| 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 | 12.0 |
| 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 |
The co-primary objectives of this study are:
1. To determine the effect of dimebon, as compared to placebo, on the primary measure of cognition, the Severe Impairment Battery (SIB) in patients with moderate to severe Alzheimer’s disease (AD)
2. To determine the effect of dimebon, as compared to placebo, on the primary measure of self-care and daily function, the Alzheimer’s Disease Cooperative Study -Activities of Daily Living (severe) (ADCS-ADLsev) scale in patients with moderate-to-severe AD |
|
| E.2.2 | Secondary objectives of the trial |
To determine the effect of dimebon, as compared to placebo on the following efficacy and safety measures in patients with moderate-to-severe AD:
Key Secondary Objectives:
1. Neuropsychiatric Inventory (NPI) total score (behaviour);
2. Sum of the delusions and hallucinations subdomain scores of the NPI (a measure of AD-related psychosis);
Other Secondary Objectives:
1. Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC+, global function);
2. Mini-Mental State Examination (MMSE, cognition);
3. Resource Utilization in Dementia (RUD-Lite) and quality of life (EuroQol 5-domain);
4. Influence of patient covariates on dimebon pharmacokinetics and PK/PD
5. Safety and tolerability assessments, including AEs, labs, and ECGs
|
|
| 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 1 of 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
c. MMSE score between 5 and 14 inclusive
d. Modified Hachinski Ischemic Score ≤4
2. Are willing and able to give informed consent. If the patient is deemed to not have capacity to provide consent, a mentally competent legally acceptable representative must provide informed consent on their behalf, and the patient must provide assent
3. Have had brain imaging such as magnetic resonance imaging (MRI) and/or computed tomography (CT) approximately within twelve months of Screening, 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 neurological disease with onset between the time of the last MRI or CT and the Screening evaluation, the scan should be repeated if considered appropriate by the Investigator
4. Must be on background anti-demtia monotherapy only with the NMDA receptor antagonist, memantine, for a minimum of six (6) months preceding the Screening MMSE and at a stable dose and regimen orally daily for at least four (4) months with no intent to change this regimen while participating in the study
5. Must be or have previously (in pre AD condition) been literate, and capable of reading, writing, and communicating effectively with others
6. 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 to supervise study drug administration, as well as report adverse events. The caregiver must be willing and able to give informed consent for their own participation, be able to read and write, and be capable of providing responses to the CIBIC plus, ADCS ADLsev, NPI, EQ 5D, and RUD Lite assessment tools
7. If female, is 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, ie, 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 be patients who have undergone menopause, hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. Menopause is defined as 1 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; and
8. If male, is 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 |
|
| E.4 | Principal exclusion criteria |
1. Have clinically important structural brain disease (eg, ischemic infarcts, subdural
hematoma, hemorrhage, etc.);
2. Have any major medical illness or unstable medical condition within six months of
Screening that, in the opinion of the investigator, 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:
a. Any physical disability that would prevent completion of study procedures or
assessments
b. A history of cancer within five years of enrollment with the exception of
non-melanoma skin cancers or prostate cancer that has been stable for at least six
months or Grade 0 or Grade 1 cancers that have a remote probability of recurrence,;
c. The following cardiovascular parameters:
• Hypotension - systolic blood pressure <86 millimeters of mercury (mmHg) or
bradycardia with heart rate less than 50 beats per minute;
• Uncontrolled hypertension as indicated by a resting systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg;
• A corrected QT interval by the Fridericia correction formula (QTcF) of greater than 470 milliseconds (msec) on an electrocardiogram (ECG) at the Screening Visit based on value from central over-read;
• Active cardiovascular disease..
d. A history of traumatic brain injury with remaining neurological deficit;
e. A diagnosis of a dementing central nervous system disease other than AD;
f. A history of epilepsy or seizure disorder requiring ongoing treatment, or any seizure or unexplained loss of consciousness within the six months preceding Screening;
g. 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 lactating females;
4. Reside in a nursing home or assisted care facility with need for direct continuous medical care and nursing supervision;
5. Have a caregiver who is paid to care for more than two patients, unless that caregiver is clinically trained;
6. Have a history of previous exposure to dimebon or who have participated in a previous dimebon clinical trial;
7. Have known human immunodeficiency virus (HIV) seropositivity.;
8. Have any of the following laboratory abnormalities at the Screening visit:
a. Clinically significant Vitamin B12 levels less than the lower limit of normal (LLN) or
on replacement Vitamin B12 for less than three months prior to enrollment;
b. Clinically significant folate levels less than the lower limit of normal or on
replacement folate therapy for less than three months prior to enrollment;
c. Thyroid-stimulating hormone (TSH) levels greater than the upper limit of normal
(ULN) AND a free thyroxine lower than the lower limit of normal;
d. Positive Rapid Plasma Reagin (RPR) confirmed by Fluorescent Treponemal
Antibody - Absorption [FTA-ABS]);
e. Total bilirubin (Tbili), alanine aminotransferase (ALT), or aspartate aminotransferase (AST) levels greater than two times the upper limit of normal;
f. Renal impairment with a serum creatinine (Cr) >133 µmol/L (1.5 mg/dL);
g. Hematocrit, absolute neutrophil count, and/or platelet count below the LLN indicating clinically significant anemia, neutropenia, and/or thrombocytopenia.
9. Taken or plan to take prescribed anti-dementia agents besides memantine, from 2 months prior to the screening MMSE through the End of Study;
10. Have taken a prescription medical food or prescription nutriceuticals marketed for AD;
11. Have used nonselective antihistamines within 7 days prior to the start of dosing (Day 1) or intend to use such agents through the end of study;
12. Have used the following medications within 30 days prior to randomization
(Study Day 1):
a. Narcotic analgesics more frequently than two days per week as needed for pain;
b. Low potency antipsychotics;
c. Agents with significant anticholinergic activity;
d. Medications for the treatment of Parkinson’s Disease;
e. Short acting/prandial insulin;
f. Lithium;
g. Clozapine;
h. Bupropion.
13. Have participated in an investigational drug or device study within 30 days prior to study entry (Screening MMSE), or 90 days prior to study entry (Screening MMSE) if the investigational drug study involved therapy for AD;
14. Have been treated with immunomodulators to treat AD within the last two years;
15. Have donated blood or blood products within 30 days of Study Day 1 or plan to donate blood during the study;
16. Are immediate family members or employees of the participating investigator, or any of the participating site staff, or are living with a family member enrolled in the study;
17. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The co primary endpoints in this trial are change from baseline in the SIB and ADCS ADLsev as cognitive and functional measures, respectively at Week 26 (LOCF). |
|
| 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 | No |
| 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 | No |
| 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 | 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 | 60 |
| 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
| |
| 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 | 15 |
| 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 | 15 |
Print
