| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To determine the benefit of Dimebon as compared to placebo on
the primary measure of cognition and memory, the Alzheimer’s
Disease Assessment Scale – cognitive subscale (ADAS-cog); and
• To determine the benefit 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). |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the benefit 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 benefit of Dimebon as compared to placebo on
a measure of behavior, the Neuropsychiatric Inventory (NPI);
• To determine the safety of treatment with Dimebon as compared
to placebo;
• To establish the covariates that may impact the variability in
pharmacokinetic parameters;
• To develop a pharmacokinetic model linking Dimebon exposure
with efficacy and safety outcomes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Males or females ≥ 50 years of age;
• Diagnosis of probable AD according to the following criteria:
• Diagnostic and Statistical Manual of Mental Disorders-IV Text
Revision (DSM-IV-TR) as listed in Appendix A;
• National Institute of Neurological and Communicative
Disorders and Stroke – Alzheimer’s Disease and Related
Disorder Association’s Criteria (NINCDS-ADRDA) for
probable AD as listed in Appendix B;
• MMSE score between 10 and 24, inclusive;
• Modified Hachinski Ischemic Score ≤ 4 (Appendix C);
• Brain imaging such as magnetic resonance imaging and/or
computed tomography within three months of enrollment;
• Patients must have at least six years of prior education and
should have previously (in pre-AD condition) been capable of
reading, writing, and communicating effectively with others;
• Patients must be able to cooperate with study drug administration
and study procedures and to abide by the study restrictions;
• Patients must be willing and able to give informed consent. If
the patient is not competent, a mentally-competent legallyacceptable
representative must provide informed consent on their
behalf, and the patient must provide assent;
• Patients must have a caregiver who assists the patient at least five
days per week for at least three hours per day and has intimate
knowledge of the patient’s cognitive, functional, and emotional
states, and of the patient’s personal care. The caregiver must be
willing to accompany the patient to all study visits, and must be
willing to supervise study drug administration. The caregiver must
be willing and able to give informed consent, be able to read and
write, and be capable of providing responses to the CIBIC-plus,
ADCS-ADL, NPI, and the RUD Lite assessment tools;
• Patients may be living in an assisted care facility if living
independently;
• Female patients must be surgically sterile or postmenopausal (for
at least two years) or agree to use double-barrier method of birth
control. Male patients must agree to utilize a double-barrier
method of birth control during the study and for at least 30 days
following the last dose of study drug. The double-barrier method
includes two of the following forms of contraception: condom,
contraceptive sponge, diaphragm, or cervical ring with
spermicidal gel or foam. |
|
| E.4 | Principal exclusion criteria |
•Major structural brain disease (e.g., ischemic infarcts, subdural hematoma, hemorrhage, hydrocephalus, brain tumors, multiple subcortical ischemic lesions, or a single lesion in a critical region);
•Any major medical illness or unstable medical condition within six months of screening that may interfere with the patient’s ability to comply with study procedures and abide by study restrictions including:
•Any physical disability that would prevent completion of study procedures or assessments;
•Active peptic ulcer disease within the last three months;
•Diabetes mellitus requiring insulin treatment;
•History of cancer within five years of enrollment with the exception of non melanoma skin cancers or prostate cancer that has been stable for six months;
•Hypotension, systolic blood pressure < 86 mmHg or bradycardia with heart rate less than 46 beats per minute on more than one occasion three months prior to enrollment;
•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 three months prior to enrollment;
•Clinically significant ECG abnormalities or ECG at the Screening visit with a corrected QT interval by the Fridericia correction formula of > 460 msec for males and > 470 msec for females;
•History of clinically-relevant ventricular arrhythmias, second-degree or complete heart block without pacemaker placement, or left bundle branch block;
•History of clinically apparent stroke;
•History of traumatic brain injury with remaining neurological deficit;
•Neurodegenerative disease other than AD (e.g., Parkinson’s Disease, Huntington’s Disease, amyotrophic lateral sclerosis);
•History of epilepsy or seizure disorder requiring ongoing treatment, or any seizure or loss of consciousness within the six months preceding enrollment;
•Any psychiatric diagnosis according to DSM-IV-TR that may interfere with the patient’s ability to perform the study and all assessments (e.g., alcohol or drug-related abuse or alcohol dependence [Appendix D], or alcohol or drug-related dementia, major depression, mental retardation, schizophrenia, bipolar disorder, etc.);
•Pregnant or lactating females;
•Residence in a nursing home or assisted care facility with need for 24-hour care and supervision;
•Caregiver is not clinically trained and is paid to care for more than two patients.
•History of hypersensitivity to Dimebon or other antihistamines;
•Known human immunodeficiency virus (HIV) seropositivity or Acquired Immunodeficiency Syndrome (AIDS); history of Hepatitis B (HBV) or Hepatitis C viral (HCV) infection. NOTE: HIV, HBV, and HCV testing will not be performed as part of the Screening visit laboratories;
•Any of the following laboratory abnormalities at the Screening visit:
•Clinically significant Vitamin B12 levels less than the lower limit of normal or on replacement Vitamin B12 for less than 3 months prior to enrollment;
•Clinically significant folate levels less than the lower limit of normal or on replacement folate therapy for less than 3 months prior to enrollment;
•Thyroid-stimulating hormone levels greater than the upper limit of normal AND a free thyroxine lower than the lower limit of normal;
•Positive Rapid Plasma Reagin (RPR) confirmed by Fluorescent Treponemal Antibody - Absorption [FTA-ABS]);
•Total bilirubin (Tbili), alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels greater than two times the upper limit of normal;
•Renal impairment with a serum creatinine (Cr) > 133 µmol/L (1.5 mg/dL);
•Hematocrit (Hct) less than 37% for males and less than 32% for females, absolute neutrophil cell count of less than or equal to 1,500/microliter (µL), or platelet cell count of less than 100,000/µL;
•Use of cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, or huperzine) or memantine within 90 days prior to enrollment;
•Use of prescription medical food (e.g., Axona™) or prescription nutriceuticals marketed for AD or cognitive impairment within 30 days of Screening and throughout the study;
•Use of non-selective antihistamines within 7 days prior to enrollment;
•Use of the following medications within 30 days prior to enrollment:
• Narcotic analgesics more frequently than two times per week as needed for pain;
• Low potency antipsychotics (e.g., chlorpromazine, thioridazine);
• Antihypertensive agents with frequent central nervous system side effects (e.g., clonidine);
• Anti-Parkinson’s Disease medications (e.g., selegiline, levodopa, amantadine) for the treatment of Parkinson's Disease;
• Lithium;
• Clozapine;
• Bupropion;
•Participation in a previous clinical trial of Dimebon.
•Participation in an investigational drug or device study within 30 days prior to study entry, or 90 days prior to study entry if the investigational drug study involved therapy for AD; |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• A comparison between the mean change from baseline in the Dimebon 20 mg TID treatment group and the placebo group on the ADAS-cog at Week 26; and
• 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.
• Key Secondary Endpoint: A comparison between the mean change from baseline to Week 26 of the Dimebon 20 mg TID treatment group and the placebo group on the ADCS-ADL;
• A comparison between the mean change from baseline to Week 26 of the Dimebon 20 mg TID treatment group and the placebo group on the NPI;
• A comparison between the Dimebon 20 mg TID treatment group and the placebo group in the emergence of new delusions and hallucinations or in the reduction of delusions and hallucinations as assessed by subdomains of the NPI;
• A comparison between the mean change from baseline to Week 26 of the Dimebon 20 mg TID treatment group and the placebo group on the MMSE;
• A comparison between the mean change from baseline to Week 26 of the Dimebon 20 mg TID treatment group and the placebo group on the RUD Lite;
• Comparisons of each outcome measure between the Dimebon 20 mg TID group and the placebo group using the mean change from baseline to Week 12 of the Dimebon 20 mg TID;
• Comparisons of each outcome measure between the Dimebon 5 mg TID group and the placebo group using the mean change from baseline to Week 26.
• The safety of Dimebon among the three treatment groups 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, as well as the frequency of new laboratory and ECG abnormalities.
• The impact of covariates will be evaluated in order to identify underlying factors responsible for the variability of pharmacokinetic parameters and to identify sub-populations. Every effort will be made to develop a model that links Dimebon exposure (e.g., the maximum plasma concentration at one hour [C1h], and the minimum or trough plasma concentration [Cmin]) with the co primary outcome measures, as well as with key adverse events. |
|
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
|
| 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
|
| The end of trial is defined as the last visit of the last patient undergoing the trial. |
|
| 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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