| 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 |
To assess the following primary and secondary objectives in patients with moderate-to-severe Alzheimer’s disease (AD) and behavioral and psychiatric symptoms:
Co-Primary Objectives
• To evaluate the efficacy of Dimebon as compared to placebo on a measure of behavior, the Neuropsychiatric Inventory (NPI);
• 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 (severe) (ADCS ADLsev).
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| E.2.2 | Secondary objectives of the trial |
Key Secondary Objective
• 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
• To evaluate the efficacy of Dimebon as compared to placebo on the primary measure of cognition, the SIB;
• To evaluate the efficacy of Dimebon as compared to placebo on the secondary measure of cognition, the MMSE;
• To evaluate the efficacy of Dimebon as compared to placebo on the primary measure of global function, the CIBIC-plus;
• To evaluate the pharmacoeconomic impact of Dimebon and placebo using the RUD Lite© instrument;
• To evaluate quality of life using the EQ-5D instrument;
• To evaluate the safety and tolerability of Dimebon, 20 mg orally TID, as compared to placebo;
• To obtain selected pharmacokinetic (PK) data for the 20 mg TID dose 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 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 – Alzheimer’s Disease and Related Disorder Association’s 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 patient’s and/or other’s 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 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, 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, 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.
12. 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.
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| E.4 | Principal exclusion criteria |
1. Have major structural brain disease;
2. Have any major medical illness or unstable medical condition w/in 6 mos of Screening that may interfere with the patient’s ability to comply with study procedures & 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 history of cancer within 5 yrs of enrollment with the exception of non melanoma skin cancers or prostate cancer that has been stable for at least 6 mos; The following cardiovascular parameters:
•Hypotension or bradycardia with heart rate < 50 bpm at Screening or on more than one occasion w/in 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 more than 1 occasion within 3 mos prior to enrollment;
•A QTcF of > 470 msec on an ECG at Screening;
•Active cardiovascular disease;
d. A history of traumatic brain injury with residual neurological deficit or stroke;
e. A diagnosis of a CNS disease other than AD;
f. A history of epilepsy or seizure disorder requiring ongoing treatment, or any seizure or loss of consciousness w/in 6 mos prior to enrollment;
g. Symptoms of delusions and hallucinations that are better accounted for by another general-medical or psychiatric condition or by direct physiological effects of a substance;
h. Symptoms of agitation and aggression that can be better explained by another medical or psychiatric condition, medication, or substance abuse;
i. Meeting DSM-IV-TR criteria for schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features;
j. Any current psychiatric diagnosis according to DSM-IV-TR that may interfere with the patient’s ability to perform the study and all assessments;
3. Are pregnant or breastfeeding females;
4. Reside in a nursing home or institution where s/he is receiving 24-hr supervision;
5. Have a caregiver who is not clinically trained and is paid to care for more than 2 patients;
6. Have known HIV seropositivity;
7. Have any of the following laboratory abnormalities at Screening:
a. Clinically significant Vitamin B12 levels < the lower limit of normal (LLN) or on replacement Vitamin B12 for < 3 mos prior to enrollment;
b. Clinically significant folate levels < the LLN or on replacement folate therapy for < 3 mos prior to enrollment;
c. TSH levels > the ULN AND a free thyroxine level lower than the LLN;
d. Positive Rapid Plasma Reagin confirmed by Fluorescent Treponemal Antibody - Absorption;
e. Total bilirubin, ALT or AST > 2 times the ULN;
f. Renal impairment with a serum creatinine > 133 µmol/L (1.5 mg/dL);
g. Hematocrit < 37% for males or < 32% for females, absolute neutrophil cell count of less than or equal to 1,500/ µL, or platelet cell count of < 120,000/µL;
8. Have taken or plan to take a cholinesterase inhibitor other than donepezil within 6 mos 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 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 7 days prior to the start of dosing;
13. Have used or plan to use the following medications from 30 days prior to Screening through the end of study: Narcotic analgesics more frequently than 2 times 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; Valproate; 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;
17. Have been treated with immunomodulators to treat AD within the last 2 years;
(list truncated due to space restrictions) |
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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:
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 |
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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 | 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.8.3 |
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 |
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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 | 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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