E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Mild-to-Moderate Huntington Disease |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020469 |
E.1.2 | Term | Huntington's chorea |
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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 |
- To determine the effect of Dimebon as compared to placebo on cognition as measured by the Mini-Mental State Examination (MMSE); and - To determine the effect of Dimebon as compared to placebo on the primary measure of global function, the Clinician s Interview-Based Impression of Change, plus caregiver input (CIBIC-plus). |
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E.2.2 | Secondary objectives of the trial |
- To determine the effect of Dimebon as compared to placebo on a measure of behavior, the Neuropsychiatric Inventory (NPI); - To determine the effect of Dimebon as compared to placebo on a measure of self-care and daily function, the Alzheimer s Disease Cooperative Study Activities of Daily Living (ADCS-ADL); - To determine the effect of Dimebon as compared to placebo on a measure of motor impairment, the Unified Huntington Disease Rating Scale (UHDRS 99) Total Motor Score; - To determine the safety of treatment with Dimebon as compared to placebo; and - To examine the relationship between Dimebon plasma concentrations and efficacy and safety outcomes. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Have clinical features of HD and a CAG polyglutammate repeat expansion >=36 2.Have Stage 1, 2, or 3 HD with a UHDRS 99 TFC between 5 and 13 (inclusive) at the Screening visit; 3.Have cognitive impairment as noted by the following: a.A Screening MMSE AND a baseline (pre-dose) MMSE score between 10 and 26 (inclusive); and b.A subjective assessment of cognitive impairment with decline from pre-HD levels by the Investigator after interviewing the subject and caregiver; 4.Are willing and able to give informed consent for study participation and cytochrome P450 (CYP) 2D6 genotyping. If the subject is not competent, a mentally-competent legally-acceptable representative must provide informed consent on his/her behalf, and the subject must provide assent; 5.Are ambulatory and do not require skilled nursing care; 6.Are aged 30 years or older; 7.If female, are either a) of reproductive potential and compliant in using adequate birth control or b) not of reproductive potential. Adequate birth control is defined as consistent practice of an effective and accepted method of contraception (hormone-based, intrauterine device, or double barrier contraception, i.e., condom and diaphragm, diaphragm and spermicidal gel or foam) throughout the duration of the study. Abstinence is an acceptable method of contraception. Female subjects not of reproductive potential may have undergone menopause, hysterectomy, bilateral oophorectomy, or tubal ligation. Menopause is defined as one year without menses. If the subject s menopausal status is in question, a follicle-stimulating hormone (FSH) level of > 40 milli-international units per milliliter (mIU/mL) must be documented. Hysterectomy, bilateral oophorectomy, or tubal ligation must be documented; 8.If male, are either a) of reproductive potential and compliant in using adequate birth control or are b) not of reproductive potential. Surgical sterilization must be documented. Adequate birth control for males is defined as a condom and spermicidal gel or foam, or abstinence throughout the duration of the study; 9.If currently taking psychotropic medications (including antidepressants and neuroleptics) or other medications to treat the symptoms of HD (with the exception of tetrabenazine) must be on stable doses for at least 30 days prior to randomization; 10.If currently taking tetrabenazine must be tolerating it well, on a stable dose for at least 60 days prior to randomization, and have the intent to continue the current dose throughout the study duration. For subjects who have previously taken tetrabenazine, subjects must be off therapy for at least 60 days prior to randomization and have the intent to remain off therapy throughout the study duration. Note: Subjects will not be allowed to initiate tetrabenazine during the study period; 11.Have at least nine years of prior education and should have previously (in pre-HD condition) been capable of reading, writing, and communicating effectively with others; 12.Have a caregiver who assists/spends time with the subject at least five days per week for at least three hours per day and has intimate knowledge of the subject s cognitive, functional, and emotional states, and of the subject s personal care. The caregiver must be willing to accompany the subject to all study visits, and must be willing to supervise study drug administration. |
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E.4 | Principal exclusion criteria |
1. Had onset of HD symptoms prior to age 18; 2. Have active suicidality as measured by a suicide ideation score of 4 or 5 on the Columbia Suicide Severity Rating Scale (Baseline version); Exclusion Criteria Subjects ineligible to participate in this study are persons who: 1. Had onset of HD symptoms prior to age 18; 2. Have active suicidality as measured by a suicide ideation score of 4 or 5 on the Columbia Suicide Severity Rating Scale (Baseline version); 3. Have any major medical illness or unstable medical condition within 180 days of screening that may interfere with the subject s ability to comply with study procedures and abide by study restrictions, or with the ability to interpret safety data, including: a. Any physical disability that would prevent completion of study procedures or assessments (e.g., blindness or significant visual impairment, deafness or significant hearing impairment, non-HD-related speech impairment); b. A diagnosis of diabetes mellitus requiring treatment with insulin; c. A history of cancer within five years of randomization with the exception of non-melanoma skin cancers or prostate cancer that has been stable for six months; 4. Have any of the following cardiovascular parameters: a. Hypotension (systolic blood pressure < 86 millimeters of mercury [mmHg]) or bradycardia with heart rate less than 45 beats per minute at Screening or on more than one occasion within three months prior to Screening; b. Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at Screening or on more than one occasion within three months prior to Screening; c. Active cardiovascular disease including any of the following: unstable angina, decompensated congestive heart failure, clinically relevant arrhythmias. NOTE: A history of these conditions is acceptable, if stable under medical management. Subjects with pacemakers, subjects on anticoagulant therapy, and subjects who are stable with a prior history if MI may be included; d. A corrected QT interval by the Fridericia correction formula (QTcF) of greater than 470 milliseconds (msec), second degree or higher heart block, or left bundle branch block on an ECG at the Screening visit; 5. Have a history of traumatic brain injury with residual neurological deficit or stroke; 6. Have another disease known to affect cognition other than HD (e.g., Parkinson disease, frontotemporal dementia, normal pressure hydrocephalus); 7. Have a history of a seizure disorder requiring ongoing treatment, febrile seizures, or any seizure including loss of consciousness within 180 days preceding randomization. NOTE: Use of anti-epileptic medication for non-seizure related treatment is allowed if the dose has remained stable for at least 30 days prior to randomization; 8. Have any current psychiatric diagnosis that may interfere with the subject s ability to perform the study and all assessments (e.g., alcohol or drug-related abuse or alcohol dependence, or alcohol or drug-related dementia, major depression, mental retardation, schizophrenia, bipolar disorder, etc.); NOTE: Depression arising in the context of HD is not an Exclusion Criterion if on stable pharmacologic and/or non-pharmacologic management for 30 days preceding randomization. Subjects who require anxiolytics, sedatives, sleeping medications, or antipsychotic medications prior to randomization are allowed if doses have remained stable for 30 days prior to randomization; 9. Are pregnant or lactating females; 10. Reside in a nursing home or assisted care facility with need for 24-hour care and supervision; 11. Have a paid caregiver who is not clinically trained that cares for more than two subjects; 12. Have been informed of their treatment assignment after participation in a previous blinded clinical study with Dimebon; 13. Have exper |
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-Primary Efficacy Outcomes  A comparison between the mean changes from baseline in the Dimebon 20 mg TID treatment group and the placebo group on the MMSE at Week 26;  A comparison of the distributions of the CIBIC-plus (ADCS-CGIC) at Week 26 in the Dimebon 20 mg TID treatment group and the placebo group. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | 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.8.3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 | Information not present in EudraCT |
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 |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |