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Clinical Trial Results:
A multi-centre, double-blind, parallel-group, randomised controlled study to investigate efficacy, safety and tolerability of orally administered BI 409306 during a 12-week treatment period compared to placebo in patients with cognitive impairment due to Alzheimer’s Disease.

Summary
EudraCT number	2013-005040-28
Trial protocol	IT PT AT GB BE NL PL
Global end of trial date	10 Oct 2017

Results information
Results version number	v1(current)
This version publication date	24 Oct 2018
First version publication date	24 Oct 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1289.7

ISRCTN number

US NCT number

NCT02337907

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

16 Nov 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Sep 2017

Global end of trial reached?

Yes

Global end of trial date

10 Oct 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this trial was to assess efficacy and safety of BI 409306 at doses of 10 milligram (mg), 25 mg and 50 mg once daily, and 25 mg twice daily compared with placebo over a 12-week treatment period in patients with the following criteria: mild dementia of Alzheimer’s type, aged ≥55 years, a Mini-Mental-State-Examination (MMSE) between 18 and 26.

Protection of trial subjects

All patients were informed that they were free to withdraw their consent at any time during the trial without penalty or prejudice. The patients were informed that their personal trialrelated data would be considered confidential and used by BI in accordance with the local data protection laws. The terms and conditions of the insurance cover were available to the investigator and the patients in the Investigator Site File (ISF).

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Mar 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 18

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Canada: 16

Country: Number of subjects enrolled

France: 32

Country: Number of subjects enrolled

Germany: 57

Country: Number of subjects enrolled

Italy: 2

Country: Number of subjects enrolled

Netherlands: 24

Country: Number of subjects enrolled

Poland: 78

Country: Number of subjects enrolled

Portugal: 49

Country: Number of subjects enrolled

United Kingdom: 34

Country: Number of subjects enrolled

United States: 71

Worldwide total number of subjects

386

EEA total number of subjects

299

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

305

85 years and over

Subject disposition

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Recruitment details

Phase II, multi-center, double-blind, randomized, placebo controlled trial with mild Alzheimer’s disease patients. 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

Screening details

2-week single-blind placebo run-in period before randomization was performed. Patients were not to be randomized to trial if any one of the specific entry criteria were violated. 3 patients were added in the Adults (65 - 84 years) age group due to missing age. Randomization ratio was 1:1:1:1:2 to dose groups of BI 409306 and placebo.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Assessor

Blinding implementation details

This was a double-blind trial.

Are arms mutually exclusive

Yes

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

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg BI 409306 once daily for 12 weeks

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

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg BI 409306 once daily for 12 weeks

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

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

50 mg BI 409306 once daily for 12 weeks

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

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg BI 409306 twice daily for 12 weeks

Placebo matching BI 409306

Arm description

Patients were administered orally tablet of Placebo matching BI 409306 once daily or twice daily in order match BID treatment arm, for 12 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matching BI 409306 once or twice daily for 12 weeks

Donepezil QD

Arm description

Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.

Arm type

Active comparator

Investigational medicinal product name

Donepezil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Capsule

Routes of administration

Oral use

Dosage and administration details

Once daily for 12 weeks

Number of subjects in period 1 ^[1]	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
Started	55	53	55	55	106	5
Completed	51	49	54	51	96	4
Not completed	4	4	1	4	10	1
Consent withdrawn by subject	2	3	-	2	5	-
Adverse event, non-fatal	1	1	1	1	4	-
Lost to follow-up	-	-	-	-	-	1
Other than listed	1	-	-	1	1	-

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.

Baseline characteristics

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Reporting group title

BI 409306 10 milligram (mg) once daily (QD)

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

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

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)

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

Reporting group description

Patients were administered orally tablet of Placebo matching BI 409306 once daily or twice daily in order match BID treatment arm, for 12 weeks.

Reporting group title

Donepezil QD

Reporting group description

Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.

Reporting group values	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
Number of subjects	55	53	55	55	106	5	329
Age categorical
Units: Subjects
Age Continuous
Age at the time of signing informed consent form is presented. Treated Set (TS) included all patients who were randomised and treated with at least one dose of trial medication.
Units: years
arithmetic mean (standard deviation)	73.7 ± 8.4	74.2 ± 7.8	73.0 ± 6.5	74.8 ± 9.1	74.0 ± 7.7	79.6 ± 7.0	-
Sex: Female, Male
Number of subjects is categorized as Male or Female. Treated Set (TS) included all patients who were randomised and treated with at least one dose of trial medication.
Units: Subjects
Female	26	30	26	30	48	3	163
Male	29	23	29	25	58	2	166
Race (NIH/OMB)
Number of subjects is categorized for race data. Treated Set (TS) included all patients who were randomised and treated with at least one dose of trial medication.
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	1	0	1	0	0	0	2
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	0	0	0	0	3	0	3
White	54	53	54	55	103	5	324
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0
Ethnicity (NIH/OMB)
Number of subjects is categorized for ethnicity data. Treated Set (TS) included all patients who were randomised and treated with at least one dose of trial medication.
Units: Subjects
Hispanic or Latino	2	2	4	2	2	1	13
Not Hispanic or Latino	53	51	51	53	104	4	316
Unknown or Not Reported	0	0	0	0	0	0	0

End points

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Reporting group title

BI 409306 10 milligram (mg) once daily (QD)

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

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

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)

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

Reporting group description

Patients were administered orally tablet of Placebo matching BI 409306 once daily or twice daily in order match BID treatment arm, for 12 weeks.

Reporting group title

Donepezil QD

Reporting group description

Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.

Subject analysis set title

Pooled BI 409306

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.

Subject analysis set title

Pooled BI 409306

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.

Primary: Change from baseline in Neuropsychological Test Battery in total z-score after 12-week treatment.

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End point title

Change from baseline in Neuropsychological Test Battery in total z-score after 12-week treatment. ^[1]

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.

End point type

Primary

End point timeframe

Baseline and 12 weeks

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	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	Pooled BI 409306
Number of subjects analysed	47 ^[2]	44 ^[3]	51 ^[4]	45 ^[5]	83 ^[6]	214 ^[7]
Units: Unit on scale
least squares mean (standard error)	0.13 ± 0.059	0.17 ± 0.061	0.16 ± 0.056	0.01 ± 0.060	0.15 ± 0.045	0.12 ± 0.30

Notes
[2] - FAS (OC)
[3] - FAS (OC)
[4] - FAS (OC)
[5] - FAS (OC)
[6] - FAS (OC)
[7] - FAS (OC)

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.7907 ^[9]

Method

Mixed Model Repeated Measurement (MMRM)

Parameter type

Mean difference (final values)

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.163

upper limit

0.124

Variability estimate

Standard error of the mean

Dispersion value

0.073

Notes
[8] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. Kenward−Roger was used to model degrees of freedom. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
[9] - p-value was nominal and not adjusted.

Statistical Analysis 2

Statistical analysis description

Comparison groups

BI 409306 25 mg QD v Placebo matching BI 409306

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.7622 ^[11]

Method

Mixed Model Repeated Measurement (MMRM)

Parameter type

Mean difference (final values)

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.125

upper limit

0.171

Variability estimate

Standard error of the mean

Dispersion value

0.075

Notes
[10] - 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.
[11] - p-value was nominal and not adjusted.

Statistical Analysis 3

Statistical analysis description

Comparison groups

BI 409306 50 mg QD v Placebo matching BI 409306

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.8789 ^[13]

Method

Mixed Model Repeated Measurement (MMRM)

Parameter type

Mean difference (net)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.13

upper limit

0.152

Variability estimate

Standard error of the mean

Dispersion value

0.071

Notes
[12] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. Kenward−Roger was used to model degrees of freedom. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
[13] - p-value was nominal and not adjusted.

Statistical Analysis 4

Statistical analysis description

Comparison groups

BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.0609 ^[15]

Method

Mixed Model Repeated Measurement (MMRM)

Parameter type

Mean difference (final values)

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.285

upper limit

0.006

Variability estimate

Standard error of the mean

Dispersion value

0.074

Notes
[14] - H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo. Kenward−Roger was used to model degrees of freedom. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
[15] - p-value was nominal and not adjusted.

Statistical Analysis 5

Statistical analysis description

Comparison groups

Placebo matching BI 409306 v Pooled BI 409306

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

= 0.5687 ^[17]

Method

Mixed Model Repeated Measurement (MMRM)

Parameter type

Mean difference (final values)

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.135

upper limit

0.074

Variability estimate

Standard error of the mean

Dispersion value

0.053

Notes
[16] - 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. Kenward−Roger was used to model degrees of freedom. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
[17] - p-value was nominal and not adjusted.

Secondary: Change from baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) total score after 12-week treatment

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End point title

Change from baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) total score after 12-week treatment ^[18]

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
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	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
Number of subjects analysed	54 ^[19]	50 ^[20]	55 ^[21]	55 ^[22]	101 ^[23]
Units: Unit on scale
least squares mean (standard error)	0.10 ± 0.853	-0.99 ± 0.892	0.35 ± 0.847	-1.07 ± 0.855	-0.58 ± 0.639

Notes
[19] - FAS
[20] - FAS
[21] - FAS
[22] - FAS
[23] - FAS

Statistical Analysis 11

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

155

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.5287 ^[25]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

-1.43

upper limit

2.77

Variability estimate

Standard error of the mean

Dispersion value

1.066

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 12

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

151

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.7105 ^[27]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-2.57

upper limit

1.76

Variability estimate

Standard error of the mean

Dispersion value

1.099

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 13

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

156

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.3822 ^[29]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

-1.16

upper limit

3.03

Variability estimate

Standard error of the mean

Dispersion value

1.064

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.

Statistical Analysis 14

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

156

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.6472 ^[31]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-2.59

upper limit

1.61

Variability estimate

Standard error of the mean

Dispersion value

1.066

Notes
[30] - 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.
[31] - p-value was nominal and not adjusted.

Secondary: Change from baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score after 12-week treatment

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End point title

Change from baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score after 12-week treatment ^[32]

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
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	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
Number of subjects analysed	54 ^[33]	50 ^[34]	55 ^[35]	55 ^[36]	101 ^[37]
Units: Unit on scale
least squares mean (standard error)	0.1 ± 0.23	0.3 ± 0.23	0.1 ± 0.21	0.2 ± 0.22	0.1 ± 0.16

Notes
[33] - FAS
[34] - FAS
[35] - FAS
[36] - FAS
[37] - FAS

Statistical Analysis 15

Statistical analysis description

Comparison groups

BI 409306 10 milligram (mg) once daily (QD) v Placebo matching BI 409306

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.7551 ^[39]

Method

Mixed-effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

0.64

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[38] - Kenward−Roger was used to model degrees of freedom. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
[39] - p-value was nominal and not adjusted.

Statistical Analysis 16

Statistical analysis description

Comparison groups

BI 409306 25 mg QD v Placebo matching BI 409306

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

P-value

= 0.3643 ^[41]

Method

Mixed-effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

0.8

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[40] - Kenward−Roger was used to model degrees of freedom. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
[41] - p-value was nominal and not adjusted.

Statistical Analysis 17

Statistical analysis description

Comparison groups

BI 409306 50 mg QD v Placebo matching BI 409306

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

= 0.7822 ^[43]

Method

Mixed-effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.27

Notes
[42] - Kenward−Roger was used to model degrees of freedom. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
[43] - p-value was nominal and not adjusted.

Statistical Analysis 18

Statistical analysis description

Comparison groups

BI 409306 25 mg twice daily (BID) v Placebo matching BI 409306

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.6889 ^[45]

Method

Mixed-effects Model for Repeated Measure

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.43

upper limit

0.65

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[44] - Kenward−Roger was used to model degrees of freedom. The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.
[45] - p-value was nominal and not adjusted.

Secondary: Change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog11) total score after 12-week treatment

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End point title

Change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog11) total score after 12-week treatment ^[46]

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
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	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
Number of subjects analysed	54 ^[47]	50 ^[48]	55 ^[49]	55 ^[50]	101 ^[51]
Units: Unit on scale
least squares mean (standard error)	1.14 ± 0.738	0.94 ± 0.776	1.11 ± 0.746	2.29 ± 0.746	-0.18 ± 0.568

Notes
[47] - FAS
[48] - FAS
[49] - FAS
[50] - FAS
[51] - FAS

Statistical Analysis 19

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

155

Analysis specification

Pre-specified

Analysis type

superiority ^[52]

P-value

= 0.1595 ^[53]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

3.15

Variability estimate

Standard error of the mean

Dispersion value

0.933

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.

Statistical Analysis 20

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

151

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.2455 ^[55]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.77

upper limit

3.01

Variability estimate

Standard error of the mean

Dispersion value

0.962

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.

Statistical Analysis 21

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

156

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.1732 ^[57]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.28

Confidence interval

level

95%

sides

2-sided

lower limit

-0.57

upper limit

3.13

Variability estimate

Standard error of the mean

Dispersion value

0.94

Notes
[56] - 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.
[57] - p-value was nominal and not adjusted.

Statistical Analysis 22

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

156

Analysis specification

Pre-specified

Analysis type

superiority ^[58]

P-value

= 0.0088 ^[59]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

2.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

4.31

Variability estimate

Standard error of the mean

Dispersion value

0.936

Notes
[58] - 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.
[59] - p-value was nominal and not adjusted.

Adverse events

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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.

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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

BI 409306 10 milligram (mg) once daily (QD)

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

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

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)

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

Reporting group description

Patients were administered orally tablet of Placebo matching BI 409306 once daily or twice daily in order match BID treatment arm, for 12 weeks.

Reporting group title

Donepezil QD

Reporting group description

Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.

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
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 55 (1.82%)	3 / 53 (5.66%)	1 / 55 (1.82%)	3 / 55 (5.45%)	8 / 106 (7.55%)	0 / 5 (0.00%)
number of deaths (all causes)	1	0	0	0	0	1
number of deaths resulting from adverse events	0	0	0	0	0	0
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	0 / 55 (0.00%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Craniocerebral injury
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery aneurysm
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 55 (0.00%)	1 / 53 (1.89%)	0 / 55 (0.00%)	0 / 55 (0.00%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 55 (0.00%)	1 / 53 (1.89%)	0 / 55 (0.00%)	0 / 55 (0.00%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dementia Alzheimer's type
subjects affected / exposed	1 / 55 (1.82%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 55 (1.82%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 55 (1.82%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Haemorrhoids
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 55 (0.00%)	1 / 53 (1.89%)	0 / 55 (0.00%)	0 / 55 (0.00%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 55 (1.82%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Respiratory tract infection viral
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-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
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 55 (10.91%)	9 / 53 (16.98%)	7 / 55 (12.73%)	2 / 55 (3.64%)	8 / 106 (7.55%)	1 / 5 (20.00%)
Nervous system disorders
Headache
subjects affected / exposed	2 / 55 (3.64%)	5 / 53 (9.43%)	1 / 55 (1.82%)	1 / 55 (1.82%)	5 / 106 (4.72%)	0 / 5 (0.00%)
occurrences all number	2	5	1	1	5	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	3 / 55 (5.45%)	0 / 55 (0.00%)	0 / 106 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	3	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 55 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 55 (0.00%)	0 / 106 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	3 / 55 (5.45%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 55 (1.82%)	2 / 106 (1.89%)	0 / 5 (0.00%)
occurrences all number	3	0	0	1	2	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 55 (1.82%)	4 / 53 (7.55%)	3 / 55 (5.45%)	0 / 55 (0.00%)	1 / 106 (0.94%)	0 / 5 (0.00%)
occurrences all number	1	4	3	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

27 Jul 2015

The donepezil arm was dropped from the trial and therefore reference to donepezil was removed. Sample size and treatment groups, inclusion criteria, trial objectives and description of Interactive Response Technology (IRT) and trial medications were adapted accordingly. The reason for this change was that Acetylcholine Esterase Inhibitors (AChEIs) (including donepezil) are the standard treatment in Alzheimer’s Disease. Therefore, the trial design was changed to allow both treatment-naïve patients and patients on standard of care to enter the trial. This change enabled the analysis of the treatment effect in the expected target population for the trial medication. As a result, stable concomitant use of AChEIs was permitted and current AChEI use (Yes, No) was added as a stratification factor to the primary analysis model and randomization. The number of neuropsychological scales was reduced to reduce patient burden during the visits. This did not have an impact on the clinical validity of 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 Cytochrome P450 (CYP)3A4 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 Magnetic Resonance Imaging (MRI) to enter the trial, the use of a Cranial Computer Tomography (CCT) to exclude other disorders causing dementia was allowed. The analysis models for secondary endpoints with different number of data collection visits were clarified. Text clarifications were also implemented.

01 Sep 2016

Iintroduced to power the trial for a smaller effect size. The sample size was changed to a total of N=354, which allowed detecting an effect size of 0.45 with 80% power, 2-sided alpha of 0.05.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

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.

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Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in Neuropsychological Test Battery in total z-score after 12-week treatment.

Primary: Change from baseline in Neuropsychological Test Battery in total z-score after 12-week treatment.

Secondary: Change from baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) total score after 12-week treatment

Secondary: Change from baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) total score after 12-week treatment

Secondary: Change from baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score after 12-week treatment

Secondary: Change from baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score after 12-week treatment

Secondary: Change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog11) total score after 12-week treatment

Secondary: Change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog11) total score after 12-week treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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