E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Alzheimer’s Disease is a brain disease that causes problems with memory, thinking and behaviour. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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
•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 |
•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);
•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;
•To evaluate quality of life using the EuroQoL 5 Domain Health Quality Assessment (EQ-5D) instrument;
•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. |
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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 in the 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 in the Protocol;
c. Screening MMSE score between 12 and 24, inclusive;
d. Modified Hachinski Ischemic Score ≤ 4 (Appendix C in the Protocol);
4. Have been taking the cholinesterase inhibitor, donepezil, at a stable dose of 10 mg daily for at least four months prior to Day 1 (and with no intent to change for the duration of the study);
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E.4 | Principal exclusion criteria |
1 Have major structural brain disease (eg 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 w/in 6mos 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 w/in 5yrs of enrollment with the exception of nonmelanoma skin cancers or prostate cancer that has been stable for 6mos, or AJCC Stage 0 or 1 cancers that have a remote probability of recurrence, in the opinion of the investigator, in consultation with the Sponsor;
-The following cardiovascular parameters:
•Hypotension (sitting SBP < 86mmHg) or bradycardia with a sitting HR < 50bpm at Screening or Day 1 or on > 1 occasion within 3mos prior to enrollment;
•Uncontrolled hypertension as indicated by a resting SBP > 170mmHg or DBP > 105mmHg at Screening or Day 1 or on > 1 occasion w/in 3mos prior to enrollment;
•A corrected QTcF greater than 470msec on an ECG at the Screening or Day 1 visit, based on the value from central over read (screening ECG may be repeated 1x, if medically indicated in the opinion of the investigator);
•Cardiovascular disease including any of the following: unstable angina, decompensated congestive heart failure, clinically relevant arhythmias. NOTE: A history of these conditions is acceptable, if stable under medical management. Patients with pacemakers or patients on anticoagulant therapy may be included;
•Active cardiovascular disease.
-A history of traumatic brain injury with residual neurological deficit or stroke;
-A diagnosis of a CNS disease other than AD;
-A history of epilepsy or seizure disorder requiring ongoing treatment, or any seizure or loss of consciousness w/in 6mos 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 (eg, alcohol or drug-related abuse or alcohol dependence, or alcohol or drug-related dementia, major depression, mental retardation, schizophrenia, bipolar disorder, etc).
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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;
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
2. Key secondary outcome measures in this study include:
a. 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 Clinician's Interview Based Impression of Change, plus caregiver input (CIBIC-plus);
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;
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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
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 | No |
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 |
Australia |
Belgium |
Finland |
France |
Germany |
Italy |
New Zealand |
Sweden |
United Kingdom |
United States |
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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 | 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 |