brain disease Huntington's disease
Conditions
Interventions
PTC518 tablets will be administered orally once a day. The PTC518 active dosing
arms will be 5 mg and 10 mg until the DSMB authorizes initiation of a 20 mg
dose as specified in the DSMB Charter.
Sponsors
PTC Therapeutics, Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Ambulatory male or female patient aged 25 years and older, inclusive 2. Subject is willing and able to provide informed consent and comply with all protocol requirements 3. Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length from 42 to 50, inclusive. CAG repeat length may be determined analytically through amplification. Eligibility for HD-ISS Stage 2 Group (Parts A, B, and C) 4. A UHDRS IS score of 100 5. A UHDRS Total Functional Capacity (TFC) score of 13 6. A score between 0.18 and 4.93 inclusive on the normed version of the HD prognostic index (PINHD) Eligibility for HD-ISS Mild Stage 3 Group (Parts D, E, and F) 9. A UHDRS TFC score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS score of
Exclusion criteria
Exclusion criteria: 1. Inability or unwillingness to swallow oral tablets 2. Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or anytime over the duration of this study, including RNA- or DNA-targeted HD-specific investigational agents, (such as antisense oligonucleotides), cell transplantation, or any other experimental brain surgery 3. Any history of gene therapy exposure for the treatment of HD 4. Participation in an investigational study or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation, etc) within 90 days prior to Screening or anytime over the duration of this study 5. Presence of an implanted deep brain stimulation device. Observational studies (such as ENROLL-HD) are not exclusionary. 6. Family history of early onset cataracts or presence of significant cataracts at Baseline. Visually significant cataract is defined as any Lens Opacity Classification System II grading >=2, Best Corrected Visual Acuity <20/40, cataract as the primary cause of vision impairment, and self-reported vision of fair or worse. 7. Brain and spinal pathology that may interfere with CSF homeostasis and circulation, increased intracranial pressure (including presence of a shunt for the drainage of CSF or an implanted central nervous system catheter), malformations, and/or tumors 8. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study 9. At significant risk of suicide as measured by the C-SSRS Baseline version with a moderate risk rating or higher score 10. Risk of a major depressive episode, psychosis, confusional state, or violent behavior as assessed by the investigator 11. Any medical history of brain or spinal disease that would interfere with the lumbar puncture process or safety assessments 12. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases 13. Any medical history or condition that would interfere with the ability to complete the protocol-specified assessments (eg, implanted shunt, conditions precluding magnetic resonance imaging scans) 14. Antidepressant, antipsychotic, or benzodiazepine use, unless receiving a stable dose for at least 6 weeks prior to Screening and with a dose regimen that is not anticipated to change during the study. Benzodiazepine use for sedation for study-related procedures during the course of the study is permitted. 15. History of illicit/illegal drug use, or alcohol use in the high-risk category of risk drinking levels according to the World Health Organization for a duration of 1 month or longer that in the opinion of the investigator could compromise the interpretability of study results 16. Clinically significant medical condition, which in the opinion of the investigator could adversely affect the safety of the subject or impair the assessment of study results (eg, inability to fast or any known hypersensitivity to PTC518 or its excipients) 17. Current significant renal impairment defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 at Screening 18. Current hepatic impairm
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety Endpoints: • Safety profile as characterized by treatment-emergent adverse events (TEAEs), laboratory abnormalities, neurofilament light chain (NfL) levels in plasma and CSF, electrocardiogram (ECG), vital signs, slit lamp eye examination, Total Neuropathy Score - Clinical (TNSc), Columbia Suicide Severity Rating Scale (C SSRS), and physical examination Primary Efficacy Endpoint: • Change from Baseline in blood tHTT protein at Month 3 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Endpoints: • Change from Baseline in caudate volume as assessed via vMRI at Month 12 (key secondary) • Change from Baseline in cUHDRS scores at Month 12 • Change from Baseline in blood tHTT protein at Month 12 • Change from Baseline in CSF mHTT protein at Month 12 • Change from Baseline in blood mHTT protein at Month 12 | — |
Countries
Netherlands
Outcome results
None listed