Clinical Trial Results:
A multi-centre, double-blind, parallel-group, randomized controlled study to investigate the efficacy, safety and tolerability of orally administered BI 409306 during a 12-week treatment period compared to placebo in patients with Alzheimer’s Disease
Summary
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EudraCT number |
2013-005031-24 |
Trial protocol |
DE IT PT ES BE AT NL GB |
Global end of trial date |
09 Oct 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Oct 2018
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First version publication date |
24 Oct 2018
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1289.5
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02240693 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
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Public contact |
QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Nov 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Sep 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Oct 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the efficacy, safety, and tolerability of different doses of BI 409306 compared with placebo in treatment of prodromal Alzheimer’s disease (AD)
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in
the study. All subjects were free to withdraw from the clinical trial at any time for any reason given.
Close monitoring of all subjects was adhered to throughout the trial conduct.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Feb 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 16
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
Canada: 27
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Country: Number of subjects enrolled |
France: 10
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Country: Number of subjects enrolled |
Germany: 65
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Country: Number of subjects enrolled |
Italy: 24
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Country: Number of subjects enrolled |
Netherlands: 16
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Country: Number of subjects enrolled |
Poland: 160
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Country: Number of subjects enrolled |
Portugal: 13
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Country: Number of subjects enrolled |
Spain: 85
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Country: Number of subjects enrolled |
United Kingdom: 24
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Country: Number of subjects enrolled |
United States: 63
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Worldwide total number of subjects |
504
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EEA total number of subjects |
414
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
78
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From 65 to 84 years |
402
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85 years and over |
24
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Recruitment
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Recruitment details |
A multi-centre, double-blind, parallel-group, randomized controlled study to investigate the efficacy, safety and tolerability of orally administered BI 409306 during a 12-week treatment period compared to placebo in patients with Alzheimer’s Disease | ||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
For this trial, patients were randomised at 36 sites in 11 countries. Following an initial Screening Visit and a single blinded 2-week placebo run-in period, patients who qualified according to the in- and exclusion criteria were randomised to one of the five treatment groups | ||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
This trial incorporated a double-blind, double-dummy trial design
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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BI 409306 10 milligram (mg) once daily (QD) | ||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
BI 409306
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg BI 409306 once daily for 12 weeks
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Arm title
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BI 409306 25 mg QD | ||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
BI 409306
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
25 mg BI 409306 once daily for 12 weeks
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Arm title
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BI 409306 50 mg QD | ||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
BI 409306
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
50 mg BI 409306 once daily for 12 weeks
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Arm title
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BI 409306 25 mg twice daily (BID) | ||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
BI 409306
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
25 mg BI 409306 twice daily for 12 weeks
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Arm title
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Placebo matching BI 409306 | ||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients were administered orally Placebo matching 10 mg/25 mg/ 50 mg BI 409306 for 12 weeks | ||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo matching 10 mg/25 mg/ 50 mg BI 409306 QD/BID for 12 weeks
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication. |
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Baseline characteristics reporting groups
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Reporting group title |
BI 409306 10 milligram (mg) once daily (QD)
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Reporting group description |
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BI 409306 25 mg QD
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Reporting group description |
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BI 409306 50 mg QD
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Reporting group description |
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BI 409306 25 mg twice daily (BID)
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Reporting group description |
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo matching BI 409306
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Reporting group description |
Patients were administered orally Placebo matching 10 mg/25 mg/ 50 mg BI 409306 for 12 weeks | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BI 409306 10 milligram (mg) once daily (QD)
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Reporting group description |
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks. | ||
Reporting group title |
BI 409306 25 mg QD
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Reporting group description |
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks. | ||
Reporting group title |
BI 409306 50 mg QD
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Reporting group description |
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks. | ||
Reporting group title |
BI 409306 25 mg twice daily (BID)
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Reporting group description |
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks. | ||
Reporting group title |
Placebo matching BI 409306
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Reporting group description |
Patients were administered orally Placebo matching 10 mg/25 mg/ 50 mg BI 409306 for 12 weeks | ||
Subject analysis set title |
Pooled BI 409306
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
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.
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Subject analysis set title |
Pooled BI 409306
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
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.
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End point title |
Change from baseline in Neuropsychological Test Battery in total z-score after 12-week treatment. | ||||||||||||||||||||||||||||
End point 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. Least Squares Mean is actually an adjusted mean change from baseline.
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).
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End point type |
Primary
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End point timeframe |
Baseline and 12 weeks
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Notes [1] - FAS (OC) [2] - FAS (OC) [3] - FAS (OC) [4] - FAS (OC) [5] - FAS (OC) [6] - FAS (OC) |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
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Comparison groups |
BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306
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Number of subjects included in analysis |
59
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | ||||||||||||||||||||||||||||
P-value |
= 0.3236 [8] | ||||||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||||||
Point estimate |
0.07
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.074 | ||||||||||||||||||||||||||||
upper limit |
0.223 | ||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.075
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Notes [7] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [8] - p-value was nominal and not adjusted. |
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
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Comparison groups |
BI 409306 25 mg QD v Placebo matching BI 409306
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Number of subjects included in analysis |
58
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Analysis specification |
Pre-specified
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Analysis type |
superiority [9] | ||||||||||||||||||||||||||||
P-value |
= 0.3694 [10] | ||||||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||||||
Point estimate |
-0.07
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.22 | ||||||||||||||||||||||||||||
upper limit |
0.082 | ||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.076
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Notes [9] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [10] - p-value was nominal and not adjusted. |
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Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
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Comparison groups |
BI 409306 50 mg QD v Placebo matching BI 409306
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Number of subjects included in analysis |
55
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Analysis specification |
Pre-specified
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Analysis type |
superiority [11] | ||||||||||||||||||||||||||||
P-value |
= 0.8374 [12] | ||||||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||||||
Point estimate |
-0.02
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.171 | ||||||||||||||||||||||||||||
upper limit |
0.139 | ||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.078
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Notes [11] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [12] - p-value was nominal and not adjusted. |
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Statistical analysis title |
Statistical Analysis 4 | ||||||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
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Comparison groups |
BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306
|
||||||||||||||||||||||||||||
Number of subjects included in analysis |
57
|
||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||
Analysis type |
superiority [13] | ||||||||||||||||||||||||||||
P-value |
= 0.5484 [14] | ||||||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||||||
Point estimate |
0.05
|
||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||
lower limit |
-0.106 | ||||||||||||||||||||||||||||
upper limit |
0.199 | ||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||||||
Dispersion value |
0.077
|
||||||||||||||||||||||||||||
Notes [13] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences [14] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 5 | ||||||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
|
||||||||||||||||||||||||||||
Comparison groups |
Placebo matching BI 409306 v Pooled BI 409306
|
||||||||||||||||||||||||||||
Number of subjects included in analysis |
112
|
||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||
Analysis type |
superiority [15] | ||||||||||||||||||||||||||||
P-value |
= 0.7905 [16] | ||||||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||||||
Point estimate |
0.01
|
||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||
lower limit |
-0.092 | ||||||||||||||||||||||||||||
upper limit |
0.121 | ||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||||||
Dispersion value |
0.054
|
||||||||||||||||||||||||||||
Notes [15] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences [16] - p-value was nominal and not adjusted. |
|
|||||||||||||||||||||||||
End point title |
Change from baseline in ADCS-MCI-ADL (Alzheimer's Disease Cooperative Study/Activities of Daily Living for patients with mild cognitive impairment) total score after 12-week treatment | ||||||||||||||||||||||||
End point 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.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline and 12 weeks
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [17] - FAS [18] - FAS [19] - FAS [20] - FAS [21] - FAS |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
56
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [22] | ||||||||||||||||||||||||
P-value |
= 0.8973 [23] | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
-0.14
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-2.33 | ||||||||||||||||||||||||
upper limit |
2.04 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
1.102
|
||||||||||||||||||||||||
Notes [22] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences [23] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 25 mg QD v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
55
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [24] | ||||||||||||||||||||||||
P-value |
= 0.2141 [25] | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
1.4
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.82 | ||||||||||||||||||||||||
upper limit |
3.63 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
1.122
|
||||||||||||||||||||||||
Notes [24] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences [25] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 50 mg QD v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
57
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [26] | ||||||||||||||||||||||||
P-value |
= 0.6553 [27] | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
-0.49
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-2.64 | ||||||||||||||||||||||||
upper limit |
1.67 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
1.085
|
||||||||||||||||||||||||
Notes [26] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [27] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 4 | ||||||||||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
54
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [28] | ||||||||||||||||||||||||
P-value |
= 0.7166 [29] | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
0.42
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-1.85 | ||||||||||||||||||||||||
upper limit |
2.69 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
1.144
|
||||||||||||||||||||||||
Notes [28] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [29] - p-value was nominal and not adjusted. |
|
|||||||||||||||||||||||||
End point title |
Change from baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score after 12-week treatment | ||||||||||||||||||||||||
End point description |
Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) is obtained through semi-structured interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is 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 (personal care is scored on a 4-point scale without a 0.5 rating available). Least Squares Mean is actually an adjusted mean change from baseline.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline and 12 weeks
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [30] - FAS [31] - FAS [32] - FAS [33] - FAS [34] - FAS |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
61
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [35] | ||||||||||||||||||||||||
P-value |
= 0.9491 [36] | ||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
0
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.49 | ||||||||||||||||||||||||
upper limit |
0.46 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
0.24
|
||||||||||||||||||||||||
Notes [35] - The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [36] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 25 mg QD v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
59
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [37] | ||||||||||||||||||||||||
P-value |
= 0.1699 [38] | ||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
0.3
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.15 | ||||||||||||||||||||||||
upper limit |
0.84 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
0.25
|
||||||||||||||||||||||||
Notes [37] - The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [38] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 50 mg QD v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
56
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [39] | ||||||||||||||||||||||||
P-value |
= 0.4948 [40] | ||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
-0.2
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.69 | ||||||||||||||||||||||||
upper limit |
0.33 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
0.26
|
||||||||||||||||||||||||
Notes [39] - The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [40] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 4 | ||||||||||||||||||||||||
Statistical analysis description |
Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction.
Kenward−Roger was used to model degrees of freedom.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
58
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [41] | ||||||||||||||||||||||||
P-value |
= 0.7548 [42] | ||||||||||||||||||||||||
Method |
Mixed Model Repeated Measurement (MMRM) | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
0.1
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-0.42 | ||||||||||||||||||||||||
upper limit |
0.58 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
0.25
|
||||||||||||||||||||||||
Notes [41] - The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [42] - p-value was nominal and not adjusted. |
|
|||||||||||||||||||||||||
End point title |
Change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog11) total score after 12-week treatment | ||||||||||||||||||||||||
End point 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. Least Squares Mean is actually an adjusted mean change from baseline.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline and 12 weeks
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Notes [43] - FAS [44] - FAS [45] - FAS [46] - FAS [47] - FAS |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
57
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [48] | ||||||||||||||||||||||||
P-value |
= 0.8137 [49] | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
-0.26
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-2.4 | ||||||||||||||||||||||||
upper limit |
1.89 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
1.081
|
||||||||||||||||||||||||
Notes [48] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [49] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 25 mg QD v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
55
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [50] | ||||||||||||||||||||||||
P-value |
= 0.5801 [51] | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
-0.62
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-2.84 | ||||||||||||||||||||||||
upper limit |
1.6 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
1.12
|
||||||||||||||||||||||||
Notes [50] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [51] - p-value was nominal and not adjusted. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||||||||||
Statistical analysis description |
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.
|
||||||||||||||||||||||||
Comparison groups |
BI 409306 50 mg QD v Placebo matching BI 409306
|
||||||||||||||||||||||||
Number of subjects included in analysis |
57
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority [52] | ||||||||||||||||||||||||
P-value |
= 0.2978 [53] | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
-1.12
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
-3.25 | ||||||||||||||||||||||||
upper limit |
1 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||
Dispersion value |
1.072
|
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Notes [52] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [53] - p-value was nominal and not adjusted. |
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Statistical analysis title |
Statistical Analysis 4 | ||||||||||||||||||||||||
Statistical analysis description |
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.
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Comparison groups |
BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306
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Number of subjects included in analysis |
57
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Analysis specification |
Pre-specified
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Analysis type |
superiority [54] | ||||||||||||||||||||||||
P-value |
= 0.0209 [55] | ||||||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||
Point estimate |
-2.51
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-4.64 | ||||||||||||||||||||||||
upper limit |
-0.39 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.072
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Notes [54] - Analyses of covariance (ANCOVA) were used to assess between−group differences in the modelled changes from baseline to Week 12. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences. [55] - p-value was nominal and not adjusted. |
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Adverse events information
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Timeframe for reporting adverse events |
From the first dose of study medication until 7 days after last administration of BI 409306, up to 16 weeks.
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Adverse event reporting additional description |
The treated set (TS) used (all patients who were randomised and treated with at least one dose of trial medication.) for safety assessment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
BI 409306 10 milligram (mg) once daily (QD)
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Reporting group description |
Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BI 409306 25 mg QD
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Reporting group description |
Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BI 409306 50 mg QD
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Reporting group description |
Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BI 409306 25 mg twice daily (BID)
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Reporting group description |
Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo matching BI 409306
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Reporting group description |
Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 Oct 2014 |
Amendment 1 introduced changes to inclusion criteria #7 and #8, to be in accordance with ICH-GCP. The option of consent by a legal representative was deleted throughout the CTP.Based on scientific advice from external experts, the cut-offs for the MMSE were changed and a cut-off for the global CDR-score was introduced to more appropriately describe the
target population. The amendment introduced changes to exclusion criterion #13: The acceptable methods of birth control for female patients of child-bearing potential were changed based on authority feedback. An additional exclusion criterion concerning birth control for male patients was added.
Relevant CYP2C19 inducers were added to the list of restricted concomitant medication.
Amendment 1 added the option of doing the neuropsychological assessments of Visit 3 on the day before, i.e. on the last day of the screening period, to increase feasibility. The change was made based on feedback from investigators. Based on feedback from authorities, Visit 4 was
changed to be a clinic visit. Serology was added, to be done in case of reported liver injury. Several changes were introduced to align the CTP with project standards:
- The follow-up period was extended to 4 weeks
- Exclusion criterion #10 was updated to include DSM-V
- The wording on reporting of visual AEs was moved and changed
- The instructions for assessment of safety laboratory parameters were reworded;
- Vitamin B12 and Folate were added.
- Transmitting ECGs to the vendor was introduced, instead of electronic storage at the site only.
- The instructions for neuropsychological assessments were reworded. |
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03 Aug 2015 |
Amendment 3 specified the definition of eligible patients further. According to feedback from the investigators, patients with prodromal AD usually ask for treatment and sometimes
take available AD medication, despite the fact that there are no treatments registered for prodromal AD. In order to avoid unnecessary limitation to the recruitment, patients who previously took AD treatment were allowed to enter the trial. The restrictions for intake of drugs for treatment of AD during trial participation were updated accordingly, to clarify that
patients who took AD treatment previously were not allowed to use these treatments during the trial.
The number of neuropsychological scales was reduced to reduce patient burden during the visits. This did not have an impact on primary and secondary analyses, as many items of the removed scales were still part of the remaining assessments.
The amendment allowed use of strong or moderate CYP3A4 inhibitors as a clinical trial did not show an impact on exposure to BI 409306 after CYP3A4 inhibition.
To allow patients with a contraindication for MRI to enter the trial, the use of a CCT to exclude other disorders causing prodromal AD was allowed.
The analysis models for secondary endpoints with different number of data collection visits were clarified. Text clarifications were also implemented. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Additional combined primary and/or secondary endpoints are defined and analyzed for trial 1289.5 and 1289.7, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT02240693 |