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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

PTC Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

7 Feb 2023 → 26 Nov 2024

Decision date (initial)

2024-04-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

PTC Therapeutics, Inc

External identifiers

EU CT number

2023-510317-26-00

EudraCT number

2021-006511-29

ClinicalTrials.gov

NCT05349721

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic

To evaluate the efficacy of PTC857 in reducing disease progression in subjects with amyotrophic lateral sclerosis (ALS)

Secondary objectives 8

1. Safety and tolerability of PTC857
2. Respiratory function in subjects randomized to PTC857 versus placebo
3. Motor/limb and bulbar function in subjects randomized to PTC857 versus placebo
4. Survival in subjects randomized to PTC857 versus placebo
5. Quality of life via 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) in subjects randomized to PTC857 versus placebo
6. Pharmacokinetics (PK) of PTC857
7. Evaluate the efficacy of PTC857 in reducing disease progression in subjects with ALS with any baseline rate of functional decline
8. Effects on plasma neurofilament light chain (NfL) activity in subjects randomized to PTC857 versus placebo

Conditions and MedDRA coding

Amyotrophic Lateral Sclerosis

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

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. 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
6. Female subjects must have a negative breast cancer imaging screening status (not considered clinically abnormal and/or requiring further evaluation/treatment) within 6 months prior to the Screening Visit or during the Screening Period
7. Standard-of-care therapy for the treatment of ALS (riluzole, edaravone, or sodium phenylbutyrate/taurursodiol) should be stable and unchanged from 30 (-3) days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study. 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.
8. 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
9. 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
10. 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
11. 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
12. Males must refrain from sperm donations from the start of the Screening Period through 90 days after the last dose of the study drug
13. Willing and able to comply with all protocol procedures

Exclusion criteria 13

1. Females who are pregnant or nursing or plan to become pregnant during the study
2. Moderate or worse renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min
3. 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
4. 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
5. 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
6. 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
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 longe
8. Subject has previously received PTC857
9. 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
10. For female subjects, any past medical history of breast cancer, regardless of remission status, or any first degree relative with history of breast cancer
11. History of allergies or adverse reactions to any of the excipients in the study drug formulation
12. 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)
13. Subject is taking a non-approved form of sodium phenylbutyrate and/or taurursodiol for the treatment of ALS

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 10

1. Change from baseline in ALSFRS-R in the ITT1 Analysis Set after 24 weeks of treatment
2. Safety and tolerability of PTC857 as measured by the severity and number of TEAEs and TESAEs, and change in clinical laboratory tests, physical examination, vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS), and 12-lead electrocardiograms (ECGs) during the Treatment Period
3. Change from baseline in slow vital capacity as assessed by pulmonary function tests (PFTs) after 24 weeks of treatment
4. Change from baseline in motor/limb and bulbar function as assessed by the Modified Norris Scale after 24 weeks of treatment
5. 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
6. Change from baseline in ALSFRS-R in the ITT2 Analysis Set after 24 weeks of treatment
7. Survival as assessed by rate of and length of time to death
8. Quality of life as assessed by ALSAQ-40 after 24 weeks of treatment
9. Change from baseline in plasma NfL activity after 24 weeks of treatment
10. Plasma PK and cerebrospinal fluid (CSF) exposure of PTC857

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

PTC Therapeutics Inc.

Sponsor organisation

PTC Therapeutics Inc.

Address

500 Warren Corporate Center Drive

City

Warren

Postcode

07059

Country

United States

Scientific contact point

Organisation

PTC Therapeutics Inc.

Contact name

Aaron Tansy

Public contact point

Organisation

PTC Therapeutics Inc.

Contact name

Aaron Tansy

Third parties 5

Sponsor responsibilities

Article 77 compliance

PTC Therapeutics Inc.

Contact point sponsor

PTC Therapeutics Inc.

Article 77 implementation

PTC Therapeutics Inc.

Locations

11 EU/EEA countries · 39 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 183 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications