Alzheimer Disease
Conditions
Keywords
Alzheimer disease moderate-to-severe memantine safety and efficacy
Brief summary
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
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.
Interventions
DRUGDimebon 20 mg po TID
Dimebon 10 mg po TID for 1 week followed by Dimebon 20 mg TID for 25 weeks
DRUGPlacebo po TID
Placebo (matched to Dimebon) po for 26 weeks
Sponsors
Medivation, Inc.
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Severe Impairment Battery (SIB) Score at Week 26 | Baseline, 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. |
| Change From Baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (Severe) (ADCS-ADLsev) Score at Week 26 | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Mini-Mental State Examination (MMSE) Score at Week 26 | Baseline, 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. |
| Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus) Scores | Week 26 | 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. |
| Resource Utilization in Dementia-Lite Version (RUD-Lite) | Baseline, Weeks 12, 18, 26 | 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. |
| Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score at Week 26 | Baseline, 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. |
| Population Pharmacokinetic (PK) Analysis | Pre-dose, 0.5 to 1.5 hours, 2.5 to 3.5 hours post-dose at Week 12 | 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. |
| Number of Participants With Adverse Events (AEs) | Baseline up to Week 30 (follow-up) | 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. |
| Euro Quality of Life - 5 Domain (EQ-5D) Assessment | Baseline, Weeks 12, 26 | 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. |
| Sum of the Delusions and Hallucinations Sub-domain Scores of the NPI | Week 26 | 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. |
Countries
Canada, Germany, Hungary, Portugal, Slovakia, Spain, Turkey (Türkiye), United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dimebon Dimebon (latrepirdine) 10 milligram (mg) tablet orally three times a day for 1 week (titration period), followed by dimebon (latrepirdine) 20 mg tablet orally three times a day up to Week 26. | 44 |
| Placebo Placebo tablet matched to 10 mg of dimebon (latrepirdine) tablet orally three times a day for 1 week (titration period), followed by placebo tablet matched to 20 mg dimebon (latrepirdine) tablet orally three times a day up to Week 26. | 42 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Study terminated by sponsor | 34 | 35 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Dimebon | Placebo | Total |
|---|---|---|---|
| Age, Customized 50 to 59 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Customized 60 to 69 years | 9 Participants | 8 Participants | 17 Participants |
| Age, Customized 70 to 79 years | 20 Participants | 16 Participants | 36 Participants |
| Age, Customized 80 to 85 years | 10 Participants | 9 Participants | 19 Participants |
| Age, Customized Greater than 85 years | 3 Participants | 8 Participants | 11 Participants |
| Sex: Female, Male Female | 27 Participants | 30 Participants | 57 Participants |
| Sex: Female, Male Male | 17 Participants | 12 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 44 | 8 / 42 |
| serious Total, serious adverse events | 4 / 44 | 3 / 42 |
Outcome results
Primary
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.
Time frame: Baseline, Week 26
Population: Data for this outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early termination of the study.
Primary
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.
Time frame: Baseline, Week 26
Population: Data for this outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early termination of the study.
Secondary
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.
Time frame: Baseline, Week 26
Population: Data for this outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early termination of the study.
Secondary
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.
Time frame: Baseline, Week 26
Population: Data for this outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early termination of the study.
Secondary
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.
Time frame: Week 26
Population: Data for this outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early termination of the study.
Secondary
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.
Time frame: Baseline, Weeks 12, 26
Population: Data for this outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early termination of the study.
Secondary
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.
Time frame: Baseline up to Week 30 (follow-up)
Population: Safety analysis set included all participants who received at least 1 dose of study medication, including partial doses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dimebon | Number of Participants With Adverse Events (AEs) | 27 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | 18 Participants |
Secondary
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.
Time frame: Pre-dose, 0.5 to 1.5 hours, 2.5 to 3.5 hours post-dose at Week 12
Secondary
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.
Time frame: Baseline, Weeks 12, 18, 26
Population: Data for this outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early termination of the study.
Secondary
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.
Time frame: Week 26
Population: Data for this outcome measure was collected and reported in individual participant listings but not statistically summarized for analysis due to early termination of the study.