A Phase 3 Efficacy Study Of Dimebon In Patients With Moderate To Severe Alzheimer's Disease

Study Overview
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Brief Summary
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No Dimebon clinical data exist yet in patients with disease that has advanced to the moderate-to-severe stage. Therefore, this study evaluates the safety and efficacy of Dimebon in patients with moderate-to-severe AD who are receiving existing background therapy with memantine.

Detailed Description
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This study was terminated on May 7, 2010 due to modification of the dimebon development plan following the lack of demonstration of efficacy in the completed DIM14 (CONNECTION) Study. The study was not terminated due to any safety findings. Dimebon has been well-tolerated in clinical trials. Demonstration of efficacy for dimebon in Alzheimer's disease is pending completion of the ongoing DIM18 (CONCERT) Study.

Official Title
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A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled 26-Week Trial To Evaluate The Efficacy And Safety Of Dimebon In Patients With Moderate-To-Severe Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Dimebon 20 mg po TID
* Drug: Placebo po TID


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are men and women ≥ 50 years of age with a diagnosis of Alzheimers disease. Have a Mini-Mental State Exam between 5 and 14 inclusive. Have been taking the medication memantine (ie., Namenda) for at least six months prior to this study. Must have a caregiver who assists the patient at least five days per week for at least three hours per day, who can accompany patient to study visits, and who has an intimate knowledge of the patient's health states and personal care. Exclusion Criteria: Have taken medicines for Alzheimers disease other than memantine (e.g., donepezil, rivastigmine, galantamine, tacrine) within 2 months prior to this study. Dementia other than Alzheimers disease. Any medical condition or reason that interferes with the ability of the patient to participate in or complete the trial or places the patient at undue risk, as judged by the study doctor.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dimebon<br> | Drug: Dimebon 20 mg po TID<br>* Dimebon 10 mg po TID for 1 week followed by Dimebon 20 mg TID for 25 weeks<br>* Other names: Latrepirdine Dihydrochloride;|
| Placebo Comparator: Placebo<br> | Drug: Placebo po TID<br>* Placebo (matched to Dimebon) po for 26 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Severe Impairment Battery (SIB) Score at Week 26 | SIB developed for evaluation of cognitive function in participants, who demented to a degree that they cannot complete conventional neuropsychological testing. Test items consisted of simple, one-step commands presented with gestural cues and instructions that were repeated if necessary. SIB test consisted of 51-item scale, divided into 9 subscales: social interaction (0-6), memory (0-14), orientation (0-6), language (0-46), attention (0-6), praxis(0-8), visuospatial ability(0-8), construction(0-4), orienting to name(0-2). Total possible score:0-100; lower score = greater cognitive impairment. | Baseline, Week 26 | 
| Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (Severe) (ADCS-ADLsev) Score at Week 26 | ADCS-ADLsev: 19-item scale measures basic and instrumental abilities in participant population and had good metric properties and reliability in detecting change. Individual score range: 0 to 5 for telephone, 0 to 4 for dressing, watch television, get around outside home, 0 to 3 for eating, walking, toilet, bathing, grooming, conversation/small talk, clear dishes, find personal belongings, obtain beverages, dispose of garbage, left on own, 0 to 1 for run water from and turn off faucet to wash hands, turn on and off light. Total score range: 0 to 54 lower scores=greater functional impairment. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 26 | NPI:12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, nighttime behavior. Severity(1=Mild to 3=Severe),frequency(1=occasionally to 4=very frequently) scales recorded for each domain; frequency*severity=each domain score(range 0-12). Total score=sum of each domain score(range 0-144);higher score=greater behavioral disturbances;negative change score from baseline=improvement. | Baseline, Week 26 | 
| Sum of the Delusions and Hallucinations Sub-domain Scores of the NPI | NPI is a 12-domain caregiver assessment of behavioral disturbances occurring in dementia. Severity (1=Mild to 3=Severe) and frequency (1=occasionally to 4=very frequently) scales were recorded separately for each domain and their product gives individual domain score (range 0-12). Sum of delusions and hallucinations sub-domain scores of NPI was calculated as a measure of Alzheimer's Disease (AD) related psychosis. Total possible score range: 0-24 with higher score indicating greater behavioral disturbances. | Week 26 | 
| Change From Baseline in the Mini-Mental State Examination (MMSE) Score at Week 26 | MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state. | Baseline, Week 26 | 
| Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus) Scores | Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) version of CIBIC-Plus was used to assess participant's overall disease severity. The corresponding baseline assessment rated participant on 7-point scale: (1) extremely severe AD to (7) no symptoms of AD. Overall impression of change from baseline was rated on a 7-point scale: 1=marked improvement; 2=moderate improvement; 3=minimal improvement; 4=no change; 5=minimal worsening; 6=moderate worsening; 7=marked worsening; all assessments are relative to baseline. Higher score = worsening of global function. | Week 26 | 
| Resource Utilization in Dementia-Lite Version (RUD-Lite) | RUD Lite: instrument used to assess amount of both formal and informal resources used by demented participants and primary caregiver. It was completed by caregivers and compiles data on following resources: use of social services, frequency and duration of hospitalizations, all contacts with health care professionals, participant living accommodations, amount of time the caregiver spends giving care and the impact of care giving on the caregiver's job. Overall cost of care was evaluated to quantify resources utilized. | Baseline, Weeks 12, 18, 26 | 
| Euro Quality of Life - 5 Domain (EQ-5D) Assessment | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state. Total possible score ranged from 5 to 15; lower score indicated a better health state. | Baseline, Weeks 12, 26 | 
| Population Pharmacokinetic (PK) Analysis | Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules. | Pre-dose, 0.5 to 1.5 hours, 2.5 to 3.5 hours post-dose at Week 12 | 
| Number of Participants With Adverse Events (AEs) | Any untoward medical occurrence (including clinially important changes in clinical safety laboratory assessments, electrocardiograms and vital signs) in a participant who received study treatment was considered an AE without regard to possibility of causal relationship. | Baseline up to Week 30 (follow-up) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer disease moderate-to-severe memantine safety and efficacy