E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Huntington's Disease (HD) |
|
E.1.1.1 | Medical condition in easily understood language |
Huntington's disease is a hereditary disorder causing degeneration of neurons in the brain that affects muscle coordination and leads to cognitive decline and emotional disturbance |
|
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 |
|
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 |
The primary objective of this study is to assess the efficacy of laquinimod (0.5 mg and 1.0 mg qd) in patients with HD after 12 months of treatment using the UHDRS-TMS. |
|
E.2.2 | Secondary objectives of the trial |
Secondary study objectives: To assess the effect of laquinimod on
• Brain atrophy in patients with HD after 12 months of treatment using MRI measures of caudate volume
• Cognitive capacity in patients with HD after 12 months of treatment using the cognitive assessment battery for patients with HD
• Clinical global impression in patients with HD after 12 months of treatment using the Clinician’s Interview-Based Impression of Change plus Caregiver Input
• Functional capacity in patients with HD after 12 months of treatment using the UHDRS-TFC scale
Safety and Tolerability Study Objectives:
• To evaluate safety and tolerability of laquinimod in patients with HD during 12 months of treatment by evaluating adverse events, electrocardiography, and clinical laboratory parameters, vital signs, physical examinations, and premature discontinuations from the study
Exploratory Study Objectives: see study protocol |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomic Sub-Study:
Pharmacogenomic (PGx) assessment will include DNA variations and RNA,gene expression pattern potentially associated with clinical treatment responses to laquinimod (e.g. clinical effect, Q-Motor, pharmacokinetics, tolerability, and safety features or disease susceptibility and severity features). Samples for DNA analysis will be collected at screening (or if not possible, at the next possible visit). Samples for RNA analysis will be collected at baseline, Month 6 and 12.
Other Ancillary Studies:
• Microglial activation state will be investigated in selected patients (N=aiming at 10 per treatment arm). Positron emission tomography (PET) scans and imaging analysis of microglial activation marker translocator protein (TSPO) will be performed at baseline and Month 12.
• Change in putaminal and frontal white matter markers of neuronal integrity (N-acetylaspartate (NAA)) and astrocytosis (myo-inositol) will be investigated at selected sites using magnetic resonance spectroscopy (MRS) (N=aiming at 20 per treatment arm) at baseline and Month 12.
• Monocyte gene expression and/or protein profile in response to treatment with laquinimod will be analyzed at selected sites and patients (N=aiming at 25 per treatment arm). Monocytes will be separated from isolated peripheral blood mononuclear cells (PBMC) and be analyzed for gene expression and/or protein profile at baseline and Month 12.
• Peripheral cytokine and proteomic analysis in response to treatment with laquinimod will be investigated in a subgroup of patients at selected sites at baseline and Months 6 and 12.
Ancillary Study Objectives (substudies):
• To explore potential correlation between genetic polymorphisms in deoxyribonucleic acid (DNA) and pharmacokinetics, clinical response to laquinimod, and/or adverse drug reactions, if these occur
• To explore potential correlation between ribonucleic acid (RNA) expression profile in blood cells and clinical response to laquinimod
• To evaluate changes in cytokines and other soluble protein levels following treatment with laquinimod as potential biomarkers for laquinimod mechanism of action and/or response predictive factors
• To explore gene expression and/or protein profile in monocytes in response to laquinimod treatment
• To explore change in microglial activation state in response to treatment with laquinimod
• To assess the correlation between microglial activation state at baseline and the clinical characteristics of HD patients (age, gender, number of triplets, disease onset, disease duration, motor and behavioral scores).
• To explore changes in MRS metabolite levels in response to treatment with laquinimod that reflect neuronal integrity (NAA) and astrocytosis (myo-inositol) in the putamen and frontal white matter. |
|
E.3 | Principal inclusion criteria |
Patients may be included in the study if they meet all of the following criteria:
a. Documentation of prior positive genetic testing for HD, or a clinical diagnosis of symptomatic HD (Diagnostic Confidence Level 4).
b. Presence of 36-49 CAG repeats, inclusive, in the huntingtin gene based on centralized CAG testing during screening.
c. Male or female between 21-55 years of age, inclusive, with an onset of HD at or after 18 years of age.
d. Women of child-bearing potential (women who are not post-menopausal or who have not undergone surgical sterilization) must practice an acceptable method of birth control for 30 days before taking the study treatment, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment was administered. Acceptable methods of birth control in this study include: Intrauterine device, barrier method (condom or diaphragm with spermicide) and hormonal methods of birth control (e.g., oral contraceptive, contraceptive patch, long-acting injectable contraceptive).
e. A sum of >5 points on the UHDRS-TMS at the screening visit
f. UHDRS- TFC ≥ 8 at the screening visit.
g. Able and willing to provide written informed consent prior to any study related procedure being performed at the screening visit. Patients with a legal guardian should be consented according to local requirements.
h. Willing to provide a blood sample for genomic CAG analysis at the screening visit.
i. Willing and able to take oral medication and able to comply with the study specific procedures.
j. Ambulatory, being able to travel to the study centre, and judged by the investigator as likely to be able to continue to travel for the duration of the study
k. Availability and willingness of a caregiver, informant, or family member to provide input at study visits assessing CIBIC-Plus, CDR-SB, PBA-s, and HD-QoL. A caregiver is recommended to be someone who attends to the patient at least 2 to 3 times per week for at least 3 hours per occasion, and the suitability of the caregiver should be judged by the investigator.
l. For patients taking allowed antidepressant medication, the dosing of medication must have been kept constant for at least 30 days before baseline and must be kept constant during the study. |
|
E.4 | Principal exclusion criteria |
Patients are excluded from participating in this study if 1 or more of the following criteria are met:
a. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 12 months prior to screening
b. Previous use of laquinimod
c. Use of moderate/strong inhibitors of cytochrome P450 (CYP)3A4 within 2 weeks prior to randomization.
d. Use of inducers of CYP3A4 within 2 weeks prior to randomization.
e. Pregnant or breastfeeding.
f. Serum levels ≥2x upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
g. Serum direct bilirubin which is ≥1.5xULN at screening.
h. Estimated creatinine clearance <60 mL/min at screening, calculated using the Cockcroft Gault equation: (140 - age) × mass (kg) × [0.85 if female] / 72 × serum creatinine (mg/dL)
i. Subjects with a clinically significant or unstable medical or surgical condition that may put the patient at risk when participating in the study or may influence the results of the study or affect the patient's ability to take part in the study, as determined by medical history, physical examinations, ECG, or laboratory tests. Such conditions may include:
1. A major cardiovascular event (e.g. myocardial infarction, acute
coronary syndrome, de-compensated congestive heart failure,
pulmonary embolism, coronary revascularization, angina) that occurred prior to randomization.
2. Significant cardiovascular risk factors (such as, but not limited to,
uncontrolled hypertension, uncontrolled diabetes), per investigator
discretion.
3. Any acute pulmonary disorder
4. A CNS disorder other than HD that may jeopardize the subject's
participation in the study, including such disorders that are
demonstrated on the baseline MRI (based on local read).
5. A gastrointestinal disorder that may affect the absorption of study medication.
6. Acute or chronic renal disease including acute kidney injury (AKI).
7. Any form of acute or chronic liver disease.
8. Known human immunodeficiency virus positive status. Patients will
undergo an HIV test at screening per local requirements, if applicable.
9. Any malignancies, excluding basal cell carcinoma, in the 5 years prior
to randomization.
j. Any clinically significant, abnormal, screening laboratory result which in the opinion of the investigator, affects the patients’ suitability for the study or puts the patient at risk if he/she enters the study
k. Unsuitable for MRI (e.g., claustrophobia, metal implants)
l. Alcohol and/or drug abuse within the 12 months prior to screening, as defined by Diagnostic and Statistical Manual of Mental Disorders –
Fourth Edition Text Revision (DSM-IV TR) criteria for substance abuse.
For former alcohol and/or drug abusers, the abstinence should be
confirmed by laboratory tests (drug testing and/or carbohydrate
deficient transferrin (CDT) level in blood).
m. Patients with active suicidal ideation during the past month 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 baseline screening Columbia-Suicide Severity Rating Scale (C-SSRS) or subjects who answer “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 subjects who, in the opinion of the investigator, present a serious risk of suicide.
n. Patients with known intracranial neoplasms, vascular malformations, or intracranial hemorrhage
o. Known drug hypersensitivity that would preclude administration of laquinimod or placebo, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.
p. Swallowing difficulties that would preclude administration of laquinimod or placebo capsules.
q. Treatment with any investigational product within 30 days of
screening or patients planning to participate in another clinical study
assessing any investigational product during the study.
Patients in non-interventional and/or observational studies will not be
excluded from participating in this study.
r. Treatment with tetrabenazine within 30 days of the study baseline
visit
s. Treatment with antipsychotic medication within 30 days of the study
baseline visit |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable and endpoint for this study is change from baseline in the UHDRS TMS (defined as the sum of the scores of all UHDRS-TMS subitems) at Month 12/ Early Termination (ET) (evaluated at baseline and Months 1, 3, 6 and 12). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline in the UHDRS TMS will be evaluated at Month 12/ ET (evaluated at baseline and Months 1, 3, 6 and 12). |
|
E.5.2 | Secondary end point(s) |
Secondary Efficacy Variables and Endpoints:
The secondary efficacy variables and endpoints for this study are:
• Percent change from baseline in caudate volume at Month 12/ET (evaluated at baseline and Month 12)
• Change from baseline in HD-CAB total score (sum of the standardized sub-components) at Month 12/ET (evaluated at baseline and Months 6 and 12)
• CIBIC-Plus global score at Month 12/ET (evaluated at Months 6 and 12) as compared to baseline (rated by an independent rater)
• Change from baseline in UHDRS- TFC at Month 12/ET (evaluated at baseline, Months 6 and 12)
Exploratory Efficacy Variables and Endpoints:
The exploratory efficacy variables and endpoints for this study are:
• Change from baseline in brain atrophy as defined by the percentage change in volume in: whole brain volume and white matter volume at Month 12/ET and absolute change in ventricular volume at Month 12/ET (evaluated at baseline and Month 12)
• Change from baseline in UHDRS- FA at Month 12/ET (evaluated at baseline and Months 6 and 12)
• Change from baseline in Q-Motor assessments at Month 12/ET (evaluated at baseline and Months 1, 3, 6 and 12)
• Change from baseline in mPPT at Month 12/ET (evaluated at baseline and Months 6 and 12)
• Change from baseline in HD QoL and EQ-5D-5L at Month 12/ET (evaluated at baseline and Month 12)
• Change from baseline in WLQ at Month 12/ET (evaluated at baseline and Month 12)
• Change from baseline in HD-CAB sub-components at Month 12/ET (evaluated at baseline and Months 6 and 12): Symbol Digit Modalities Test (SDMT), Emotion Recognition, Trail Making Test, Hopkins Verbal Learning Test, revised (HVLT-R), Paced Tapping at 3 Hz, One Touch Stockings of Cambridge (OTS, abbreviated 10 trial version)
• Change from baseline in CDR-SB at Month 12/ET (evaluated at baseline and Month 12)
• Change from baseline in HADS at Month 12/ET (evaluated at baseline and Month 12)
• Change from baseline in PBA-s at Month 12/ET (evaluated at baseline and Month 12)
Safety Variables and Endpoints:
Safety variables and endpoints will include the following:
• Adverse events reports throughout the study
• ECG findings throughout the study
• Clinical safety laboratory tests throughout the study
• Vital signs measurements throughout the study
• Physical examination findings throughout the study
• Changes from baseline suicidality (C-SSRS) scores throughout the study
Tolerability variables and endpoints:
• Proportion of subjects (%) who prematurely discontinued from the study, reason of discontinuation and the time to ET
• Proportion of subjects (%) who prematurely discontinued from the study due to AEs and the time to ET |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Variables/Endpoints: Changes from baseline (BL) will be determined at Month 12/ET and evaluated as follows: Caudate volume (BL, Month 12), HD-CAB total score (BL, Months 6 and 12), CIBIC-Plus global score (BL, Months 6 and 12), UHDRS- TFC (BL, Months 6 and 12)
Exploratory Efficacy Variables/Endpoints: Change from BL will be determined at Month 12/ET and evaluated as follows: Brain atrophy (BL, Month 12), UHDRS- FA (BL, Months 6 and 12), Q-Motor assessments (BL, Months 1, 3, 6 and 12), mPPT (BL, Months 6 and 12), HD QoL/EQ-5D-5L (BL, Month 12), WLQ (BL, Month 12), HD-CAB subcomponents (BL, Months 6 and 12), CDR-SB (BL, Month 12), HADS (BL, Month 12), PBA-s (BL, Month 12)
Tolerability Variables/Endpoints will be determined at Month 12 |
|
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 | No |
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) | 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 | 3 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
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 |
Czech Republic |
Germany |
Italy |
Netherlands |
Portugal |
Russian Federation |
Spain |
United Kingdom |
United States |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |