This study has been transitioned to CTIS with ID 2023-510317-26-00 check the CTIS register for the current data. To evaluate the efficacy of PTC857 in reducing disease progression in subjects with amyotrophic lateral sclerosis (ALS)
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the change from baseline in ALS Functional Rating
Scale-Revised (ALSFRS-R) in the Intent-To-Treat 1 (ITT1) Analysis Set after 24
weeks of treatment.
Secondary outcome
The secondary endpoints of the study are the following:
1. Change from baseline in ALSFRS-R in the Intent-to-Treat 2 (ITT2) Analysis
Set after 24 weeks of treatment
2. Safety and tolerability of PTC857 as measured by the severity and number of
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
3. Change from baseline in respiratory function as assessed by pulmonary
function tests (PFTs) after 24 weeks of treatment
4. Change from baseline in motor/limb and bulbar function as assessed by the
Modified Norris Scale after 24 weeks of treatment
5. Change from baseline in neuropsychological function as assessed by the ALS
Cognitive Behavioral Screen (ALS CBS) after 24 weeks of treatment
6. Survival as assessed by rate of and length of time to needing respiratory
support/intubation and/or death
7. Survival and functional change as assessed by the Combined Assessment of
Function and Survival (CAFS) after 24 weeks of treatment
8. Quality of life as assessed by ALSAQ-40 after 24 weeks of treatment
9. Plasma PK and cerebrospinal fluid (CSF) exposure of PTC857
Background summary
Currently, there is no cure for amyotrophic lateral sclerosis (ALS), and
treatment of patients with ALS is largely limited to management of symptoms.
The only approved treatments, in some countries, for ALS are riluzole (Rilutek,
administered orally; Tiglutik, oral solution; and Exservan, oral film) and
edaravone (Radicava, administered intravenously). 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. PTC857 (also
known as utreloxastat) is an orally bioavailable small molecule (a proprietary
cyclohexadiene-dione compound) being developed by PTC Therapeutics, Inc. for
the treatment of neurological diseases characterized by high levels of
oxidative stress and mitochondrial pathology, including 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. 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 Study
PTC857-CNS-002-HV, a Phase 1, 2-period, crossover, relative bioavailability
study of 2 formulations in healthy volunteers. There were no TESAEs, no TEAEs
leading to discontinuation of PTC857, and no TEAEs leading to death. Exposure
to PTC857 in Studies PTC857-CNS-001-PD and PTC857CNS002-HV included 84 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.
Study objective
This study has been transitioned to CTIS with ID 2023-510317-26-00 check the CTIS register for the current data.
To evaluate the efficacy of PTC857 in reducing disease progression in subjects
with amyotrophic lateral sclerosis (ALS)
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. The study consists of 5 periods: Screening, Treatment, LTE,
Continued LTE, and Follow-Up.
Intervention
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.
Study burden and risks
Drugs that work through the brain and nervous system can potentially cause
changes in mood and thoughts, including suicidal feelings
The lumbar puncture procedure could cause headache, nausea and vomiting,
dizziness, double vision, and ringing ears.
It is possible that the subject might experience new side effects that have not
been observed in the prior animal or human studies. For example, allergic
reactions or interactions with another medication could occur.
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.
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.
Benefit - Overall, PTC857 has been safe and well tolerated in subjects in the 2
studies of healthy volunteers. There is no guarantee that ALS subjects will
receive personal benefit from participating in this study. But based on the
in-vitro studies, the protective activity and potency of PTC857 against
ferroptotic cell death in human astrocytes were demonstrated. In an ALS mouse
model study, PTC857 was demonstrated to protect innervation of the
neuromuscular junction within the lumbar spinal cord. 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.
CORPORATE COURT 100
SOUTH PLAINFIELD, NJ 07080
US
CORPORATE COURT 100
SOUTH PLAINFIELD, NJ 07080
US
Listed location countries
Age
Inclusion criteria
1. Males or females aged between 18 and 80 years at the time of the initial
Screening Visit
2. ALS with preserved function, defined as:
a. Onset of the first symptom leading to the diagnosis of ALS < 24 months at
the time of the initial Screening Visit
b. Revised EL Escorial criteria of either:
(i) Clinically definite ALS
(ii) Clinically probable ALS
3. A total ALSFRS-R score of at least 34 at the start of the Screening Period
4. No significant respiratory compromise as evidenced by slow vital capacity
60% at the start of the Screening Period
5. 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. 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
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
Exclusion criteria
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 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 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
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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-510317-26-00 |
| EudraCT | EUCTR2021-006511-29-NL |
| ClinicalTrials.gov | NCT05349721 |
| CCMO | NL81540.041.22 |