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 and pharmacodynamic effects of 3 different doses of PTC518 and placebo in subjects with HD. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives: • Determine the effect of PTC518 on HTT mRNA in blood and mHTT protein in CSF • Reduction in blood mHTT levels
Exploratory Objectives: • Assess the effect of PTC518 on change in whole brain, caudate, and putamen volume via volumetric magnetic resonance imaging • Assess the effect of PTC518 on change in ventricular volume via vMRI • Assess change after 12 weeks of treatment in clinical scales
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 (or legally authorized representative) is willing and able to provide informed consent and comply with all protocol requirements 3. Genetically confirmed HD diagnosis with a CAG repeat length from 42 to 50, inclusive 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) 7. 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. 8. 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, 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 6. Family history of early onset cataracts or presence of cataracts at Baseline 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 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 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 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. 17. Current significant renal impairment defined as estimated glomerular filtration rate <60 mL/min/1.73m2 at Screening 18. Current hepatic impairment resulting in elevated liver function tests (aspartate transaminase [AST], alanine transaminase [ALT], alanine 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Safety Endpoints: • Safety profile as characterized by TEAEs, laboratory abnormalities, NfL levels in plasma and CSF, YKL-40 levels in CSF, ECG, vital signs, slit lamp eye examination, and physical examination
Primary Efficacy Endpoint: • Change from Baseline in blood tHTT protein at Day 85
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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 blood HTT mRNA at Days 29, 57, and 85 • Change from Baseline in CSF mHTT at Day 85 • Change from Baseline in blood mHTT protein at Day 85
Exploratory Endpoints: • Change from Baseline in whole brain, caudate, putamen, and ventricular volume (as assessed by vMRI) at Day 85 • Change from Baseline in UHDRS scores, with the exception of Behavioural Examination, at Day 85 • Change from Baseline in the short form of the Problem Behaviors Assessment (PBA-s) at Day 85 (substituting for the UHDRS Behavioral Examination) • Change from Baseline in wearable accelerometer assessment of Timed Up and Go (TUG), 2-minute walk distance, and postural sway at Day 85 • Change from Baseline in the FuRST 2.0 questionnaire at Day 85
Pharmacokinetic Endpoints • Plasma trough concentration (Ctrough) and accumulation ratio of PTC518 in plasma at Visits 3, 4, and 5 and accumulation ratio of PTC518 in CSF at Visit 5 |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Australia |
United States |
France |
Netherlands |
Germany |
United Kingdom |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial months | 11 |