Alzheimer Disease
Conditions
Brief summary
The study is designed to compare the effects of BI 425809 compared to placebo in patients with cognitive impairment due to Alzheimer's Disease.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with early signs of dementia of Alzheimer Type * Male and female patients with an age of at least 55 years * Concomitant use of acetylcholinesterase inhibitors (AChEIs) is allowed but not required. Patients who are currently taking AChEIs are eligible as long as they have been using a stable dose for at least 3 months prior to screening and no change is foreseen for the duration of the study. This dose must be consistent with the product label in the concerned country. Patients who are not currently taking AChEIs but have taken them in the past are also eligible if AChEIs were stopped at least 3 months prior to screening. * Patients must have at least 6 years of formal education and fluency in the test language as verbally confirmed by the patient and documented by the study investigator. * Patients must have a reliable study partner (per investigator judgement, for instance a family member, partner etc., guardian) * Further inclusion criteria apply
Exclusion criteria
* Cognitive impairment or dementia with any etiology other than Alzheimer's Dementia (AD) * Substantial concomitant cerebrovascular disease (defined by a history of a stroke / intracranial haemorrhagia) temporally related to the onset of worsening of cognitive impairment per investigator judgement * Medical history or diagnosis of any of symptomatic and unstable/uncontrolled conditions per investigator judgement * Patients receiving prescribed drugs for treatment of dementia of Alzheimer Type (other than Acetylcholine Esterase Inhibitors) at screening or within 3 months prior to screening * Previous participation in investigational drug studies of dementia of Alzheimer's Type within three months prior to screening. Patients having received any active treatment in studies targeting disease modification of AD are excluded. Previous participation in studies with non-prescription medications, vitamins or other nutritional formulations is allowed. * Clinically significant uncompensated hearing loss in the judgment of the investigator. Use of hearing aids is allowed. * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment | On day 1 (visit 2, baseline) and day 85 (end of trial) | The ADAS-Cog11 is an 11-item cognitive subscale that objectively measures memory, language, orientation and praxis with a total score range of 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. Multiple comparison procedures and modelling (MCPmod) in combination with mixed model repeated measures (MMRM) is used for primary analysis of the primary endpoint. MMRM included fixed, categorical covariates of treatment, visit, baseline Mini Mental State Examination MMSE (\>=20, \<20) and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. Patient was considered as random effect. The unstructured covariance structure was used to model the within patient measurements. The same MMRM model used in the primary analysis is used for the secondary analysis of the primary endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment | On day 1 (visit 2, baseline) and day 85 (end of trial) | Change from baseline in the ADCS-ADL score after 12 weeks of treatment is presented. The ADCS-ADL is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum score could range from 0 to 78, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline. Abbreviation: MMSE = Mini Mental State Examination |
| Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment | On day 1 (visit 2, baseline) and day 85 (end of trial) | Clinician's Interview-Based Impression of Change (CIBIC+) score is based on semi-structured interview covering domains of function and cognition. It additionally requires the assessment of psychiatric signs and symptoms. The patient and their caregiver are interviewed and questioned by the clinician. Change rate is based on an unanchored 7-point scale (with 0 being not assessed, 1-3 being very much improved to minimally improved, 4 being no change, and 5-7 being minimally worse to very much worse). For the ANCOVA model, the baseline value for CIBIC+ is represented by CIBIS which is clinician's interview-based impression of severity score (scores range from 0-7, with 0 being not assessed, 1 being normal, and 7 being most extremely ill) in order to adjust for potential baseline heterogeneity. Abbreviation: MMSE = Mini Mental State Examination |
Countries
Austria, Canada, Finland, France, Germany, Greece, Hungary, Italy, Japan, Norway, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
This is a multi-centre, double-blind, parallel-group, randomised controlled study to investigate efficacy and safety of orally administered BI 425809 during a 12-week treatment period compared to placebo in patients with cognitive impairment due to Alzheimer's Disease.
Pre-assignment details
Subjects were screened prior to participation and attended a specialist site which ensured that they strictly met all inclusion/exclusion criteria. Subjects were not to be allocated to a treatment group if any of the criteria were violated. One subject was randomized by error via Interactive Response Technology (IRT) but never took a drug.
Participants by arm
| Arm | Count |
|---|---|
| 2 mg BI 425809 Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food. | 123 |
| 5 mg BI 425809 Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food. | 122 |
| 10 mg BI 425809 Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food. | 122 |
| 25 mg BI 425809 Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food. | 123 |
| Placebo Group Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food. | 120 |
| Total | 610 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 8 | 4 | 2 | 2 |
| Overall Study | Decision by the study team | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Subject decided to stop taking treatment | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 2 | 3 | 1 |
Baseline characteristics
| Characteristic | 2 mg BI 425809 | Total | Placebo Group | 25 mg BI 425809 | 10 mg BI 425809 | 5 mg BI 425809 |
|---|---|---|---|---|---|---|
| ADASCOG baseline cognitive assessment data | 18.8 score on a scale STANDARD_DEVIATION 7.9 | 19.0 score on a scale STANDARD_DEVIATION 7.7 | 18.2 score on a scale STANDARD_DEVIATION 8 | 19.6 score on a scale STANDARD_DEVIATION 7.3 | 19.6 score on a scale STANDARD_DEVIATION 7.8 | 18.8 score on a scale STANDARD_DEVIATION 7.4 |
| Age, Continuous | 72.3 Years STANDARD_DEVIATION 7.5 | 72.9 Years STANDARD_DEVIATION 7.7 | 72.4 Years STANDARD_DEVIATION 7.9 | 72.9 Years STANDARD_DEVIATION 7.7 | 74.4 Years STANDARD_DEVIATION 6.9 | 72.5 Years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 86 Participants | 20 Participants | 16 Participants | 11 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 101 Participants | 502 Participants | 94 Participants | 103 Participants | 106 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 22 Participants | 6 Participants | 4 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 58 Participants | 11 Participants | 14 Participants | 12 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 30 Participants | 8 Participants | 3 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 6 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 21 Participants | 6 Participants | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) White | 97 Participants | 495 Participants | 93 Participants | 102 Participants | 100 Participants | 103 Participants |
| Sex: Female, Male Female | 68 Participants | 324 Participants | 64 Participants | 64 Participants | 66 Participants | 62 Participants |
| Sex: Female, Male Male | 55 Participants | 286 Participants | 56 Participants | 59 Participants | 56 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 123 | 0 / 122 | 0 / 122 | 0 / 123 | 0 / 120 |
| other Total, other adverse events | 17 / 123 | 22 / 122 | 14 / 122 | 19 / 123 | 12 / 120 |
| serious Total, serious adverse events | 5 / 123 | 4 / 122 | 4 / 122 | 4 / 123 | 5 / 120 |
Outcome results
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment
The ADAS-Cog11 is an 11-item cognitive subscale that objectively measures memory, language, orientation and praxis with a total score range of 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. Multiple comparison procedures and modelling (MCPmod) in combination with mixed model repeated measures (MMRM) is used for primary analysis of the primary endpoint. MMRM included fixed, categorical covariates of treatment, visit, baseline Mini Mental State Examination MMSE (\>=20, \<20) and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. Patient was considered as random effect. The unstructured covariance structure was used to model the within patient measurements. The same MMRM model used in the primary analysis is used for the secondary analysis of the primary endpoint.
Time frame: On day 1 (visit 2, baseline) and day 85 (end of trial)
Population: Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2 mg BI 425809 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment | 0.026 score on a scale | Standard Deviation 4.864 |
| 5 mg BI 425809 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment | 0.175 score on a scale | Standard Deviation 4.471 |
| 10 mg BI 425809 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment | 0.699 score on a scale | Standard Deviation 4.313 |
| 25 mg BI 425809 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment | -0.174 score on a scale | Standard Deviation 4.044 |
| Placebo Group | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment | 0.138 score on a scale | Standard Deviation 4.939 |
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.p-value: 0.9931MCPMod Beta model fit.
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.p-value: 0.9225MCPMod Emax model fit.
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.p-value: 0.9287MCPMod Sigmoidal Emax model fit.
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.p-value: 0.7646MCPMod linear model fit.
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.p-value: 0.9335MCPMod linear in log model fit.
Comparison: Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.p-value: 0.8199MCPMod logistic model fit.
Comparison: Mixed model repeated measures (MMRM)p-value: 0.93495% CI: [-1.09, 1.18]MMRM
Comparison: Mixed model repeated measures (MMRM)p-value: 0.604195% CI: [-0.84, 1.44]MMRM
Comparison: Mixed model repeated measures (MMRM)p-value: 0.192695% CI: [-0.38, 1.9]MMRM
Comparison: Mixed model repeated measures (MMRM)p-value: 0.973995% CI: [-1.16, 1.12]MMRM
Secondary
Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment
Change from baseline in the ADCS-ADL score after 12 weeks of treatment is presented. The ADCS-ADL is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum score could range from 0 to 78, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline. Abbreviation: MMSE = Mini Mental State Examination
Time frame: On day 1 (visit 2, baseline) and day 85 (end of trial)
Population: Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2 mg BI 425809 | Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment | 0.283 score on a scale | Standard Deviation 6.805 |
| 5 mg BI 425809 | Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment | 0.577 score on a scale | Standard Deviation 5.852 |
| 10 mg BI 425809 | Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment | -1.145 score on a scale | Standard Deviation 4.764 |
| 25 mg BI 425809 | Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment | -1.828 score on a scale | Standard Deviation 7.034 |
| Placebo Group | Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment | 0.261 score on a scale | Standard Deviation 4.842 |
Comparison: Analysis of Covariance (ANCOVA)p-value: 0.97995% CI: [-1.48, 1.52]ANCOVA
Comparison: Analysis of Covariance (ANCOVA)p-value: 0.52195% CI: [-1.01, 2]ANCOVA
Comparison: Analysis of Covariance (ANCOVA)p-value: 0.04795% CI: [-3.04, -0.02]ANCOVA
Comparison: Analysis of Covariance (ANCOVA)p-value: 0.00595% CI: [-3.65, -0.67]ANCOVA
Secondary
Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment
Clinician's Interview-Based Impression of Change (CIBIC+) score is based on semi-structured interview covering domains of function and cognition. It additionally requires the assessment of psychiatric signs and symptoms. The patient and their caregiver are interviewed and questioned by the clinician. Change rate is based on an unanchored 7-point scale (with 0 being not assessed, 1-3 being very much improved to minimally improved, 4 being no change, and 5-7 being minimally worse to very much worse). For the ANCOVA model, the baseline value for CIBIC+ is represented by CIBIS which is clinician's interview-based impression of severity score (scores range from 0-7, with 0 being not assessed, 1 being normal, and 7 being most extremely ill) in order to adjust for potential baseline heterogeneity. Abbreviation: MMSE = Mini Mental State Examination
Time frame: On day 1 (visit 2, baseline) and day 85 (end of trial)
Population: Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2 mg BI 425809 | Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment | 4.000 score on a scale | Standard Deviation 0.941 |
| 5 mg BI 425809 | Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment | 4.080 score on a scale | Standard Deviation 0.773 |
| 10 mg BI 425809 | Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment | 4.209 score on a scale | Standard Deviation 0.679 |
| 25 mg BI 425809 | Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment | 4.224 score on a scale | Standard Deviation 0.781 |
| Placebo Group | Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment | 4.080 score on a scale | Standard Deviation 0.829 |
Comparison: Analysis of Covariance (ANCOVA)p-value: 0.34395% CI: [-0.32, 0.11]ANCOVA
Comparison: Analysis of Covariance (ANCOVA)p-value: 0.64595% CI: [-0.26, 0.16]ANCOVA
Comparison: Analysis of Covariance (ANCOVA)p-value: 0.44895% CI: [-0.13, 0.3]ANCOVA
Comparison: Analysis of Covariance (ANCOVA)p-value: 0.3495% CI: [-0.11, 0.32]ANCOVA