E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Huntington’s disease is an illness caused by a faulty gene in the DNA. Huntington’s affects the body’s nervous system – which can cause changes in movement, learning, thinking and emotions. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10070668 |
E.1.2 | Term | Huntington's disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• Evaluate the safety of PTC518 compared with placebo in subjects with Huntington's Disease • Evaluate the pharmacodynamic (PD) effects of PTC518 through the reduction in blood total huntingtin (tHTT) protein levels |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives: • Assess the effects of PTC518 on change in caudate volume via volumetric magnetic resonance imaging (vMRI) (key secondary) • Assess the effects of PTC518 on change in composite Unified Huntington's Disease Rating Scale (cUHDRS) • Determine the effect of PTC518 on mutant huntingtin (mHTT) protein in cerebrospinal fluid (CSF) at Month 12 • Determine the effect of PTC518 on blood mHTT levels at Month 12
Exploratory Objectives: • Determine the effect of PTC518 on mHTT protein in CSF at Month 3 • Determine the effect of PTC518 on blood mHTT levels at Month 3 • Assess the effect of PTC518 on change in whole brain, and putamen volume via vMRI • Assess the effect of PTC518 on change in ventricular volume via vMRI • Assess change after 12 months of treatment in clinical scales • Determine the effect of PTC518 on HTT mRNA in blood
Pharmacokinetic Objective: • Evaluate the concentration of PTC518 in subjects with HD
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Ambulatory male or female patients 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 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): 7. A UHDRS TFC score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS score of </=100
8. Women of childbearing potential (WOCBP) must agree to use highly effective methods of contraception during dosing and for 6 months after stopping the study medication. 9. Sexually active and fertile males must agree to use a condom during intercourse while taking study drug and for 6 months after stopping study drug and should neither father a child nor donate sperm in this period. A condom is required to be used also by vasectomized men in order to prevent potential delivery of the drug via seminal fluid. |
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E.4 | Principal 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. Observational studies (such as ENROLL-HD) are not exclusionary. 5. Presence of an implanted deep brain stimulation device 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 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 processor 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 MRI 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 impairment resulting in elevated liver function tests (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP]) at 3 times the upper limit of normal at Screening 19. Pregnancy, planning on becoming pregnant during the course of the study or within 6 months of end of treatment, or currently breastfeeding 20. Use of medications that are moderate or strong inhibitors of cytochrome P450 (CYP) 3A4 within 1 week of Screening or medications that are moderate or strong inducers of CYP3A4 within 2 weeks of Screening or planned use of moderate or strong CYP3A4 inhibitor or inducer medications during the study period 21. A diagnosis of Juvenile-Onset Huntington's Disease |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Endpoints: • Safety profile as characterized by TEAEs, laboratory abnormalities, NfL levels in plasma and CSF, ECG, vital signs, Columbia Suicide Severity Rating Scale (C-SSRS), slit lamp eye examination, TNSc, and physical examination
Primary Efficacy Endpoint: • Change from Baseline in blood tHTT protein at Month 3
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints: • Change from Baseline in cUHDRS scores at Month 12 • Change from Baseline in caudate volume as assessed via vMRI at Month 12 (key secondary) • 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
Exploratory Endpoints: • Change from Baseline in CSF mHTT protein at Month 3 • Change from Baseline in blood mHTT protein at Month 3 • Change from Baseline in whole brain, putamen, and ventricular volume (as assessed by vMRI) at Month 12 • Change from Baseline in in Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) sub-score at Month 12 • Change from Baseline in other UHDRS sub-scores, including Total Motor Score (TMS), Symbol Digit Modalities Test (SDMT), and Independence Scale (IS) at Month 12 • Change from Baseline in the short form of the Problem Behaviors Assessment (PBA-s) (substituting for the UHDRS Behavioral Examination) at Month 12 • Change from Baseline in wearable accelerometer assessment Timed Up and Go (TUG), 2-minute walk distance, and postural sway at Month 12 • Change from Baseline in the FuRST 2.0 questionnaire at Month 12 • Change over time in blood HTT mRNA • Change over time in plasma and CSF NfL • Change over time in CSF YKL-40
Pharmacokinetic Endpoints • Plasma trough concentration (Ctrough) and accumulation ratio of PTC518 in plasma over time and accumulation ratio of PTC518 in CSF at Visits 5 through 8 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
New Zealand |
Australia |
Canada |
United Kingdom |
United States |
Austria |
France |
Germany |
Italy |
Netherlands |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |