A Phase 3, Randomized, Double-Blind, Placebo-Controlled Safety and Efficacy Study of Dimebon in Patients with Mild-to-Moderate Huntington Disease

Subjects eligible to participate in this study are persons who:
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 five 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.

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 responding *yes* to question 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 at least six months, or American Joint Committee on 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 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 experienced a serious adverse event assessed as at least possibly related to study drug use in a previous clinical study of Dimebon;
14. Have a known history of human immunodeficiency virus (HIV) seropositivity; NOTE: HIV testing will not be performed as part of the Screening visit laboratories;
15. Have any of the following laboratory abnormalities at the Screening visit:
a. Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) levels greater than two times the upper limit of normal;
b. Renal impairment with a serum creatinine (Cr) > 1.5 mg/dL (133 µmol/L);
c. Hematocrit less than 37% for males and less than 32% for females, absolute neutrophil cell count of less than 1,500/µL, or platelet cell count of less than 120,000/µL;
16. Have taken or plan to take a cholinesterase inhibitor (donepezil, rivastigmine, galantamine, tacrine, or huperzine) 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 seven 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 two 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.