| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| 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 |
Co-Primary Objectives:
• 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 |
Secondary Objectives:
• 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 polyglutamate 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 childbearing potential and compliant in using adequate birth control or b) not of childbearing potential. Adequate birth control is defined as consistent practice of an effective and accepted method of contraception (hormone-based, intrauterine device, barrier contraception [e.g., condom or occlusive cap {diaphragm or cervical/vault caps} with spermicidal foam/gel/film/cream/
suppository], vasectomized partner, or sexual abstinence) throughout the duration of the study. Women not of childbearing potential may have undergone menopause or permanent sterilization (hysterectomy, bilateral oophorectomy, or bilateral tubal ligation). Menopause is defined as one year without menses. If the patient’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 bilateral tubal ligation must be documented;
8. If male, is either a) of reproductive potential and compliant in using adequate birth control through 30 days after the last dose of study drug or 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 eight 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 as many study visits as possible, but at a minimum the Screening, Baseline, Week 13 and Week 26 visits, and be available to speak by telephone for other study visits if they are not in attendance. The caregiver must be willing to supervise study drug administration and be able to give informed consent for his/her participation, be able to read and write, and be capable of providing responses to the CIBIC-plus, NPI, and the ADCS-ADL;
13. Capable of complying with study procedures, including being able to swallow tablets the size of the study drug. |
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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 responding “yes” to question 4 or 5 on the Columbia Suicide Severity Rating Scale (Baseline version)
3. 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 5 years of randomization with the exception of non-melanoma skin cancers or prostate cancer that has been stable for at least 6 months, or American Joint Committeeon Cancer Grade 0 or Grade 1 cancers that have a remote probability of recurrence, in the opinion of the Site Investigator, in consultation with the Medical Monitor and study Principal Investigator;
4. Have any of the following cardiovascular parameters:
a. Hypotension (systolic BP< 86 mmHg) or bradycardia with heart rate less than 45 bpm at Screening or on more than 1 occasion within 3 months prior to Screening;
b. Uncontrolled hypertension as indicated by a resting systolic BP> 170 mmHg or diastolic BP> 105 mmHg at Screening or on more than 1 occasion within 3 months prior to Screening;
c. Active cardiovascular disease;
d. A corrected QT interval by the Fridericia correction formula (QTcF) of >470 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;
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;
8. Have any current psychiatric diagnosis that may interfere with the subject’s ability to perform the study and all assessments;
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 experienced a serious adverse event assessed as at least possibly related to study drug use in a previous clinical study of Dimebon;
14. Have known HIV seropositivity;
15. Have any of the following laboratory abnormalities at the Screening visit:
a. Total bilirubin, ALT), or AST) levels >2 times the upper limit of normal;
b. Renal impairment with a serum creatinine > 1.5 mg/dL (133 μmol/L);
c. Hematocrit <37% for males and <32% for females, absolute neutrophil cell count of <1,500/μL, or platelet cell count of <120,000/μL;
16. Have taken or plan to take a cholinesterase inhibitor or memantine within 90 days prior to randomization through the end of the study;
17. Have taken or plan to take non-selective antihistamines within 7 days prior to randomization through the end of the study including diphenhydramine, chlorpheniramine;
18. Have taken or plan to take clozapine or bupropion within 30 days prior to randomization through the end of the study;
19. Have taken or plan to take narcotic analgesics more frequently than 2 times per week as needed for pain within 30 days prior to randomization through the end of the study;
20. Have participated in an investigational drug or device study within 30 days prior to randomization, or 90 days prior to randomization if the investigational drug study involved therapy for HD;
21. Have donated blood or blood products within 30 days of randomization or plan to donate blood during the study;
22. Are immediate family members or employees of the participating Site Investigator, or any of the participating site staff;
23. Are living in the same household with another subject that is enrolled in the study;
24. Have any condition or reason that, in the opinion of the Site Investigator, interferes with the ability of the subject to participate in or complete the study, which places the subject at undue risk, or complicates the interpretation of safety or efficacy data.
(List truncated due to space restrictions) |
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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.
Safety Outcomes
The safety of Dimebon compared to placebo will be assessed by the frequency of serious adverse events, the frequency of discontinuation of Dimebon treatment due to an adverse event, the frequency and severity of adverse events, the frequency of new laboratory and ECG abnormalities. In addition, the Columbia Suicide Severity Rating Scale will be administered at each study visit to collect and record suicidal ideation and attempts in a standardized fashion.
Pharmacokinetic Outcomes
There are no specific PK outcome measures for this study. The PK data from this study will be used in conjunction with data from other studies to develop a population PK model that links Dimebon exposure with efficacy and safety outcome measures.
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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 | No |
| 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 | 1 |
| 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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| The end of trial is defined as the last visit of the last patient 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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