| 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 | 12.1 |
| 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 |
1. To evaluate the efficacy of Dimebon as compared to placebo on a measure of behavior, the Neuropsychiatric Inventory (NPI);
2. To evaluate the efficacy of Dimebon as compared to placebo on a measure of self-care and daily function, the Alzheimers Disease Cooperative Study Activities of Daily Living (severe) (ADCS-ADLsev). |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objective:
1.To evaluate the efficacy of Dimebon as compared to placebo on a measure of the psychosis of AD as measured by the delusions and hallucinations domains of the NPI;
Secondary Objectives
1.To evaluate the efficacy of Dimebon as compared to placebo on the primary measure of cognition, the Severe Impairment Battery (SIB);
2.To evaluate the efficacy of Dimebon as compared to placebo on the secondary measure of cognition, the Mini-Mental State Examination (MMSE);
3.To evaluate the efficacy of Dimebon as compared to placebo on the primary measure of global function, the Clinicians Interview-Based Impression of Change, plus caregiver input (CIBIC-plus);
4.To evaluate the pharmacoeconomic impact of Dimebon and placebo using the Resource Utilization in Dementia Lite (RUD Lite�) instrument;
5.To evaluate quality of life using the EuroQoL 5 Domain Health Quality Assessment (EQ-5D) instrument;
6.To evaluate the safety andtolerability of Dimebon,20 mg orally |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Are men and women ≥ 50 years of age with probable AD judged to be moderate-to-severe (based on a Screening MMSE of 5 to 14, inclusive) and who are diagnosed according to the following criteria:
a. Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision (DSM-IV-TR) as listed in Appendix A;
b. National Institute of Neurological and Communicative Disorders and Stroke Alzheimers Disease and Related Disorder Associations Criteria (NINCDS-ADRDA) for probable AD as listed in Appendix B;
c. MMSE score between 5 and 14, inclusive;
d. Modified Hachinski Ischemic Score ≤ 4 (Appendix C);
2. Have either:
a. NPI score ≥ 6 on the domains of delusions and hallucinations, with delusions and/or visual or auditory hallucinations present at least intermittently for a minimum of four weeks; or
b. NPI total score ≥ 15 without delusions and hallucinations and a CMAI score ≥ 15;
3. Have symptoms of delusions and/or hallucinations, if present, that developed after the onset of dementia and that are judged by the investigator and caregiver to be severe enough to disrupt the patients and/or others functioning;
4. Are willing and able to give informed consent. If, and only 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 assent, if appropriate per local ethics committee judgment and consistent with local laws;
5. 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 central nervous system disease as assessed by the investigator with onset between the time of the last CT or MRI and the Screening visit, the scan should be repeated;
6. Have been taking the cholinesterase inhibitor, donepezil, for at least six months, with stable dosing at 5 or 10 mg/day for at least the last four months prior to Screening (and with no intent to change for the duration of the study);
7. Ambulatory and permitted to use an assistance device (e.g., walker or cane);
8. Were previously (in pre-AD condition) capable of reading, writing, and communicating effectively with others;
9. 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 patients cognitive, functional, and emotional states, and of the patients personal care. The caregiver must be willing to accompany the patient to all study visits, supervise study drug administration, and (in addition to the patient) report adverse events. 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 NPI, ADCS-ADLsev, CIBIC-plus, RUD Lite�, and EQ-5D assessment tools;
10. Living in the community (not under 24-hour supervision in a nursing home or institution);
11.If female, is either a) of reproductive potential and compliant in using adequate birth control or b) not of reproductive potential.
12. If male, is either a) of reproductive potential and compliant in using adequate birth control or b) not of reproductive potential. |
|
| 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 [e.g., thalamus, hippocampus]);
2. Have any major medical illness or unstable medical condition within six months of the Screening visit that may interfere with the patients ability to comply with study procedures and abide by study restrictions, or with the ability to interpret safety data.3.Are pregnant or breastfeeding females;
Reside in a nursing home or institution where s/he is receiving 24-hour supervision;
5. Have a caregiver who is not clinically trained and is paid to care for more than two patients;
6. Have known human immunodeficiency virus (HIV) seropositivity; NOTE: HIV testing will not be performed as part of the Screening visit laboratories;
7.Have any of the following laboratory abnormalities at the Screening visit:a.Clinically significant Vitamin B12 levels less than the lower limit of normal or on replacement Vitamin B12 for fewer than three months prior to enrollment;b.Clinically significant folate levels less than the lower limit of normal or on replacement folate therapy for fewer than three months prior to enrollment;c.Thyroid-stimulating hormone (TSH) levels greater than the upper limit of normal AND a free thyroxine level lower than the lower limit of normal;d.Positive Rapid Plasma Reagin (RPR) confirmed by Fluorescent Treponemal Antibody - Absorption [FTA-ABS]);e.Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than two times the upper limit ofnormal;f.Renal impairment with a serum creatinine (Cr) > 133 �mol/L (1.5 mg/dL);g.Hematocrit (Hct) less than 37% for males or less than 32% for females, absolute neutrophil cell count of less than or equal to 1,500/ �L, or platelet cell count of less than 120,000/�L;8.Have taken or plan to take a cholinesterase inhibitor other than donepezil within six months prior to Screening through the end of study;
9.Have taken or plan to take memantine within 90 days prior to Screening through the end of study;
10. Have taken or plan to take a prescription medical food (e.g., Axona) or prescription nutriceutical marketed for AD or cognitive impairment within 30 days of Screening through the end of study;11.Have a history of hypersensitivity to Dimebon or other antihistamines;12.Have used non-selective antihistamines within seven days prior to the start of dosing (Day 1); 13. Have used or plan to use the following medications from 30 days prior to Screening through the end of study:a.Narcotic analgesics more frequently than two times per week as needed for pain; b.Low potency antipsychotics
;Anti-Parkinsons Disease medications for the treatment of Parkinsonian Symptom Complex;Insulin;
Lithium;Clozapine;Bupropion;Valproate;or Tertiary amine anti-depressants;14. Have psychiatric or behavioral symptoms severe enough at Screening such that it is likely, in the opinion of the investigator, that a) initiation of new psychotropic therapy or b) an increase in the dose of existing psychotropic therapy, will be required during the double-blind treatment period;15.Have previously participated in a clinical trial evaluating Dimebon;
16. Have participated in an investigational drug or device study within 30 days prior to Screening, or 90 days prior to Screening if the investigational drug study involved therapy for AD; |
|
| 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:
a. A comparison between the mean change from Baseline to Week 26 in the Dimebon group and the placebo group on the NPI total score;
b. A comparison between the mean change from Baseline to Week 26 in the Dimebon group and the placebo group on the ADCS-ADLsev;
2. Key secondary outcome measures:
a. A comparison of the response rates based on the NPI domains of delusions and hallucinations at Week 26;
3. Additional secondary outcomes:
a. A comparison between the mean change from Baseline to Week 26 of the Dimebon group and the placebo group on the SIB and on the MMSE;
b. A comparison between the distributions of the Dimebon group and the placebo group on the CIBIC-plus (ADCS-CGIC) at Week 26;
c. Comparisons of the Dimebon group and the placebo group at Weeks 6, 12, and 18 for all outcomes, as applicable;
d. 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 study drug treatment due to an adverse event, the frequency and severity of adverse events, as well as the frequency of new and clinically significant laboratory and ECG abnormalities among the treatment groups.
Pharmacokinetics:
Dimebon plasma concentrations will be measured at Baseline and Week 12. 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.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 | 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 | 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.8.2.3.1 | Comparator description |
| - same IMP used at different dosage |
|
| 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 | 9 |
| 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 |
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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
| |
| 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 | |
| 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 |
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