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

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)

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

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: PTC857; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 336
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1015ABR
    • Iadin Srl.
  • Ciudad Autonoma de Buenos Aires, Argentina, CP 1221
    • Hospital Ramos Mejía
  • Buenos Aires
    • Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina, C1023AAB
      • STAT Research S.A.
• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
    • Southport, Queensland, Australia, 4215
      • Gold Coast Hospital
  • Victoria
    • Caulfield South, Victoria, Australia, 3162
      • Calvary Health Care Bethlehem
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
• Belgium
  • Gent, Belgium, 9000
    • AZ Sint-Lucas Gent
  • Leuven, Belgium, 3000
    • UZ Leuven
• Czechia
  • Brno, Czechia, 62500
    • University hospital Brno, Department of Neurology
  • Prague 6, Czechia, 160 00
    • FORBELI s.r.o.
• France
  • Bordeaux Cedex, France, 33076
    • CHU de Bordeaux
  • Bron Cedex, France, 69677
    • Hopital Neurologique Pierre Wertheimer
  • Clermont-Ferrand, France, 63000
    • Chu Gabriel Montpied
  • Lille Cedex, France, 59037
    • CHRU Lille - Hôpital Roger Salengro
  • Limoges, France, 87000
    • CHU Dupuytren 1 Limoges
  • Montpellier, France, 34295
    • CHU Gui de Chauliac (Pharmacie Saint-Eloi & Gui de Chauliac, Hopital Saint-Eloi)
  • Nice, France, 06200
    • CRMR SLA - MNM du CHU de Nice
• Germany
  • Berlin, Germany, 13353
    • Charite - Universitatsmedizin - Berlin
  • Hannover, Germany, 30625
    • Hannover Medical School
  • Jena, Germany, 7747
    • University Hospital Jena
  • Lubeck, Germany, 23538
    • Universitaetsklinikum Schleswig-Holstein (UKSH) Campus Luebeck, Klinik fuer Neurologie, Praezisionsneurologie
  • Ulm, Germany, 89081
    • University of Ulm, Dept. of Neurology
• Italy
  • Brescia, Italy, 25123
    • Centro Clinico Nemo Brescia
  • Milano, Italy, 20138
    • Istituti Clinici Scientifici Maugeri IRCCS
  • Milano, Italy, 20149
    • Istituto Auxolgoico Italiano
  • Modena, Italy, 41126
    • Azienda Ospedaliero Universitaria Di Modena
  • Novara, Italy, 28100
    • Maggiore della Carita University Hospital, Neurology department, ALS center
  • Palermo, Italy, 90127
    • ALS Clinical Research Center, University Hospital Policlinico "P Giaccone"
  • Pavia, Italy, 27100
    • IRCCS Fondazione Mondino - Reparto Neuroncologia/Neuroinfiammazione
  • Roma, Italy, 00161
    • Policlinico Umberto I
  • Torino, Italy, 10126
    • AOU Citta Della Salute e Scienza
• Japan
  • Japanese City, Japan
    • PTC Clinical Site
• Netherlands
  • Utrecht, Netherlands, 3584 CW
    • UMC Utrecht
• Poland
  • Warsaw, Poland, 02-473
    • City Clinic Research Sp. Z o.o
  • Warszawa, Poland, 01-684
    • Centrum Medyczne Neuro Protect
• Spain
  • Barcelona, Spain, 08035
    • Unidad Neuromuscular. Servicio de Neurologia Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08041
    • H. St Pau
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La Fe
• Sweden
  • Malmo, Sweden, SE-211 24
    • Skanes universitetssjukhus, VE Neurologi
  • Umea, Sweden, 90185
    • Norrlands universitetssjukhus Neurologens Forskningsavdelning
• United States
  • California
    • Orange, California, United States, 92868
      • UC Irvine Health ALS and Neuromuscular Center
    • San Francisco, California, United States, 94109
      • Forbes Norris MDA/ALS Research Center at California Pacific Medical Center
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital, Phil Smith Neuroscience Institute
    • Tampa, Florida, United States, 33612
      • University of South Florida - Carol and Frank Morsani Center for Advanced Healthcare
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Kansas
    • Kansas City, Kansas, United States, 66205
      • University of Kansas Medical Center (KUMC) - Landon Center on Aging
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System Department of Neurology
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Neurology Associates, P.C. / Somnos Clinical Research
    • Omaha, Nebraska, United States, 68198-8440
      • University of Nebraska Medical Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Brain and Spine Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Lewis Katz School of Medicine at Temple Universtiy
  • Texas
    • Austin, Texas, United States, 78759
      • National Neuromuscular Research Institute
    • Houston, Texas, United States, 77030
      • Nerve and Muscle Center of Texas
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• ALS with preserved function, defined as:

  1. Onset of the first symptom leading to the diagnosis of ALS ≤24 months at the time of the initial Screening Visit
  2. Revised EL Escorial criteria of either:

  (i) Clinically definite ALS (ii) Clinically probable ALS

• A total ALSFRS-R score of at least 34 at the start of the Screening Period
• No significant respiratory compromise as evidenced by slow vital capacity ≥60% at the start of the Screening Period
• All chronic concomitant medications (both prescription and over the counter), and non-pharmacologic therapy regimens, excluding standard-of-care therapy riluzole, edaravone, or sodium phenylbutyrate/taurursodiol, should be stable and unchanged from 14 days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study
• Female participants must have a negative breast cancer imaging screening status (not considered clinically abnormal and/or requiring further evaluation/treatment) within 6 months prior to the Screening Visit, or during the Screening Period.
• Standard-of-care therapy for the treatment of ALS (riluzole, edaravone, or sodium phenylbutyrate/taurursodiol) should be stable and unchanged from 30 (-3) days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study.

Key Exclusion Criteria:

• Females who are pregnant or nursing or plan to become pregnant during the study
• Participants with clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular/ischemic disease or any other condition that, in the opinion of the investigator would jeopardize the safety of the participant or impact the validity of the study results
• Any clinically significant medical or psychiatric condition or medical history that, in the opinion of the investigator or the medical monitor, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant
• Current participation in any other investigational study with an investigational product or participation within 30 days prior to the start of the Screening Period or 5 half-lives of the previously taken investigational drug, whichever is longer
• Participant has previously received PTC857
• Participant is receiving a combination of edaravone and sodium phenylbutyrate/taurursodiol treatment, where applicable, within 30 days prior to the start of the Screening Period
• For female participants, any past medical history of breast cancer, regardless of remission status, or any first degree relative with history of breast cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combined Assessment of Function (ALS Functional Rating Scale-Revised [ALSFRS-R]) and Survival (CAFS) Rank After 24 Weeks of Treatment (Intention-to-Treat [ITT] 1 Analysis Population)	The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 [better], 0 [tie], -1 [worse]), and summed scores were ranked, from 1 to 306 (ITT1 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. Multiple imputation was used to impute participants with missing ALSFRS-R score at Week 24. A higher rank was considered a better outcome. Least square (LS) means and standard error (SE) were calculated using analysis of covariance (ANCOVA) model.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combined Assessment of Function (ALSFRS-R) and Survival (CAFS) Rank After 24 Weeks of Treatment (ITT2 Analysis Population)	The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 [better], 0 [tie], -1 [worse]), and summed scores were ranked, from 1 to 334 (ITT2 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. A higher rank was considered a better outcome. LS mean and SE were calculated using ANCOVA model.	Week 24
Change From Baseline in ALSFRS-R Score at Week 24 (ITT1 Analysis Population)	The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the participant's 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 was 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. LS mean and SE were calculated using mixed model repeated measures (MMRM).	Baseline, Week 24
Change From Baseline in ALSFRS-R Score at Week 24 (ITT2 Analysis Population)	The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the participant's 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 was 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. LS mean and SE were calculated using MMRM.	Baseline, Week 24
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A TEAE was defined as an AE that began after the first administration of study drug or any existing AEs that worsened after the first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.	Day 1 through Week 24
Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 24	The SVC is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent of predicted SVC is reported. LS mean and SE were calculated using MMRM.	Baseline, Week 24
Change From Baseline in Modified Norris Scale Total Score at Week 24	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 was rated in 4 ordinal categories, corresponding to the following values and ratings or functional scores: normal (3 points), somewhat impaired (2 points), inadequate (1 point), and "cannot do at all" (0 points). The total score was calculated by summing all the scales, ranging from 0 (worst) to 102 (best) where higher scores indicated better functional abilities. LS mean and SE were calculated using MMRM.	Baseline, Week 24
Overall Survival Rate	Overall survival rate was defined as percentage of participants who were alive at given timepoint. Overall survival was 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.	Baseline to Week 24
Overall Survival	Overall survival was 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.	Baseline to Week 24
Change From Baseline in ALS Assessment Questionnaire (ALSAQ-40) Total Score at Week 24	The ALSAQ-40 is a disease-specific measure of health-related quality of life (QOL) for ALS. The ALSAQ-40 is comprised of 40 questions measuring 5 discrete dimensions of health status that are affected by the disease: physical mobility (10 items); activities of daily living and independence (10 items); eating and drinking (3 items); communication (7 items); emotional reactions (10 items). Participants were asked to indicate the frequency of each event by selecting one of 5 options (Likert scale: 0-4): never/rarely/sometimes/often/ always or cannot do at all. The total score ranging from 0 (no impairment) to 160 (severe impairment) was calculated by adding the 5 domain scores. A lower score indicates a better health state. LS mean and SE were calculated using MMRM.	Baseline, Week 24
Change From Baseline in Neurofilament Light Chain (NfL) Activity at Week 24	The NfL is a marker of axonal degeneration and is robustly elevated in the blood of many neurological and neurodegenerative conditions.	Baseline, Week 24
Area Under the Concentration-time Curve From 0 to Measurable Timepoint (AUC0-t) of Utreloxastat in Plasma		Day 1 and Day 29
Maximum Observed Concentration (Cmax) of Utreloxastat in Plasma		Day 1 and Day 29
Mean Concentration of Utreloxastat in Cerebrospinal Fluid (CSF)		Day 1 and Day 29

Collaborators and Investigators

• Sponsor: PTC Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2022
• Primary Completion (Actual): September 26, 2024
• Study Completion (Actual): January 30, 2025

Study Registration Dates

• First Submitted: April 21, 2022
• First Submitted That Met QC Criteria: April 21, 2022
• First Posted (Actual): April 27, 2022

Study Record Updates

• Last Update Posted (Actual): August 1, 2025
• Last Update Submitted That Met QC Criteria: July 15, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: PTC857-CNS-001-ALS; 2021-006511-29 (EudraCT Number); 2023-510317-26-00 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No