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    Summary
    EudraCT Number:2021-003852-18
    Sponsor's Protocol Code Number:PTC518-CNS-002-HD
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-02-18
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2021-003852-18
    A.3Full title of the trial
    A PHASE 2A, RANDOMIZED, PLACEBO-CONTROLLED, DOSE-RANGING STUDY TO EVALUATE THE SAFETY AND EFFICACY OF PTC518 IN SUBJECTS WITH HUNTINGTON'S DISEASE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2A study of PTC518 in patients with Huntington's Disease
    A.3.2Name or abbreviated title of the trial where available
    PIVOT-HD
    A.4.1Sponsor's protocol code numberPTC518-CNS-002-HD
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05358717
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPTC Therapeutics, INC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPTC Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPTC Therapeutics, INC
    B.5.2Functional name of contact pointPatient Advocacy
    B.5.3 Address:
    B.5.3.1Street Address100 Corporate Court
    B.5.3.2Town/ city South Plainfield
    B.5.3.3Post codeNJ 07080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+19082227000
    B.5.6E-mailmedinfo@ptcbio.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePTC518 tablet 5 mg
    D.3.2Product code PTC518
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 2407849-89-0
    D.3.9.2Current sponsor codePTC518
    D.3.9.3Other descriptive namePTC518
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePTC518 tablet 20 mg
    D.3.2Product code PTC518
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available
    D.3.9.1CAS number 2407849-89-0
    D.3.9.2Current sponsor codePTC518
    D.3.9.3Other descriptive namePTC518
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Huntington’s disease
    E.1.1.1Medical 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.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10070668
    E.1.2Term Huntington's disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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):
    9. A UHDRS TFC score of 11 or 12, or a UHDRS TFC score of 13 with an
    UHDRS IS score of </=100

    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.
    E.4Principal 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 selfreported 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
    E.5 End points
    E.5.1Primary 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

    E.5.1.1Timepoint(s) of evaluation of this end point
    At Month 3
    E.5.2Secondary 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    Month 12
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days10
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 216
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state52
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 252
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-04-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-06
    P. End of Trial
    P.End of Trial StatusOngoing
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