A study to evaluate the safety and efficacy of PTC518 in participants with Huntington's disease (HD)
| ISRCTN | ISRCTN97180769 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN97180769 |
| EudraCT/CTIS number | 2021-003852-18 |
| IRAS number | 1004960 |
| ClinicalTrials.gov number | NCT05358717 |
| Secondary identifying numbers | PTC518-CNS-002-HD, IRAS 1004960, CPMS 51614 |
- Submission date
- 03/03/2022
- Registration date
- 08/08/2022
- Last edited
- 08/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Genetic Diseases
Plain English summary of protocol
Background and study aims
The safety and efficacy of three doses of PTC518 (investigational medicine), for participants with Huntington's Disease (HD), will be studied in this Clinical Trial.
PTC518 is being studied to determine if it can slow the progression of HD and its associated symptoms by reducing the production of an abnormal version of a protein called huntingtin protein (sometimes called a mutant version or mHTT).
Who can participate?
Approximately 252 participants, aged 25 years and older will participate across approximately 20 sites in North America, Europe, and Australia.
What does the study involve?
The study is divided into the below periods:
- Screening period (to check participant eligibility to join the study)
- Baseline visit (to further confirm participant eligibility and initial dosing)
- Treatment period
- Safety follow-up period (to check participants' overall health and safety)
The study medicine comes in tablet form and is to be taken orally, in the morning, at least 2 hours before the first meal of the day (fasting).
Participation in the study will last up to 18 months, from screening to the final follow-up visit. The study treatment period will last approximately 12 months. Participation is voluntary. Participants will be expected to attend clinic visit whereby study assessments will take place e.g., blood and urine collection, vital signs monitoring, assessments of motor function & gait, cognition & behavioral and mental health, and completion of questionnaires.
What are the possible benefits and risks of participating?
Not provided at time of registration
Where is the study run from?
PTC Therapeutics International Limited (Ireland)
When is the study starting and how long is it expected to run for?
September 2021 to August 2025
Who is funding the study?
PTC Therapeutics, Inc. (USA)
Who is the main contact?
Dr Sarah Tabrizi, s.tabrizi@ucl.ac.uk
Contact information
Scientific
PTC Therapeutics, Inc.
100 Corporate Court
South Plainfield
07080
United States of America
| Phone | +1 908 2227000 |
|---|---|
| medinfo@ptcbio.com |
Principal Investigator
University College London
National Hospital for Neurology and Neurosurgery
Queen Square
London
WC1N 3BG
United Kingdom
| s.tabrizi@ucl.ac.uk |
Study information
| Study design | Interventional double-blind randomized parallel group placebo-controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A Phase 2a, randomized, placebo-controlled, dose-ranging study to evaluate the safety and efficacy of PTC518 in subjects with Huntington's disease |
| Study acronym | PIVOT HD |
| Study objectives | Current study hypothesis as of 25/07/2023: Primary objective: • Evaluate the safety of PTC518 compared with placebo in participants with Huntington's Disease (HD) • Evaluate the pharmacodynamic (PD) effects of PTC518 through the reduction in blood total huntingtin (tHTT) protein levels 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 Previous study hypothesis: Primary objective: • Evaluate the safety and pharmacodynamic effects of 3 different doses of PTC518 and placebo in subjects with Huntington's Disease (HD) Secondary Objectives: • Determine the effect of PTC518 on huntingtin (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 (vMRI) • 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 |
| Ethics approval(s) | Approved 03/05/2022, London Research Ethics Committee (80 London Road, Skipton House, London, SE1 6LH, UK; +44 (0)2071048387; londonbridge.rec@hra.nhs.uk), ref: 22/LO/0229 |
| Health condition(s) or problem(s) studied | 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. |
| Intervention | Current interventions as of 25/07/2023: Participants will first be randomized to Part A or Part B or Parts D or E in a 1:1 randomization ratio, depending on their Huntington’s disease Integrated Staging System (HD-ISS) staging criteria and then to active treatment (PTC518 5 mg in Parts A and D and 10 mg in Parts B and E) or matching placebo within each part in a 2:1 ratio of active treatment to placebo. A Drug Safety Monitoring Board (DSMB) will undertake an unblinded review of safety data from the 5 and 10 mg dosing groups and provide a recommendation on when Parts C and F (with a 20 mg active treatment arm) can be initiated. At that time, participants will be randomized to any study Part that is currently open for enrollment, and then to either active treatment or placebo (in a 2:1 ratio) within that Part. The participant will receive the assigned treatment for approximately 12 months. After the treatment period ends, there is a safety follow-up period for all arms with follow-up safety visits at Month 13, Month 16, and Month 18. Previous interventions: There are three treatment arms: 1) Part A (5 mg or placebo), 2 Part B (10 mg or placebo), and 3) Part C (20 mg or placebo). Participants will be assigned to either Part A, Part B, or Part C based on which parts of the study are open at the time of consent. A computer program (an interactive response technology system) will do the part assignment and assign the participant to either the study drug or placebo. The participant will have a 2 in 3 chance of receiving the study drug versus placebo. The subject will receive the assigned treatment for approximately 85 days or 12 weeks. After the treatment period ends, there is a safety follow-up period for all arms. The safety follow-up period includes two visits on Day 113 (approximately one month after the treatment period ends) and Day 185 (approximately 4 months after the treatment period ends.) |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacodynamic |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | PTC518 |
| Primary outcome measure | Current primary outcome measures as of 25/07/2023: 1. Number of participants with adverse events (AEs) [time frame: baseline up to month 18] 2. Change from baseline in blood total huntingtin protein (tHTT) at Month 3 [time frame: baseline, month 3] Previous primary outcome measures: Primary Safety Endpoints: 1. 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: 2. Change from Baseline in blood tHTT protein at Day 85 |
| Secondary outcome measures | Current secondary outcome measures as of 25/07/2023: 1. Change from baseline in caudate volume as assessed via vMRI at month 12 [time frame: baseline, month 12] 2. Change from baseline in Composite Unified Huntington’s Disease Rating Scale (cUHDRS) Scores at month 12 [time frame: baseline, month 12] 3. Change from baseline in blood tHTT protein at month 12 [time frame: baseline, month 12] 4. Change from baseline in CSF mHTT at month 12 [time frame: baseline, month 12] 5. Change from baseline in blood mHTT protein at month 12 [time frame: baseline, month 12] Previous secondary outcome measures: 1. Change from Baseline in blood HTT mRNA at Days 29, 57, and 85 2. Change from Baseline in CSF mHTT at Day 85 3. Change from Baseline in blood mHTT protein at Day 85 Exploratory Endpoints 4. Change from Baseline in whole brain, caudate, putamen, and ventricular volume (as assessed by vMRI) at Day 85 5. Change from Baseline in UHDRS scores, with the exception of Behavioral Examination, at Day 85 6. Change from Baseline in the short form of the Problem Behaviors Assessment (PBA-s) at Day 85 (substituting for the UHDRS Behavioral Examination) 7. Change from Baseline in wearable accelerometer assessment of Timed Up and Go (TUG), 2-minute walk distance, and postural sway at Day 85 8. Change from Baseline in the FuRST 2.0 questionnaire at Day 85 Pharmacokinetic Endpoints 9. 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 |
| Overall study start date | 21/09/2021 |
| Completion date | 15/08/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 25 Years |
| Sex | Both |
| Target number of participants | 252 |
| Total final enrolment | 159 |
| Key inclusion criteria | Current inclusion criteria as of 25/07/2023: Key Inclusion Criteria: 1. Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length from 40 to 50, inclusive Eligibility for HD-ISS Stage 2 Group (Parts A, B, and C): 1. A Unified Huntington’s Disease Rating Scale (UHDRS)-Independence Scale (IS) score of 100 2. A UHDRS Total Functional Capacity (TFC) score of 13 3. 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): 1. A UHDRS Total Functional Capacity (TFC) score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS score of <100 Note: Other inclusion criteria may apply. Previous 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 the study drug and for 6 months after stopping the 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 the potential delivery of the drug via seminal fluid. |
| Key exclusion criteria | Current exclusion criteria as of 25/07/2023: Key Exclusion Criteria: 1. Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or anytime over the duration of this study, including ribonucleic acid (RNA)- or deoxyribonucleic acid (DNA)-targeted HD-specific investigational agents such as antisense oligonucleotides, cell transplantation, or any other experimental brain surgery 2. Any history of gene therapy exposure for the treatment of HD 3. 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 4. Any medical history of brain or spinal disease that would interfere with the lumbar puncture process safety assessments 5. Any medical history or condition that would interfere with the ability to complete the protocol-specified assessments (for example, implanted shunt, conditions precluding magnetic resonance imaging [MRI] scans) 6. Pregnancy, planning on becoming pregnant during the course of the study or within 6 months of the end of treatment, or currently breastfeeding Note: Other exclusion criteria may apply. Previous 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), 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 (e.g. inability to fast) 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], 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. |
| Date of first enrolment | 25/04/2022 |
| Date of final enrolment | 31/12/2023 |
Locations
Countries of recruitment
- Australia
- England
- France
- Germany
- Netherlands
- United Kingdom
- United States of America
- Wales
Study participating centres
WC1N 3BG
United Kingdom
CD10 3AX
United Kingdom
2333 ZA
Netherlands
48149
Germany
44791
Germany
89081
Germany
49100
France
13385
France
75013
France
2145
Australia
3168
Australia
Sponsor information
Industry
Unit 1, 52-55 Sir John Rogerson’s Quay
Dublin
D02 NA07
Ireland
| Phone | +353 (0)1 906 8700 |
|---|---|
| medinfo@ptcbio.com |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- PTC Therapeutics Inc., PTC Therapeutics, Inc., PTC Therapeutics Incorporated, PTC Therapeutics, Inc, PTC
- Location
- United States of America
Results and Publications
| Intention to publish date | 15/02/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Peer reviewed scientific journals Internal report Conference presentation Publication on website Other publication Submission to regulatory authorities |
| IPD sharing plan | Study participants will provide appropriate consent to enable the sharing of study data. Through the consent form, participants will be informed of the possibility of their data being shared with other research teams and research collaborators in other countries. All third parties involved with the research will have appropriate safeguards and confidentiality agreements in place to assure that same level of confidentiality as within the UK will be maintained. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
08/04/2025: The following changes were made to the study record:
1. Sponsor details updated.
2. Total final enrolment added.
3. The overall study end date was changed from 31/07/2024 to 15/08/2025.
4. The intention to publish date was changed from 30/06/2024 to 15/02/2026.
25/07/2023: The following changes were made to the study record:
1. The public title was changed from 'A phase 2a study of PTC518 in patients with Huntington's Disease' to 'A study to evaluate the safety and efficacy of PTC518 in participants with Huntington's disease (HD)'.
2. The scientific title was changed from 'A phase 2a, randomized, placebo-controlled, dose-ranging study to evaluate the safety and efficacy of PTC518 in subjects with Huntington's disease' to 'A Phase 2a, randomized, placebo-controlled, dose-ranging study to evaluate the safety and efficacy of PTC518 in subjects with Huntington's disease'.
3. The study hypothesis, ethics approval, interventions, primary and secondary outcome measures, inclusion and exclusion criteria were updated.
4. The recruitment start date was changed from 01/04/2022 to 25/04/2022.
5. The recruitment end date was changed from 30/09/2022 to 31/12/2023.
6. The overall study end date was changed from 31/12/2022 to 31/07/2024.
7. The intention to publish date was changed from 31/12/2023 to 30/06/2024.
8. The target number of participants was changed from 162 to 252.
9. UCL Queen Square Institute of Neurology National Hospital for Neurology Neurosurgery, Cardiff University Schools of Medicine and Biosciences, Leiden University Medical Center, George-Huntington-Institut, Ruhr-Univ.Bochum St. Joseph-Hospital, Ulm University, UKU, Dep. of Neurology, Centre Hospitalier Universitaire d'Angers, Hôpital Universitaire de Marseille Hôpital de la Timone, Brain and Spine Institute Paris, Westmead Hospital, Monash Health were added to the study participating centres.
05/09/2022: Internal review.
03/03/2022: Trial's existence confirmed by NHS HRA.
