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 |
A hereditary disorder of the central nervous system that affects muscle coordination and leads to cognitive decline and psychiatric problems. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Main study: To assess the effect of pridopidine on functional capacity in participants with stage 1-2 HD OLE study: Efficacy: To evaluate the long-term treatment effect of pridopidine in participants with HD who previously completed the Main study Safety and Tolerability: To evaluate long-term safety and tolerability of pridopidine in participants with HD who previously completed the Main study |
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E.2.2 | Secondary objectives of the trial |
Key Secondary • TFC responder analysis following pridopidine treatment Secondary • To evaluate the effect of pridopidine on motor function • To evaluate the effect of pridopidine on other measures of efficacy Safety and Tolerability: • To evaluate the safety and tolerability of pridopidine |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Main study: 1. Twenty-five years of age (inclusive) and older, at the time of signing the informed consent. 2. Diagnosis of HD based on clinical features and the presence of ≥36 CAG repeats in the HTT, confirmed by historical laboratory quantified results or by a diagnostic test at screening. 3. Diagnostic confidence level (DCL) of 4 (unequivocal motor signs, ≥ 99% confidence) on the standardized motor exam UHDRS-TMS. 4. Adult-onset HD with onset of signs and symptoms ≥18 years of age. 5. Stage 1 or Stage 2 HD, defined as a UHDRS-TFC score of ≥7, at screening. 6. UHDRS-Independence Scale (IS) score ≤90% at screening. 7. UHDRS-TMS ≥20 at the Screening visit. 8. Must meet all criteria required to move forward with the Randomization Authorization Flow (RAF) and be considered eligible by the RAF Reviewer. 9. Male or female. 10. Female participants of childbearing potential must have a negative β-human chorionic gonadotropin (β-HCG) test at screening and baseline, be sterile, or be postmenopausal. 11. Female participants of childbearing potential whose male partners are potentially fertile (i.e., no vasectomy) must use highly effective birth control methods stable for at least 3 months prior to screening, for the duration of the study and for 30 days after discontinuation of the study drug. 12. Male participants must be sterile, or if they are potentially fertile/reproductively competent (not surgically [e.g., vasectomy] or congenitally sterile) and their female partners are of childbearing potential, they must use, together with their female partners, effective birth control methods for the duration of the study and for 90 days after study drug discontinuation. 13. For participants taking allowed antipsychotic, antidepressant, or other psychotropic medication, the dosing of medication as listed in Section 10.6, must be stable for at least 4 weeks before the Baseline visit and throughout the study (unless clinically necessary to change). 14. For participants taking allowed concomitant medications, dosing of medications must be stable for a t least 4 weeks prior to the Baseline visit (note: Amiodarone is not allowed within 6 weeks of Baseline visit) 15. Capable of providing signed informed consent for the Main study which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Open-label Extension: 1. Completed the EoS visit of the Main study on treatment without important protocol deviations impacting efficacy and safety assessments. 2.Capable and willing to provide signed informed consent for the OLE. 3.Must meet all criteria required to move forward with the OLE assessments. |
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E.4 | Principal exclusion criteria |
Main study: 1. Prolonged QTcF interval (defined as a QTcF interval of >450 ms for male and >470 ms for female) at screening. 2. Clinically significant heart disease within 12 weeks before randomization, defined as follows: a. Participants with clinically significant heart disease, a clinically significant history of arrhythmia, symptomatic or uncontrolled atrial fibrillation despite treatment, or confirmed ventricular tachycardia, or presence of left bundle branch block. b. Participants with a known history of congenital long QT syndrome or a first degree relative with this condition. c. Clinically significant bradycardia, sick sinus syndrome, complete atrioventricular block, congestive heart failure, polymorphic ventricular tachycardia, clinically relevant hypocalcemia, hypokalemia or hypomagnesemia 3. History of epilepsy or seizures within the last 5 years. 4. Serious medical illness (includes, but not limited to, uncontrolled hypertension; respiratory disease, including severe forms of asthma; severe hepatic disease (confirmed Hepatitis B virus [HBV], Hepatitis C virus [HCV];, confirmed human immunodeficiency virus [HIV]); renal disease; acquired immune deficiency syndrome; and unstable psychiatric or other neurologic disorders) and metastatic cancer. For serious kidney and liver and liver illnesses see also exclusion criterion 12 (laboratory test abnormalities) 5. Known intracranial neoplasms, vascular malformations, history of cerebrovascular accident, or intracranial hemorrhage. 6. Female participants who are pregnant, planning to become pregnant or breastfeeding 7. Medications that prolong QT interval, taken within 4 weeks of the Baseline visit (note, Amiodarone is not allowed within 6 weeks of the Baseline visit) or at any timepoint during the study, including non-allowed antipsychotic medications, tricyclic antidepressants, and/or Class I antiarrhythmics 8. Use of pridopidine within 12 months before the Baseline visit. 9. Treatment with any investigational product within 6 weeks or 5 half-lives (whichever is longer) before the Screening visit or a plan to participate in another clinical study that assesses any investigational product during the study. 10. Gene therapy at any time 11. Prior participation in studies with tominersen at any time. 12. Laboratory values that fall outside of the central laboratory’s reference range at screening and are considered clinically significantly abnormal by the Investigator, and affect the participant's suitability to participate in the study or put the participant at risk if he/she enters the study in the Investigator’s opinion. 13. Have any of the following laboratory test abnormalities at screening a. CrCl <30 mL/min at screening, calculated using the CockcroftGault equation: (140–age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/dL). b. Aspartate aminotransferase (AST) ≥2.5 × upper limit of normal (ULN) c. Alanine aminotransferase (ALT) ≥2.5 × ULN d. Gamma- glutamyl transferase (GGT) ≥3.0 × ULN e. Total bilirubin >1,5 mg/dL, except participants with unconjugated hyperbilirubinemia without other liver function derangements or other explanations for the elevated bilirubin (consistent with diagnosis of Gilbert's syndrome) 14. Alcohol and/or substance use disorder within the 6 months prior to screening, as defined by the Diagnostic and Statistical Manual–Fifth Edition (DSM-5) Text Revision criteria for substance use. 15. Active suicidal ideation as measured by a most severe suicide ideation score of 4 (Active Suicidal Ideation with Some Intent to Act, without Specific Plan) or 5 (Active Suicidal Ideation with Specific Plan and Intent) on the C-SSRS if the ideation occurred within 1 year of Screening, or participants who answered “Yes” on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior), if the attempt or acts were performed within 1 year of screening, or participants who, in the opinion of the investigator, present a serious risk of suicide. 16. Known allergy to any ingredient of the study drug (pridopidine, silicified microcrystalline cellulose, or magnesium stearate) 17. Vulnerable participant (e.g., people kept in detention), or participant unfit to participate in a clinical study due to living circumstances, e.g. without sufficient family or social support, stable residence, sustainable financial and general healthcare and resources. 18. An employee or a family member of an employee of the Sponsor, Investigator or Investigator study site, or otherwise dependent on the Sponsor, the Investigator or the Investigator study site. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Main study: Change from baseline to Week 65 in the UHDRS-TFC score OLE study: Efficacy: Change in UHDRS-TFC; UHDRS-TMS; Quantitative motor (QMotor): o finger tapping (Digitomotography) o pronation/supination (Dysdiadochomotography) Safety and Tolerability: Incidence (count and rate) of AEs and SAEs overall, by severity, by relationship to study drug, and those that led to withdrawal from the study •Incidence and shifts of clinically significant abnormalities in ECG, laboratory tests and vital signs •Analysis of C-SSRS throughout the study •Tolerability: -The number (%) of participants who complete the OLE treatment period -The number (%) of participants who fail to complete the OLE treatment period due to AEs |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Main study: Baseline and week 65 OLE study: according to the protocol |
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E.5.2 | Secondary end point(s) |
Key Secondary 1. Proportion of participants with no worsening (change ≥ 0 point) from baseline to Week 65 in UHDRS-TFC Secondary 2. Change from baseline to Week 65 in the UHDRS-Total Motor Score (TMS) 3. Change from baseline to Week 65 in Quantitative motor (Q-Motor) finger tapping (Digitomotography) 4. Change from baseline to Week 65 in Composite UDHRS (cUHDRS) total score 5. Change from baseline to Week 52 in UHDRS-TFC score 6. Change from baseline to Week 52 in UHDRS-TMS score 7. Proportion of participants with no worsening from baseline in Clinical Global Impression of Change (CGI-C) at Week 65 8. Change from baseline to Week 78 in UHDRS-TFC score Safety and Tolerability • Incidence (count and rate) of AEs and serious AEs (SAEs) overall, by severity, by relationship to study drug, and those that led to withdrawal from the study • Incidence and shifts of clinically significant abnormalities in electrocardiogram (ECG), laboratory tests and vital signs • Analysis of Columbia Suicide Severity Rating Scale (C-SSRS) throughout the study • Tolerability: − The number (%) of participants who complete the treatment period − The number (%) of participants who fail to complete the treatment period due to AEs − The number (%) of participants who fail to complete the treatment period due to the prolongation of the Fridericia corrected QT interval (QTcF) compared to baseline and QT-change stopping rules |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
According to the protocol |
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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 | Yes |
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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 2 |
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 | 30 |
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 |
Canada |
United States |
European Union |
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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The Main study will be considered completed when all participants either complete the study through Week 65 or discontinue earlier (ET visit). OLE: The OLE study will be considered completed 6 months after the last participant completes the double-blind Treatment period. OLE duration may be extended pending emerging data from the double-blind portion of the study. A substantial protocol amendment for the extension of the OLE will be submitted after analysis of the data from the Main study
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 6 |