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BI 409306 in Patients With Cognitive Impairment Due to Alzheimer's Disease.

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ClinicalTrials.gov Identifier: NCT02337907
Recruitment Status : Completed
First Posted : January 14, 2015
Results First Posted : November 14, 2018
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Alzheimer Disease
Interventions Drug: Placebo
Drug: BI 409306
Drug: Donepezil
Enrollment 329
Recruitment Details This was a Phase II, multi-centre, double-blind, parallel-group, randomised, placebo controlled trial with patients with mild Alzheimer’s disease. The randomisation allocation ratio was 1:1:1:1:2 of 10 milligram (mg), 25 mg, 50 mg once daily (QD), 25 mg twice a day (BID) of BI 409306 and placebo respectively.
Pre-assignment Details All patients were screened for eligibility. All patients eligible after screening underwent a 2-week single-blind placebo run-in period before randomisation. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were not met.
Arm/Group Title BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306 Donepezil QD
Hide Arm/Group Description Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks. Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks. Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.
Period Title: Overall Study
Started 55 53 55 55 106 5
Completed 51 49 54 51 96 4
Not Completed 4 4 1 4 10 1
Reason Not Completed
Other than listed             1             0             0             1             1             0
Withdrawal by Subject             2             3             0             2             5             0
Lost to Follow-up             0             0             0             0             0             1
Adverse Event             1             1             1             1             4             0
Arm/Group Title BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306 Donepezil QD Total
Hide Arm/Group Description Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks. Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks. Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks. Total of all reporting groups
Overall Number of Baseline Participants 55 53 55 55 106 5 329
Hide Baseline Analysis Population Description
Treated Set (TS) included all patients who were randomised and treated with at least one dose of trial medication.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 55 participants 53 participants 55 participants 55 participants 106 participants 5 participants 329 participants
73.7  (8.4) 74.2  (7.8) 73.0  (6.5) 74.8  (9.1) 74.0  (7.7) 79.6  (7.0) 74.0  (7.9)
[1]
Measure Description: Age at the time of signing informed consent form is presented.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants 53 participants 55 participants 55 participants 106 participants 5 participants 329 participants
Female
26
  47.3%
30
  56.6%
26
  47.3%
30
  54.5%
48
  45.3%
3
  60.0%
163
  49.5%
Male
29
  52.7%
23
  43.4%
29
  52.7%
25
  45.5%
58
  54.7%
2
  40.0%
166
  50.5%
[1]
Measure Description: Number of subjects is categorized as Male or Female.
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants 53 participants 55 participants 55 participants 106 participants 5 participants 329 participants
Hispanic or Latino
2
   3.6%
2
   3.8%
4
   7.3%
2
   3.6%
2
   1.9%
1
  20.0%
13
   4.0%
Not Hispanic or Latino
53
  96.4%
51
  96.2%
51
  92.7%
53
  96.4%
104
  98.1%
4
  80.0%
316
  96.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Number of subjects is categorized for ethnicity data.
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants 53 participants 55 participants 55 participants 106 participants 5 participants 329 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   1.8%
0
   0.0%
1
   1.8%
0
   0.0%
0
   0.0%
0
   0.0%
2
   0.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
   2.8%
0
   0.0%
3
   0.9%
White
54
  98.2%
53
 100.0%
54
  98.2%
55
 100.0%
103
  97.2%
5
 100.0%
324
  98.5%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Number of subjects is categorized for race data.
1.Primary Outcome
Title Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment.
Hide Description Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame Baseline and 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The full analysis set (FAS): FAS includes all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one post-baseline on-treatment primary endpoint NTB or secondary endpoint assessment. Observed cases (OC)
Arm/Group Title BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Pooled BI 409306 Placebo Matching BI 409306
Hide Arm/Group Description:
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.
Patients were administered orally a tablet of BI 409306 (10 mg, 25 mg, 50 mg once daily and 25 mg twice daily)for 12 weeks.
Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Overall Number of Participants Analyzed 54 50 55 55 214 101
Least Squares Mean (Standard Error)
Unit of Measure: Z-score
0.13  (0.059) 0.17  (0.061) 0.16  (0.056) 0.01  (0.060) 0.12  (0.30) 0.15  (0.045)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 409306 10 Milligram (mg) Once Daily (QD), Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.7907
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.02
Confidence Interval (2-Sided) 95%
-0.163 to 0.124
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.073
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg QD, Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.7622
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.02
Confidence Interval (2-Sided) 95%
-0.125 to 0.171
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.075
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BI 409306 50 mg QD, Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.8789
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.01
Confidence Interval (2-Sided) 95%
-0.130 to 0.152
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.071
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg Twice Daily (BID), Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.0609
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.14
Confidence Interval (2-Sided) 95%
-0.285 to 0.006
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.074
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Pooled BI 409306, Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments H1-0: Mean NTB response of pooled doses of 10 mg QD, 25 mg QD, 25 mg BID and 50 mg QD = Mean NTB response of placebo
Statistical Test of Hypothesis P-Value 0.5687
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.03
Confidence Interval (2-Sided) 95%
-0.135 to 0.074
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.053
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences
2.Primary Outcome
Title Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment From Two Sister Trials, Present 1289.5 (NCT02240693) and 1289.7 (NCT02337907)
Hide Description Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. The number of low test scores decreased with higher levels of intellectual abilities. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame Baseline and 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS (OC) and for pooled group FAS
Arm/Group Title BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Pooled BI 409306 Placebo Matching BI 409306
Hide Arm/Group Description:
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.
Patients were administered orally a tablet of BI 409306 (10 mg, 25 mg, 50 mg once daily and 25 mg twice daily)for 12 weeks.
Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Overall Number of Participants Analyzed 76 71 76 76 299 144
Least Squares Mean (Standard Error)
Unit of Measure: Z-score
0.20  (0.046) 0.19  (0.048) 0.19  (0.046) 0.10  (0.047) 0.17  (0.025) 0.19  (0.035)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 409306 10 Milligram (mg) Once Daily (QD), Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
Type of Statistical Test Superiority
Comments H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.8694
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.01
Confidence Interval (2-Sided) 95%
-0.101 to 0.120
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.056
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg QD, Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
Type of Statistical Test Superiority
Comments H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.9512
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.116 to 0.109
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.057
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BI 409306 50 mg QD, Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
Type of Statistical Test Superiority
Comments H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.9321
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
-0.105 to 0.115
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.056
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg Twice Daily (BID), Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
Type of Statistical Test Superiority
Comments H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.1288
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.09
Confidence Interval (2-Sided) 95%
-0.199 to 0.025
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.057
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Pooled BI 409306, Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.
Type of Statistical Test Superiority
Comments H1-0: Mean NTB response of pooled doses of 10 mg QD, 25 mg QD, 25 mg BID and 50 mg QD = Mean NTB response of placebo.
Statistical Test of Hypothesis P-Value 0.6492
Comments p-value was nominal and not adjusted.
Method Mixed Model Repeated Measurement (MMRM)
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.02
Confidence Interval (2-Sided) 95%
-0.098 to 0.061
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.041
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences
3.Secondary Outcome
Title Change From Baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Total Score After 12-week Treatment
Hide Description Alzheimer's Disease Cooperative Study/Activities of Daily Living (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 can range from 0 to 78. Higher scores indicate better function. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame Baseline and 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306
Hide Arm/Group Description:
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.
Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Overall Number of Participants Analyzed 54 50 55 55 101
Least Squares Mean (Standard Error)
Unit of Measure: Unit on scale
0.10  (0.853) -0.99  (0.892) 0.35  (0.847) -1.07  (0.855) -0.58  (0.639)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 409306 10 Milligram (mg) Once Daily (QD), Placebo Matching BI 409306
Comments The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
Type of Statistical Test Superiority
Comments Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis P-Value 0.5287
Comments p-value was nominal and not adjusted.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
-1.43 to 2.77
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.066
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg QD, Placebo Matching BI 409306
Comments The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
Type of Statistical Test Superiority
Comments Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis P-Value 0.7105
Comments p-value was nominal and not adjusted.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.41
Confidence Interval (2-Sided) 95%
-2.57 to 1.76
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.099
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BI 409306 50 mg QD, Placebo Matching BI 409306
Comments The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
Type of Statistical Test Superiority
Comments Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis P-Value 0.3822
Comments p-value was nominal and not adjusted.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
-1.16 to 3.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.064
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg Twice Daily (BID), Placebo Matching BI 409306
Comments The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
Type of Statistical Test Superiority
Comments Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis P-Value 0.6472
Comments p-value was nominal and not adjusted.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.49
Confidence Interval (2-Sided) 95%
-2.59 to 1.61
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.066
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
4.Secondary Outcome
Title Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Total Score After 12-week Treatment
Hide Description The CDR-SB is obtained through semi-structured interviews of patients and informants, and cognitive functioning was rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Each domain was rated on a 5-point scale of functioning as follows: 0-no impairment; 0.5-questionable impairment; 1-mild impairment; 2-moderate impairment and 3-severe impairment. Only personal care was scored on a 4-point scale without a 0.5 rating available. The higher the score, the greater the severity of dementia. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame Baseline and 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306
Hide Arm/Group Description:
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.
Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Overall Number of Participants Analyzed 54 50 55 55 101
Least Squares Mean (Standard Error)
Unit of Measure: Unit on scale
0.1  (0.23) 0.3  (0.23) 0.1  (0.21) 0.2  (0.22) 0.1  (0.16)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 409306 10 Milligram (mg) Once Daily (QD), Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7551
Comments p-value was nominal and not adjusted.
Method Mixed-effects Model for Repeated Measure
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.46 to 0.64
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.28
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg QD, Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3643
Comments p-value was nominal and not adjusted.
Method Mixed-effects Model for Repeated Measure
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.3
Confidence Interval (2-Sided) 95%
-0.29 to 0.80
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.28
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BI 409306 50 mg QD, Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7822
Comments p-value was nominal and not adjusted.
Method Mixed-effects Model for Repeated Measure
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.45 to 0.60
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.27
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg Twice Daily (BID), Placebo Matching BI 409306
Comments Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6889
Comments p-value was nominal and not adjusted.
Method Mixed-effects Model for Repeated Measure
Comments Kenward−Roger was used to model degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.43 to 0.65
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.28
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
5.Secondary Outcome
Title Change From Baseline in Alzheimer’s Disease Assessment Scale-cognitive Subscale (ADAS-cog11) Total Score After 12-week Treatment
Hide Description Alzheimer’s Disease Assessment Scale-cognitive subscale (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. The greater the dysfunction, the greater the score. Least Squares Mean is actually an adjusted mean change from baseline.
Time Frame Baseline and 12 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306
Hide Arm/Group Description:
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.
Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
Overall Number of Participants Analyzed 54 50 55 55 101
Least Squares Mean (Standard Error)
Unit of Measure: Unit on scale
1.14  (0.738) 0.94  (0.776) 1.11  (0.746) 2.29  (0.746) -0.18  (0.568)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 409306 10 Milligram (mg) Once Daily (QD), Placebo Matching BI 409306
Comments The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
Type of Statistical Test Superiority
Comments Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis P-Value 0.1595
Comments p-value was nominal and not adjusted.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.32
Confidence Interval (2-Sided) 95%
-0.52 to 3.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.933
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg QD, Placebo Matching BI 409306
Comments The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
Type of Statistical Test Superiority
Comments Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis P-Value 0.2455
Comments p-value was nominal and not adjusted.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.12
Confidence Interval (2-Sided) 95%
-0.77 to 3.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.962
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BI 409306 50 mg QD, Placebo Matching BI 409306
Comments The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
Type of Statistical Test Superiority
Comments Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis P-Value 0.1732
Comments p-value was nominal and not adjusted.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.28
Confidence Interval (2-Sided) 95%
-0.57 to 3.13
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.940
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BI 409306 25 mg Twice Daily (BID), Placebo Matching BI 409306
Comments The dependent variable was the change from the baseline score at Week 12. The model included fixed, categorical covariates of treatment as well as fixed continuous covariates of baseline score.
Type of Statistical Test Superiority
Comments Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12.
Statistical Test of Hypothesis P-Value 0.0088
Comments p-value was nominal and not adjusted.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.47
Confidence Interval (2-Sided) 95%
0.63 to 4.31
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.936
Estimation Comments The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
Time Frame From the first dose of study medication until 7 days after last administration of BI 409306, up to 16 weeks.
Adverse Event Reporting Description The treated set (TS) used (all patients who were randomised and treated with at least one dose of trial medication.) for safety assessment.
 
Arm/Group Title BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306 Donepezil QD
Hide Arm/Group Description Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks. Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks. Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks. Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.
All-Cause Mortality
BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306 Donepezil QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/55 (1.82%)   0/53 (0.00%)   0/55 (0.00%)   0/55 (0.00%)   0/106 (0.00%)   0/5 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306 Donepezil QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/55 (1.82%)   3/53 (5.66%)   1/55 (1.82%)   3/55 (5.45%)   8/106 (7.55%)   0/5 (0.00%) 
Cardiac disorders             
Angina pectoris  1  0/55 (0.00%)  1/53 (1.89%)  0/55 (0.00%)  0/55 (0.00%)  0/106 (0.00%)  0/5 (0.00%) 
Ear and labyrinth disorders             
Vertigo positional  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  1/55 (1.82%)  0/106 (0.00%)  0/5 (0.00%) 
Gastrointestinal disorders             
Haemorrhoids  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Infections and infestations             
Respiratory tract infection viral  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Injury, poisoning and procedural complications             
Craniocerebral injury  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Fall  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Investigations             
Electrocardiogram QT prolonged  1  0/55 (0.00%)  0/53 (0.00%)  1/55 (1.82%)  0/55 (0.00%)  0/106 (0.00%)  0/5 (0.00%) 
Nervous system disorders             
Cerebrovascular accident  1  0/55 (0.00%)  1/53 (1.89%)  0/55 (0.00%)  0/55 (0.00%)  0/106 (0.00%)  0/5 (0.00%) 
Dementia Alzheimer's type  1  1/55 (1.82%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  0/106 (0.00%)  0/5 (0.00%) 
Encephalopathy  1  1/55 (1.82%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  0/106 (0.00%)  0/5 (0.00%) 
Epilepsy  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Loss of consciousness  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Psychiatric disorders             
Delirium  1  0/55 (0.00%)  1/53 (1.89%)  0/55 (0.00%)  0/55 (0.00%)  0/106 (0.00%)  0/5 (0.00%) 
Suicidal ideation  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  2/55 (3.64%)  1/106 (0.94%)  0/5 (0.00%) 
Renal and urinary disorders             
Nephrolithiasis  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  1/55 (1.82%)  0/106 (0.00%)  0/5 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Pulmonary embolism  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Vascular disorders             
Deep vein thrombosis  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Peripheral artery aneurysm  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
BI 409306 10 Milligram (mg) Once Daily (QD) BI 409306 25 mg QD BI 409306 50 mg QD BI 409306 25 mg Twice Daily (BID) Placebo Matching BI 409306 Donepezil QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/55 (10.91%)   9/53 (16.98%)   7/55 (12.73%)   2/55 (3.64%)   8/106 (7.55%)   1/5 (20.00%) 
Infections and infestations             
Nasopharyngitis  1  1/55 (1.82%)  4/53 (7.55%)  3/55 (5.45%)  0/55 (0.00%)  1/106 (0.94%)  0/5 (0.00%) 
Musculoskeletal and connective tissue disorders             
Back pain  1  3/55 (5.45%)  0/53 (0.00%)  0/55 (0.00%)  1/55 (1.82%)  2/106 (1.89%)  0/5 (0.00%) 
Nervous system disorders             
Headache  1  2/55 (3.64%)  5/53 (9.43%)  1/55 (1.82%)  1/55 (1.82%)  5/106 (4.72%)  0/5 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Cough  1  0/55 (0.00%)  0/53 (0.00%)  3/55 (5.45%)  0/55 (0.00%)  0/106 (0.00%)  0/5 (0.00%) 
Rhinitis allergic  1  0/55 (0.00%)  0/53 (0.00%)  0/55 (0.00%)  0/55 (0.00%)  0/106 (0.00%)  1/5 (20.00%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
There were 5 patients who were randomised to donepezil arm which was dropped from the trial with protocol amendment. No further patients were randomised to this arm, but patients already randomised continued in the trial as originally planned.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Name/Title: Boehringer Ingelheim, Call Centre
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02337907     History of Changes
Other Study ID Numbers: 1289.7
2013-005040-28 ( EudraCT Number )
First Submitted: December 23, 2014
First Posted: January 14, 2015
Results First Submitted: August 29, 2018
Results First Posted: November 14, 2018
Last Update Posted: November 14, 2018