12-Lead Electrocardiogram  
The following 12-lead ECG will be performed at Screening, Day 1, Day 85, Day 169, Day 253, 
Day 365, Day 533, Day 701, Day 869, and Day 1037 as well as the ET visit where applicable. 
• Heart rate (bpm) 
• QRS Interval (msec) 
• PR Interval (msec) 
• QT interval (msec) 
• QTcF Interval (msec) 
• Overall Interpretation 
Descriptive summaries will be presented for the ECG parameter values and change from baseline 
by visit for all quantitative measurements. Overall interpretation of ECG assessment will be 
summarized by counts and percentages. QT and QTcF will be categorized as follows, and the 
category based on actual value will be summarized by treatment group at each visit as well as the 
category at each post-baseline visit based on change from baseline per the following criteria: 
Type of Value 
Category 1 
Category 2 
Category 3 
Actual value 
> 450 ms 
> 480 ms 
>500 ms 
Change from Baseline 
> 30 ms 
>60 ms 
 
A by-subject listing of all ECG parameters will be provided. 
6.7. 
Physical Examination  
A detailed physical examination will be performed at Screening visit and targeted physical 
examination will be performed at Day 1, Day 85, Day 169, Day 253, Day 365, Day 533, Day 
701, Day 869, and Day 1037 as well as the ET visit where applicable. 
For the remaining visits, a symptom-driven physical examination will be performed as per the 
investigators’ discretion. Physical examination including details of clinically significant findings, 
will be listed. 
6.8. 
 Columbia-Suicide Severity Rating Scale   
The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and suicidal behavior 
(Posner 2011). The C-SSRS, which uses a semi-structured interview to probe subject responses, 
is administered by an individual who has received training and certification in its administration. 
During the Screening Visit (Day -56), the “baseline” version of the C-SSRS is administered. This 
version assesses suicidal ideation and suicidal behavior during the subject’s lifetime. At all 
subsequent visits, the “since last visit” version is administered. 
Counts and percentage of subjects who experience suicidal ideation, suicidal behavior or neither 
(no ideation or behavior) will be summarized during the long-term extension periods and entire 
study period.  


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The C-SSR instrument consists of 11 Yes/No questions as shown in the table below and is 
grouped by question category, i.e., suicidal ideation questions and suicidal behavior questions. 
Within each type/group the questions are re-ordered by increasing severity. In addition, subjects 
are assessed for any self-injurious behavior without suicidal intent. 
 
C-SSRS Item 
Derivation 
Suicidal ideation 
A “yes” answer to any one of the following five questions. 
1. Wish to be dead. 
2. Non-specific active suicidal thoughts. 
3. Active suicidal ideation with any methods (not plan) without 
intent to act. 
4. Active suicidal ideation with some intent to act, without 
specific plan. 
5. Active suicidal ideation with specific plan and intent. 
Suicidal behavior 
A “yes” answer to any one of the following five questions. 
• 
Preparatory acts or behavior 
• 
Aborted attempt 
• 
Interrupted attempt 
• 
Actual attempt 
• 
Suicidal behavior 
• 
Completed suicide 
Self-injurious behavior without 
suicidal intent 
A “yes” answer to the following question from suicidal behavior 
section on the C-SSRS: Has subject engaged in Non-Suicidal 
Self-Injurious behavior? 
Suicidal Ideation Score 
Is defined as the maximum suicidal ideation category (1-5 on the 
C-SSRS) present at the assessment. A score of 0 is assigned if 
no ideation is present. 
For the overall assessment of suicidal ideation and behavior during the long-term extension 
periods a subject’s worst finding during that period will be used. 
The following tables will be generated at the end of the Continued LTE Period: 
• Counts and Percentage of Subjects with Suicidal Ideation, Suicidal Behavior, and 
Self-Injurious Behavior without Suicidal Intent Based on the C-SSRS by Treatment 
group during the double-blind treatment and LTE period. 
• Counts and Percentage of Subjects with Suicide-Related Treatment Emergent Events 
Based on C-SSRS by Treatment Condition during the Double-Blind Treatment Period 
and LTE period. 
• Shift table in changes in C-SSRS categories from baseline to Week 160. 
• Shift table in Changes in C-SSRS Suicidal Ideation scores from baseline to Week 160 
by Treatment Condition. 
All C-SSRS assessments will be listed. 


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6.9. 
Body Weight, BMI, Breast Imaging and Pregnancies  
 
Bodyweight and BMI  
Bodyweight is assessed at Screening, Day 1, Day 85, Day 169, Day 253, Day 365, Day 533, Day 
701, Day 869 and Day 1037 as well as the ET visit where applicable. Height is assessed once at 
the screening visit. 
The observed bodyweight and BMI values at each visit, along with the change from baseline to 
each post-baseline visit will be summarized descriptively as continuous variables by treatment 
group and overall. The following abnormality categorizations will additionally be summarized 
for body weight at each visit: 
Category 
Change from Baseline 
Category 1 
≥ 10% loss 
Category 2 
≥ 5 - 10% loss 
Category 3 
-5% < Weight change <+5% 
Category 4 
>5 - 10% increase 
Category 5 
≥ 10% increase 
Breast Imaging and Pregnancies 
At the investigator’s discretion, an ultrasound or MRI may be performed for breast imaging in 
female subjects if clinically indicated. These examinations will take place on study days 169, 
365, 701, and 1121.  
Summary statistics will be used to describe the breast imaging results. 
Pregnancy test results will be listed.  
6.10. 
Subgroup Analyses of Safety  
The count and percentage of subjects who report at least one TEAE will be summarized by 
treatment group and PT for the subgroups outlined below.  
• Sex (male, female) 
• Race (White, Non-white) 
• Age at baseline (<65, ≥ 65 years)  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Geographic region (North America, Europe, South America, Asia) 
• Slow vital capacity (80%, >80%) 
• Use of approved background therapy for ALS (Y/N)  
 


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7. 
PHARMACOKINETIC OUTCOMES  
The PK analysis plan will be detailed in a separate PK analysis plan. 
 
 
 
 


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8. 
REFERENCES  
Group, WGEM-AS. Safety and efficacy of edaravone in well-defined patients with amyotrophic 
lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017; 
16(7): 505-512. 
Berry JD, Miller R, Moore DH, Cudkowicz ME, van den Berg LH, Kerr DA, Dong Y, Ingersoll 
EW, Archibald D. The Combined Assessment of Function and Survival (CAFS): a new endpoint 
for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Apr;14(3):162-8. 
doi: 10.3109/21678421.2012.762930. Epub 2013 Jan 17. PMID: 23323713. 
Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The 
ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory 
function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31;169(1-2):13-21. doi: 
10.1016/s0022-510x(99)00210-5. PMID: 10540002. 
Norris FH, Calanchini PR, Fallat RJ, Panchari S, and Jewett B. The administration of guanidine 
in amyotrophic lateral sclerosis. Neurology, Vol 24 | Number 8, August 01, 1974. 
Jenkinson C, Fitzpatrick R, Brennan C, Bromberg M, Swash M. Development and validation of 
a short measure of health status for individuals with amyotrophic lateral sclerosis/motor neurone 
disease: the ALSAQ-40. J Neurol. 1999 Nov;246 Suppl 3:III16-21. doi: 10.1007/BF03161085. 
PMID: 10631656. 
Garcia-Hernandex, A and Rizopoulos, D. %JM: A SAS Macro to Fit Jointly Generalized Mixed 
Models for Longitudinal Data and Time-to-Event Responses. Journal of Statistical Software. 
2018 Apr; 84(12), doi:10.18637/jss.v084.i12. 
Westeneng HJ, Debray TPA, Visser AE, et al. Prognosis for patients with amyotrophic lateral 
sclerosis: development and validation of a personalised prediction model. Lancet Neurol 
2018;17:423-433 
van Eijk RPA, Westeneng HJ, Nikolakopoulos S, et al. Refining eligibility criteria for 
amyotrophic lateral sclerosis clinical trials. Neurology 2019;92:451-460 
van Eijk RPA, Roes KCB, van den Berg LH, Lu Y. Joint modeling of endpoints can be used to 
answer various research questions in randomized clinical trials. J Clin Epidemiol. 2022 
Jul;147:32-39. doi: 10.1016/j.jclinepi.2022.03.009. Epub 2022 Mar 26. PMID: 35346783. 
TRICALS Eligibility, Standard Operating Procedure, version 1.0, 2020, 
https://tricals.shinyapps.io/risk-profile/ 
van Eijk RPA, et al. Innovating Clinical Trials for Amyotrophic Lateral Sclerosis. Challenging 
the Established Order, Neurology Sep 2021, 97 (11) 528-536; DOI: 
10.1212/WNL.0000000000012545 
Westeneng HJ, Debray TPA, Visser AE, et al. Prognosis for patients with amyotrophic lateral 
sclerosis: development and validation of a personalised prediction model. Lancet Neurol 
2018;17:423-433 
Rubika Balendra, Ashley Jones, Naheed Jivraj, Catherine Knights, Catherine M. Ellis, Rachel 
Burman, Martin R. Turner, P. Nigel Leigh, Christopher E. Shaw & Ammar Al- 


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Chalabi (2014) Estimating clinical stage of amyotrophic lateral sclerosis from the ALS 
Functional Rating Scale, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15:3-
4, 279-284, DOI: 10.3109/21678421.2014.897357 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity 
and internal consistency findings from three multisite studies with adolescents and adults. Am J 
Psychiatry. 2011 Dec;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704. PMID: 22193671; 
PMCID: PMC3893686. 
 


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9. 
PROGRAMMING CONSIDERATIONS  
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for 
Windows, Release 9.4 or higher (SAS Institute Inc., Cary, NC, USA). Computer-generated table, 
listing and figure output will adhere to the following specifications.  
1. One SAS program can create several outputs. 
2. Each output will be stored in a separate file. 
3. Output files will be delivered in Word format. 
4. The numbering of TFLs will follow ICH E3 guidance. 
5. All tables and listings will be produced in landscape orientation. Figures use the 
orientation that best facilitates interpretation of the data. 
6. All TFLs will be produced using the Courier New font, size 10. The smallest acceptable 
point size for the Regulatory Authorities is 8. 
7. Headers and footers for figures will be in Courier New font, size 8, which is the smallest 
acceptable point size for the Regulatory Authorities. 
8. TFLs will be in black and white (no color), unless otherwise specified. 
9. Specialized text styles, such as bolding, italics, borders, shading, and color are not used in 
the tables and listings, unless otherwise specified. Color may be used in figures 
containing multiple plotted lines as long as information is not lost when the figure is 
reproduced in monotone. 
10. A mixed case will be used for titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
11. For categorical parameters, all categories will be presented in the table, even if n=0 for all 
treatment groups in each category. For example, the frequency distribution for symptom 
severity would appear as: 
Severity Rating 
n 
Mild 
2 
Moderate 
5 
Severe 
0 
• An Unknown or Missing category will be added to each parameter for which 
information is not available for 1 or more subjects. 
• Unless otherwise specified, the estimated mean, median, Q1 and Q3 for a set of 
values will be printed out to 1 more significant digit than the original values, and 
standard deviations and standard errors will be printed out to 2 more significant digits 
than the original values. The minimum and maximum will report the same significant 
digits as the original values. 
• Confidence intervals are displayed within round brackets and separated by a comma. 
The lower limit is presented first, and the upper limit is presented second. The 
confidence interval is placed either beside or below the corresponding estimate. The 
estimate and the confidence limits are presented using the same degree of precision. 


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• P-values will be output in the format: ‘0.xxx’, where xxx is the value rounded to 3 
decimal places. Every p-value less than 0.001 will be presented as <0.001. If the p-
value is returned as >0.999, then present as >0.999. 
• Percentage values will be printed to one decimal place. Unless otherwise noted, for 
all percentages, the number of subjects in the analysis population for the treatment 
group who have an observation will be the denominator. Percentages after zero 
counts will not be displayed and percentages equating to 100% will be presented as 
100%, without decimal places.  
• Tabular display of data for medical history, prior/concomitant medications, and all 
tabular displays of adverse event data will be presented by the body system, treatment 
class, or SOC with the highest occurrence in the active treatment group in decreasing 
order, assuming all terms are coded. Within the body system, drug class and SOC, 
medical history (by preferred term), drugs (Medication class), and adverse events (by 
preferred term) will be displayed in decreasing order. If incidence for more than 1 
term is identical, they will then be sorted alphabetically.  
• Missing descriptive statistics or p-values which cannot be estimated will be reported 
as ‘-’ Missing values for numeric and character variables are displayed as blanks in 
data listings. 
• The percentage of subjects will normally be calculated as a proportion of the number 
of subjects assessed in the relevant treatment group (or overall) for the analysis 
population presented. However, careful consideration is required in many instances 
due to the complicated nature of selecting the denominator, usually the appropriate 
number of subjects exposed. Details will be described in footnotes or programming 
notes, as necessary.  
• If no relevant data are available at all for a display, then present “No data to Report”. 
 


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10. 
MOCK TABLES, LISTINGS, AND GRAPHS  
The study tables, listings and graphs shells will be provided in a separate document. 


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11. 
APPENDIX 1: SCHEDULE OF ASSESSMENT  
Schedule of Assessments for Screening and Double-Blind Treatment Period (Part A) 
 
 
 


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Schedule of Assessments for Long-Term Extension Period (Part B) 
 
 


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Schedule of Assessments for Continued Long-Term Extension Period (Part C) 
 


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12. 
APPENDIX 2: MISSING DATE AND MISSING ALSFRS-R PROCEDURE  
Prior/Concomitant Medications 
For the purpose of assessing whether a medication is prior or concomitant, if a medication has a 
completely missing start date it will be considered a prior medication, and if a medication has a 
completely missing stop date it will be considered a concomitant medication. If a partial start or 
stop date occurs, the following imputation process will be implemented: 
Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for 
Stop Date 
Day missing, month 
and year present 
• 
Month and/or year different to month and year of first 
study drug dose: Impute day with “01” 
• 
Month and/or year same as month and year of first 
study drug dose: Impute day with same day as first 
dose of study drug. 
Impute day with last 
day of the month 
Day and month 
missing, year 
present 
• 
Year different to year of first study drug dose: Impute 
day and month with “01JAN” 
• 
Year same as year of first study drug dose: Impute 
month and day with same month and day as first dose 
of study drug. 
Impute day and 
month with 
“31DEC” 
Month missing, day 
and year present 
• 
Year different to year of first study drug dose: Impute 
month with “JAN” 
• 
Year same as year of first study drug dose: Impute 
month with same month as first dose of study drug. 
Impute with “DEC” 
Caveats 
• 
If any imputed start date leads to a start date that is after the stop date, then 
the start date will be imputed with the date of the stop of medication. 
• 
No stop date will be imputed if the treatment is ongoing. 
Adverse Events 
For the purpose of assessing whether an AE is treatment emergent, if an AE has a completely 
missing start and stop date, it will be considered treatment emergent; if the stop date is not 
missing, but the start date is completely missing, it will be considered treatment emergent unless 
the stop date occurs prior to the first dose of study drug.  
For assessing treatment emergence or for calculation of duration of AE, if a partial start or stop 
date occurs, the following imputation process will be implemented: 
Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for Stop 
Date 
Day missing, month 
and year present 
• 
Month and/or year different to month and year of 
first study drug dose: Impute day with “01”. 
• 
Month and/or year same as month and year of first 
study drug dose: Impute day with same day as first 
dose of study drug. 
Impute day with last 
day of the month 
Day and month 
missing, year 
present 
• 
Year different to year of first study drug dose: 
Impute day and month with “01JAN”. 
• 
Year same as year of first study drug dose: Impute 
month and day with same month and day as first 
dose of study drug.  
Impute day and 
month with “31DEC” 


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Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for Stop 
Date 
Month missing, day 
and year present 
• 
Year different to year of first study drug dose: 
Impute month with “JAN”. 
• 
Year same as year of first study drug dose: Impute 
month with same month as first dose of study drug. 
Impute with “DEC” 
Caveats 
• 
If any imputed start date leads to a start date that is after the stop date, then 
the start date will be imputed with the date of the stop of AE. 
ALSFRS-R incomplete / missing data 
This section describes visit level imputations performed prior to the multiple imputation 
procedure.  
If 1 item is missing within a domain (e.g. Bulbar), then the domain item will be inputted using 
the following formula:  
Imputed domain score = mean of non-missing items multiplied by 3. 
If item 12 on the ALSFRS score is missing, and the patient is not reported as having received 
non-invasive ventilation at the time of the visit (concomitant procedures CRFs) then item 12 will 
be imputed as a 4. 
Total Score: 
If a whole domain is missing or two items are missing, then the total ALSFRS-R total score will 
be imputed from the remaining 3 domains as the mean of all answered item scores in the 3 
domains x 12. Total score will not be imputed if more than 1 domain has 2 or more missing 
items.  


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13. 
APPENDIX 3: TRICALS RISK PROFILE CALCULATOR  
TRICALS Risk Profile Calculator, v2.01 (2022-02-20), Source: https://tricals.shinyapps.io/risk-
profile/ 
The TRICALS Risk Profile is a prognostic summary value of seven patient characteristics and 
can be used for patient selection in clinical trials. The Risk Profile Calculator estimates the 
TRICALS Risk Profile. 
References 
1. Westeneng HJ, Debray TPA, Visser AE, et al. Prognosis for patients with amyotrophic 
lateral sclerosis: development and validation of a personalised prediction model. Lancet 
Neurol 2018;17:423-433 
2. van Eijk RPA, Westeneng HJ, Nikolakopoulos S, et al. Refining eligibility criteria for 
amyotrophic lateral sclerosis clinical trials. Neurology 2019;92:451-460 
3. van Eijk RPA, Nikolakopoulos S, Roes KCB et al. Innovating clinical trials for 
amyotrophic lateral sclerosis: challenging the established order. Neurology 2021 
Estimation of the TRICALS Risk Profile 
The TRICALS Risk Profile is based the ENCALS (European Network to Cure ALS) survival 
prediction model, a cross-validated model to predict the composite endpoint death or respiratory 
insufficiency based on data of 11,475 patients with ALS. Patient selection is based on the linear 
predictor of the model and not on the absolute risk predictions as (1) the baseline hazard 
significantly varies across countries, and (2) the ENCALS model estimates the absolute survival 
probability from disease onset rather than trial enrolment. The linear predictor of the model, 
hereafter stated as TRICALS Risk Profile, can be conceptualized as a relative summary of 
prognostic information. The risk profile indicates how patients compare to each other (i.e. who is 
faster or slower progressing than average) without estimating the absolute survival time or 
probability. 
The TRICALS Risk Profile is calculated as: 
𝑹𝑹𝑹𝑹𝑹𝑹𝑹𝑹 𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑𝒑= (0.474 × 𝑉𝑉𝑉𝑉𝑡𝑡) - (2.376 × 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑡𝑡) - (1.839 × ∆𝐹𝐹𝑅𝑅𝐹𝐹𝑡𝑡) – (0.264 × 𝐴𝐴𝑔𝑔𝐴𝐴𝑡𝑡) + 
(0.271 × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵) + (0.238 × 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷) + (0.415 × 𝐹𝐹𝐹𝐹𝐹𝐹)  
Where t represents the non-linear transformations for continuous variables, VC the vital capacity 
(in %predicted), Age is age at onset in years, diagnostic delay (DxDelay) in months, FTD the 
presence of frontotemporal dementia and ΔFRS (points per month) is the progression rate of the 
ALS functional rating scale (ALSFRS-R). 
𝐴𝐴𝑔𝑔𝐴𝐴𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡. = ቀ
𝐴𝐴𝐴𝐴𝐴𝐴 𝑎𝑎𝑎𝑎 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜
100
ቁ
−2
    
 
 
 
 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡. = ቀ
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
10
ቁ
− 1
2 + ln ቀ
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
10
ቁ 
∆𝐹𝐹𝑅𝑅𝐹𝐹𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡. = (∆𝐹𝐹𝑅𝑅𝐹𝐹+ 0.1)− 1
2  
 
 
 
𝑉𝑉𝑉𝑉𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡. = ቀ
𝑉𝑉𝑉𝑉
100ቁ
−1
+ ቀ
𝑉𝑉𝑉𝑉
100ቁ
− 1
2 
∆𝐹𝐹𝑅𝑅𝐹𝐹𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡= ൫48 −𝐹𝐹𝑅𝑅𝐹𝐹𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑖𝑖𝑠𝑠𝑠𝑠൯÷ 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 


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PTC857-CNS-001-ALS 
Statistical Analysis Plan 
V1.0 
PTC Therapeutics - Confidential 
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14. 
APPENDIX 4: SAS CODE  
Mixed Model Repeated Measure 
The following is example SAS syntax for producing least squares estimates, for the MMRM 
analysis: 
proc mixed data=ALSFRS_LONG method=reml; 
class ID TRTRND(ref=”0”) STADCARE(ref=”3”) CHANGE(ref=”0”) TIME(ref=”4”); 
model DELFRS = TIME VALUEBL CHANGE STADCARE TIME*TRTRND TIME*VALUEBL TRP 
TIME*TRP / ddfm=kr solution; 
repeated TIME / type=UN subject=id; 
lsmeans trtrnd / pdiff=control('0' '5')cl; 
run; 
where id is the subject identifier, trtrnd is the randomized treatment arm, stadcare is a 
factor variable for the SoC stratification group at baseline, change is the amount of change in 
the subject’s ALSFRS-R score during the Screening Period, time is the categorical variable for 
study visit, Valuebl is the baseline ALSFRS-R score, TRP represents the TRICALS risk profile 
at baseline, and the response variable DELFRS is the change from baseline in ALSFRS-R score.: 
ANCOVA with Multiple Imputation 
SAS code for the ALSFRS-R endpoint at 24 weeks: 
proc mi data = ALSFRS_DATA out = ALSFRS_DATA_OUT  
seed = 20221219 nimpute = 100 noprint; 
class trtrnd stadcare change sex; 
var trtrnd Valuebl change stadcare sex age trp  
ALSFRS_R_4 ALSFRS_R_8 ALSFRS_R_12 ALSFRS_R_16 ALSFRS_R_20 ALSFRS_R_24; 
fcs reg(ALSFRS_R_4 ALSFRS_R_8 ALSFRS_R_12 ALSFRS_R_16 ALSFRS_R_20 
ALSFRS_R_24); 
run; 
The next set of code performs the analyses for the ALSFRS-R 24-week endpoint: 
proc reg data=ALSFRS_DATA_OUT  utset=outreg covout noprint; 
model ALSFRS_24 = trtrnd Valuebl change stadcare TRP; 
by _Imputation_; 
run; 
This step will combine the results: 
proc mianalyze data=outreg; 
modeleffects Intercept trtrnd Valuebl change stadcare TRP; 
run; 
 
Survival Analysis 
The following is sample code for producing a Kaplan-Meier survival plot: 
proc lifetest data=survdata plots=survival(cl cb=hw test atrisk); 
time time*status(0); 
strata trtrnd / test=logrand adjust=sidak; 
run; 


PTC Therapeutics  
PTC857-CNS-001-ALS 
Statistical Analysis Plan 
V1.0 
PTC Therapeutics - Confidential 
Page 47 of 49 
where time is the time of event or censoring, status is the variable indicating censored (1) or 
not censored (0), i.e., death observed, trtrnd is the treatment allocation variable and is the 
TRP TRICALS risk score. The follow code runs a Cox regression model: 
 
proc phreg data=survdata atrisk plots(cl)=(survival cumhaz); 
class trtrnd stadcare TRP;  
model time*status(0)= trtrnd change stadcare / rl=pl; 
run; 
where time is the time of event or censoring, status is the variable indicating censored (1) or 
not censored (0), i.e., death observed, and trtrnd is the treatment allocation variable. 


PTC Therapeutics  
PTC857-CNS-001-ALS 
Statistical Analysis Plan 
V1.0 
PTC Therapeutics - Confidential 
Page 48 of 49 
15. 
APPENDIX 5. MAPPING ALSFRS-R TO KING’S STAGE  
The King’s clinical staging criteria for ALS is defined as a count of involved central nervous 
system (CNS) regions (Stage 1, 2 or 3), requirement for gastrostomy or noninvasive ventilation 
(Stage 4) and death (Stage 5).  
Stage 
Definition 
1 
Functional involvement of one CNS region (symptom onset) 
2 
Functional involvement of two CNS regions 
3 
Functional involvement of three CNS regions 
4 
Need for gastrostomy (4A) or non-invasive ventilation (4B) 
5 
Death 
Per the study’s eligibility criteria, there will be no subjects with Stages 4 or 5 
1. Bulbar region is involved: If the subject dropped any points on any of the three ALSFRS-
R questions regarding speech (question 1), salivation (question 2) or swallowing 
(question 3). 
2. Upper limb region is involved: If the subject dropped any points on either of the two 
ALSFRS-R questions regarding hand function, which are handwriting (question 4) and 
ability to cut food and handle utensils (question 5A). 
3. Lower limb region is involved: If the subject dropped any points on the ALSFRS-R 
question regarding ability to walk (question 8). 
4. Stage 4A attained: If question 5B rather than question 5A, which is only answered by 
patients without a gastrostomy. 
5. Stage 4B reached: If a patient scored 0 points on question 10 or less than 4 points on 
question 12. 


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PTC857-CNS-001-ALS 
Statistical Analysis Plan 
V1.0 
PTC Therapeutics - Confidential 
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16. 
REVISION HISTORY  
Version Number 
Date 
Description 
1.0 
25 SEPTEMBER 2024 
Initial release