| 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 | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
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| 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 |
Co-Primary Objectives
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To evaluate the efficacy of Dimebon as compared to placebo on the primary measure of cognition and memory, the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog);
•
To evaluate the efficacy 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). |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
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To evaluate the efficacy 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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To evaluate the efficacy of Dimebon as compared to placebo on a measure of behavior, the Neuropsychiatric Inventory (NPI);
•
To evaluate the pharmacoeconomic benefit of Dimebon as compared with placebo using the Resource Utilization in Dementia Lite (RUD Lite©) instrument;
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To evaluate quality of life using the EuroQoL 5 Domain Health Quality Assessment (EQ-5D) instrument;
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To evaluate the safety and tolerability of Dimebon at two doses, 20 mg orally three times per day (TID) and 5 mg orally TID over 52 weeks;
•
To obtain selected pharmacokinetic (PK) data for both the 5 mg TID and 20 mg TID doses of Dimebon. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Are men and women ≥ 50 years of age with a diagnosis of probable AD according to the following criteria:
a. Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision (DSM-IV-TR) as listed in Appendix A of the study protocol;
b. 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 of the study protocol;
c. MMSE score between 12 and 24, inclusive;
d. Modified Hachinski Ischemic Score ≤ 4 (Appendix C) of the study protocol;
2. Are willing and able to give informed consent. If the patient is not competent, a mentally-competent legally-acceptable representative must provide informed consent on his/her behalf, and the patient must provide verbal assent;
3. Have had brain imaging such as computed tomography (CT) and/or magnetic resonance imaging (MRI) within 12 months of enrollment, consistent with a diagnosis of probable AD without any other clinically significant co-morbid pathologies found. If there has been a significant change in clinical status suggestive of stroke or other possible neurological disease with onset between the time of the last CT or MRI and the Screening evaluation, the scan should be repeated if considered appropriate by the investigator;
4. Have been taking the cholinesterase inhibitor, donepezil, for at least six months, with stable dosing at 10 mg/day for at least the last four months (and with no intent to change for the duration of the study) prior to Day 1;
5. Have at least eight years of prior education and should have previously (in pre-AD condition) been capable of reading, writing, and communicating effectively with others;
6. Have a caregiver who assists (or directly supervises) 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 ADCS-ADL, CIBIC-plus, NPI, the RUD Lite©, and EQ-5D assessment tools;
7. May be living in an assisted care facility if living independently;
8. 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 patients not of reproductive potential may have undergone menopause, hysterectomy, bilateral oophorectomy, or 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 tubal ligation must be documented;
9. 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. |
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| E.4 | Principal exclusion criteria |
1 Have 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);
2 Have any major medical illness or unstable medical condition within 6 mos. of Screening that may interfere with the patient’s ability to comply with study procedures and abide by study restrictions, or with the ability to interpret safety data, including:
-Any physical disability that would prevent completion of study procedures or assessments;
-A diagnosis of diabetes mellitus requiring insulin treatment;
-A history of cancer within 5 yrs of enrollment with the exception of non-melanoma skin cancers or prostate cancer that has been stable for 6 mos.;
-The following cardiovascular parameters:
•Hypotension (systolic blood pressure < 86 mmHg) or bradycardia with heart rate < 50 bpm at Screening or on > 1 occasion within 3 mos. 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 > 1 occasion within 3 mos. prior to enrollment;
•A corrected QTcF interval of > 470 msec on an ECG at the Screening visit;
•Active cardiovascular disease including any of the following: unstable angina, decompensated congestive heart failure, clinically relevant arrhythmias.
-A history of traumatic brain injury with residual neurological deficit or stroke;
-A diagnosis of a central nervous system disease other than AD;
-A history of epilepsy or seizure disorder requiring ongoing treatment, or any seizure or loss of consciousness within 6 mos. prior to enrollment;
-Any current 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, or alcohol or drug-related dementia, major depression, mental retardation, schizophrenia, bipolar disorder, etc.).
3 Are pregnant or breastfeeding females;
4 Reside in a nursing home or assisted care facility with need for 24-hr care and supervision;
5 Have a caregiver who is not clinically trained and is paid to care for > 2 patients;
6 Have known HIV seropositivity;
7 Have any of the following laboratory abnormalities at the Screening visit:
-Clinically significant Vitamin B12 levels < the LLN or on replacement Vitamin B12 for < 3 mos. prior to enrollment;
-Clinically significant folate levels < the LLN or on replacement folate therapy for < 3 mos. prior to enrollment;
-TSH levels > the ULN and a free thyroxine level < the LLN;
-Positive Rapid Plasma Reagin confirmed by Fluorescent Treponemal Antibody - Absorption);
-Total bilirubin, alanine aminotransferase or aspartate aminotransferase > 2x the ULN;
-Renal impairment with a serum creatinine > 133 μmol/L (1.5 mg/dL);
-Hematocrit < 37% for males and < 32% for females, absolute neutrophil cell count of ≤ 1,500/ μL, or platelet cell count of < 120,000/μL;
8 Have taken or plan to take non-donepezil cholinesterase inhibitors 6 mos. prior to Day 1 through the end of study;
9 Have taken or plan to take memantine within 90 days prior to Day 1 through the end of study;
10 Use of prescription medical food or prescription nutriceuticals marketed for AD or cognitive impairment within 30 days of Screening and throughout the study;
11 History of hypersensitivity to Dimebon or other antihistamines;
12 Have used non-selective antihistamines within 7 days prior to Day 1;
13 Have used or plan to use the following medications from 30 days prior to Day 1 through the end of study:
-Narcotic analgesics more frequently than 2x per week as needed for pain;
-Low potency antipsychotics;
-Anti-Parkinson’s Disease medications for the treatment of Parkinsonian Symptom Complex;
-Insulin;
-Lithium;
-Clozapine;
-Bupropion;
14 Have previously participated in a clinical trial evaluating Dimebon;
15 Have participated in an investigational drug or device study within 30 days prior to Day 1, or 90 days prior to Day 1 if the investigational drug study involved therapy for AD;
1 Have been treated with immunomodulators to treat AD within the last 2 yrs;
17 Have donated blood/blood products within 30 days of Day 1 or plan to donate blood during the study;
18 Are immediate family members or employees of the participating investigator, or any of the participating site staff;
19 Have any condition or reason that, in the opinion of the investigator, interferes with the ability of the patient to participate in or complete the trial, which places the patient at undue risk, or complicates the interpretation of safety data. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Efficacy outcome measures in this study include the following:
1. Co-primary outcome measures in this study:
a. A comparison between the mean change from Baseline to Week 52 in the Dimebon 20 mg TID treatment group and the placebo group on the ADAS-cog;
b. A comparison between the mean change from Baseline to Week 52 in the Dimebon 20 mg TID treatment group and the placebo group on the ADCS-ADL;
2. Key secondary outcome measures in this study include:
a. A comparison of rates of change in ADCS-ADL across time between the Dimebon 20 mg TID treatment group and the placebo group;
b. A comparison between the mean change from Baseline to Week 52 in the Dimebon 5 mg TID treatment group and the placebo group on the ADAS-cog;
c. A comparison between the mean change from Baseline to Week 52 in the Dimebon 5 mg TID treatment group and the placebo group on the ADCS-ADL;
3. Additional secondary endpoints for this study include:
a. A comparison between the distributions of the Dimebon 20 mg TID treatment group and the placebo group on the ADCS-CGIC at Week 52;
b. A comparison between the mean change from Baseline to Week 52 of the Dimebon 20 mg TID treatment group and the placebo group on the NPI;
c. A comparison between the mean change from Baseline to Week 52 of the Dimebon 20 mg TID treatment group and the placebo group on the MMSE;
d. Comparisons of the Dimebon 20 mg TID treatment group and the placebo group at Weeks 13, 26, and 39 for all outcomes;
e. Comparisons of the Dimebon 5 mg TID treatment group and the placebo group at Weeks 13, 26, and 39 for all outcomes and at Week 52 for outcomes other than the co-primary outcomes;
f. RUD Lite© and EQ-5D data summarized descriptively by treatment group.
Safety:
The safety of Dimebon 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 among the three treatment groups. Safety measures thus include adverse events, vital signs, physical examinations, ECGs, and clinical laboratory testing.
Pharmacokinetics:
Dimebon plasma concentrations will be measured at Baseline and Week 13. The impact of covariates will be evaluated in order to identify underlying factors responsible for the variability of PK parameters and to identify sub-populations. |
|
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 40 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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