BI 409306 in Patients With Cognitive Impairment Due to Al... | NCT02337907

ID	Type	Description	Link
2013-005040-28	EudraCT Number

BI 409306 in Patients With Cognitive Impairment Due to Al... | NCT02337907 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Intervention Names
Placebo comparator	Placebo Comparator	Drug: Placebo
BI 409306 dose 1	Experimental	Drug: Placebo Drug: BI 409306
BI 409306 dose 2	Experimental	Drug: Placebo Drug: BI 409306
BI 409306 dose 3	Experimental	Drug: Placebo Drug: BI 409306
Active Comparator Donepezil	Active Comparator	Drug: Placebo Drug: Donepezil
BI 409306 dose 4	Experimental	Drug: Placebo Drug: BI 409306

Name	Type	Description	Arm Group Labels	Other Names
Placebo	Drug	for blinding purposes	Active Comparator Donepezil BI 409306 dose 1 BI 409306 dose 2 BI 409306 dose 3 BI 409306 dose 4

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment.	Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. Least Squares Mean is actually an adjusted mean change from baseline.	Baseline and 12 weeks
Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment From Two Sister Trials, Present 1289.5 (NCT02240693) and 1289.7 (NCT02337907)	Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. The number of low test scores decreased with higher levels of intellectual abilities. Least Squares Mean is actually an adjusted mean change from baseline.	Baseline and 12 weeks

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Total Score After 12-week Treatment	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.

Eligibility Module

Contacts/Locations Module

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
California Neuroscience Research		Sherman Oaks	California	91403	United States
Bioclinica Research

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
30755255	Derived	Frolich L, Wunderlich G, Thamer C, Roehrle M, Garcia M Jr, Dubois B. Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease. Alzheimers Res Ther. 2019 Feb 12;11(1):18. doi: 10.1186/s13195-019-0467-2.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	BI 409306 10 Milligram (mg) Once Daily (QD)	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
FG001	BI 409306 25 mg QD	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Document Section

Large Document Module

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Jun 13, 2017	Aug 29, 2018

Type	Comment	Reasons
Other than listed		FG0001 subjects FG0010 subjects FG0020 subjects FG0031 subjects FG0041 subjects FG0050 subjects
Withdrawal by Subject		FG0002 subjects FG0013 subjects FG0020 subjects FG0032 subjects FG004
Lost to Follow-up		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects FG004
Adverse Event		FG0001 subjects FG0011 subjects FG0021 subjects FG0031 subjects FG004

Arm/Group Information

ID	Title	Description
BG000	BI 409306 10 Milligram (mg) Once Daily (QD)	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
BG001	BI 409306 25 mg QD	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
BG002	BI 409306 50 mg QD	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
BG003	BI 409306 25 mg Twice Daily (BID)	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.
BG004	Placebo Matching BI 409306	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.
BG005	Donepezil QD	Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.
BG006	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Age at the time of signing informed consent form is presented.

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00073.7± 8.4 BG00174.2± 7.8 BG00273.0± 6.5 BG003

Sex: Female, Male

Number of subjects is categorized as Male or Female.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00026 BG00130 BG002

Ethnicity (NIH/OMB)

Number of subjects is categorized for ethnicity data.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0002 BG0012 BG002

Race (NIH/OMB)

Number of subjects is categorized for race data.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment.

Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. Least Squares Mean is actually an adjusted mean change from baseline.

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)

Posted

Least Squares Mean

Standard Error

Z-score

Baseline and 12 weeks

ID	Title	Description
OG000	BI 409306 10 Milligram (mg) Once Daily (QD)	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
OG001	BI 409306 25 mg QD	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
OG002	BI 409306 50 mg QD	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
OG003	BI 409306 25 mg Twice Daily (BID)	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.
OG004	Pooled BI 409306	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.
OG005	Placebo Matching BI 409306	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.

Units	Counts
Participants	OG00054 OG00150 OG00255 OG003

Title

Denominators

Categories

Title	Measurements
	OG0000.13± 0.059 OG0010.17± 0.061 OG0020.16± 0.056 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG005	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.	Mixed Model Repeated Measurement (MMRM)	Kenward-Roger was used to model degrees of freedom.	0.7907	p-value was nominal and not adjusted.	Mean Difference (Final Values)	-0.02	Standard Error of the Mean	0.073	2-Sided	95	-0.163	0.124			The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.

Primary

Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment From Two Sister Trials, Present 1289.5 (NCT02240693) and 1289.7 (NCT02337907)

Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB consists of 9 validated components. Raw scores on each of the 9 NTB tests were converted to z-scores using the baseline means and standard deviations (SDs) for each test. The resultant z-scores were averaged to obtain a total z-score, incorporating all 9 NTB tests. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. The number of low test scores decreased with higher levels of intellectual abilities. Least Squares Mean is actually an adjusted mean change from baseline.

FAS (OC) and for pooled group FAS

Posted

Least Squares Mean

Standard Error

Z-score

Baseline and 12 weeks

ID	Title	Description
OG000	BI 409306 10 Milligram (mg) Once Daily (QD)	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
OG001	BI 409306 25 mg QD	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
OG002

Secondary

Change From Baseline in Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Total Score After 12-week Treatment

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.

FAS

Posted

Least Squares Mean

Standard Error

Unit on scale

Baseline and 12 weeks

ID	Title	Description
OG000	BI 409306 10 Milligram (mg) Once Daily (QD)	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
OG001	BI 409306 25 mg QD	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
OG002	BI 409306 50 mg QD	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
OG003

Secondary

Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Total Score After 12-week Treatment

The CDR-SB is obtained through semi-structured interviews of patients and informants, and cognitive functioning was rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Each domain was rated on a 5-point scale of functioning as follows: 0-no impairment; 0.5-questionable impairment; 1-mild impairment; 2-moderate impairment and 3-severe impairment. Only personal care was scored on a 4-point scale without a 0.5 rating available. The higher the score, the greater the severity of dementia. Least Squares Mean is actually an adjusted mean change from baseline.

FAS

Posted

Least Squares Mean

Standard Error

Unit on scale

Baseline and 12 weeks

ID	Title	Description
OG000	BI 409306 10 Milligram (mg) Once Daily (QD)	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
OG001	BI 409306 25 mg QD	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
OG002	BI 409306 50 mg QD	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.

Secondary

Change From Baseline in Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog11) Total Score After 12-week Treatment

Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog11) is an 11-item cognitive subscale that objectively measures memory, language, orientation, and praxis with a total score range of 0 to 70. The greater the dysfunction, the greater the score. Least Squares Mean is actually an adjusted mean change from baseline.

FAS

Posted

Least Squares Mean

Standard Error

Unit on scale

Baseline and 12 weeks

ID	Title	Description
OG000	BI 409306 10 Milligram (mg) Once Daily (QD)	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.
OG001	BI 409306 25 mg QD	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.
OG002	BI 409306 50 mg QD	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.
OG003	BI 409306 25 mg Twice Daily (BID)

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	BI 409306 10 Milligram (mg) Once Daily (QD)	Patients were administered orally a tablet of 10 mg BI 409306 once daily for 12 weeks.	1	55	1	55	6	55
EG001	BI 409306 25 mg QD	Patients were administered orally a tablet of 25 mg BI 409306 once daily for 12 weeks.	0	53	3	53	9	53
EG002	BI 409306 50 mg QD	Patients were administered orally a tablet of 50 mg BI 409306 once daily for 12 weeks.	0	55	1	55	7	55
EG003	BI 409306 25 mg Twice Daily (BID)	Patients were administered orally a tablet of 25 mg BI 409306 twice daily for 12 weeks.	0	55	3	55	2	55
EG004	Placebo Matching BI 409306	Patients were administered orally tablet of Placebo matching BI 409306 once daily for 12 weeks.	0	106	8	106	8	106
EG005	Donepezil QD	Patients were administered orally over capsulated tablet of Donepezil once daily for 12 weeks.	0	5	0	5	1	5

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Angina pectoris	Cardiac disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0011 affected53 at risk EG0020 affected55 at risk EG0030 affected55 at risk EG0040 affected106 at risk EG0050 affected5 at risk
Vertigo positional	Ear and labyrinth disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Haemorrhoids	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Respiratory tract infection viral	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Craniocerebral injury	Injury, poisoning and procedural complications	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Electrocardiogram QT prolonged	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0021 affected55 at risk EG003
Cerebrovascular accident	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0011 affected53 at risk EG0020 affected55 at risk EG003
Dementia Alzheimer's type	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Encephalopathy	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0001 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Epilepsy	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Loss of consciousness	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Delirium	Psychiatric disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0011 affected53 at risk EG0020 affected55 at risk EG003
Suicidal ideation	Psychiatric disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Nephrolithiasis	Renal and urinary disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Peripheral artery aneurysm	Vascular disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nasopharyngitis	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0001 affected55 at risk EG0014 affected53 at risk EG0023 affected55 at risk EG0030 affected55 at risk EG0041 affected106 at risk EG0050 affected5 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0003 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003
Headache	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0002 affected55 at risk EG0015 affected53 at risk EG0021 affected55 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0023 affected55 at risk EG003
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 affected55 at risk EG0010 affected53 at risk EG0020 affected55 at risk EG003

Ancestor Terms

ID	Term
D003704	Dementia
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D024801	Tauopathies
D019636	Neurodegenerative Diseases
D019965	Neurocognitive Disorders
D001523	Mental Disorders

Ancestor Terms

ID	Term
D007189	Indans
D007192	Indenes
D011084	Polycyclic Aromatic Hydrocarbons
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals
D010880	Piperidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D011083	Polycyclic Compounds

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Non-Inferiority Type	Non-Inferiority Comment
OG000 OG005	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.	Mixed Model Repeated Measurement (MMRM)	Kenward-Roger was used to model degrees of freedom.	0.8694	p-value was nominal and not adjusted.	Mean Difference (Final Values)	0.01	Standard Error of the Mean	0.056	2-Sided	95	-0.101	0.120	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
OG001 OG005	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.	Mixed Model Repeated Measurement (MMRM)	Kenward-Roger was used to model degrees of freedom.	0.9512	p-value was nominal and not adjusted.	Mean Difference (Final Values)	0.00	Standard Error of the Mean	0.057	2-Sided	95	-0.116	0.109	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
OG002 OG005	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.	Mixed Model Repeated Measurement (MMRM)	Kenward-Roger was used to model degrees of freedom.	0.9321	p-value was nominal and not adjusted.	Mean Difference (Net)	0.00	Standard Error of the Mean	0.056	2-Sided	95	-0.105	0.115	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
OG003 OG005	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.	Mixed Model Repeated Measurement (MMRM)	Kenward-Roger was used to model degrees of freedom.	0.1288	p-value was nominal and not adjusted.	Mean Difference (Final Values)	-0.09	Standard Error of the Mean	0.057	2-Sided	95	-0.199	0.025	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences	Superiority	H0: The dose group with the peak response in the respective model Mean NTB response = Mean NTB response of placebo.
OG004 OG005	Mixed Model Repeated Measurement (MMRM) includes fixed, categorical effects of treatment, visit, current Acetylcholine Esterase Inhibitor (AChEI) use (Yes, No), and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline, and baseline-by-visit interaction. The study identifier is also a categorical covariate for the twin studies analyses.	Mixed Model Repeated Measurement (MMRM)	Kenward-Roger was used to model degrees of freedom.	0.6492	p-value was nominal and not adjusted.	Mean Difference (Final Values)	-0.02	Standard Error of the Mean	0.041	2-Sided	95	-0.098	0.061	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences	Superiority	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.

Group IDs	Group Description	Statistical Method	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Non-Inferiority Type	Non-Inferiority Comment
OG000 OG004	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.	ANCOVA	0.5287	p-value was nominal and not adjusted.	Mean Difference (Final Values)	0.67	Standard Error of the Mean	1.066	2-Sided	95	-1.43	2.77	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
OG001 OG004	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.	ANCOVA	0.7105	p-value was nominal and not adjusted.	Mean Difference (Final Values)	-0.41	Standard Error of the Mean	1.099	2-Sided	95	-2.57	1.76	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
OG002 OG004	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.	ANCOVA	0.3822	p-value was nominal and not adjusted.	Mean Difference (Final Values)	0.93	Standard Error of the Mean	1.064	2-Sided	95	-1.16	3.03	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
OG003 OG004	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.	ANCOVA	0.6472	p-value was nominal and not adjusted.	Mean Difference (Final Values)	-0.49	Standard Error of the Mean	1.066	2-Sided	95	-2.59	1.61	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Non-Inferiority Type
OG000 OG004	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.	Mixed-effects Model for Repeated Measure	Kenward-Roger was used to model degrees of freedom.	0.7551	p-value was nominal and not adjusted.	Mean Difference (Final Values)	0.1	Standard Error of the Mean	0.28	2-Sided	95	-0.46	0.64	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority
OG001 OG004	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.	Mixed-effects Model for Repeated Measure	Kenward-Roger was used to model degrees of freedom.	0.3643	p-value was nominal and not adjusted.	Mean Difference (Final Values)	0.3	Standard Error of the Mean	0.28	2-Sided	95	-0.29	0.80	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority
OG002 OG004	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.	Mixed-effects Model for Repeated Measure	Kenward-Roger was used to model degrees of freedom.	0.7822	p-value was nominal and not adjusted.	Mean Difference (Final Values)	0.1	Standard Error of the Mean	0.27	2-Sided	95	-0.45	0.60	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority
OG003 OG004	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.	Mixed-effects Model for Repeated Measure	Kenward-Roger was used to model degrees of freedom.	0.6889	p-value was nominal and not adjusted.	Mean Difference (Final Values)	0.1	Standard Error of the Mean	0.28	2-Sided	95	-0.43	0.65	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority

Group IDs	Group Description	Statistical Method	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Non-Inferiority Type	Non-Inferiority Comment
OG000 OG004	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.	ANCOVA	0.1595	p-value was nominal and not adjusted.	Mean Difference (Final Values)	1.32	Standard Error of the Mean	0.933	2-Sided	95	-0.52	3.15	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
OG001 OG004	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.	ANCOVA	0.2455	p-value was nominal and not adjusted.	Mean Difference (Final Values)	1.12	Standard Error of the Mean	0.962	2-Sided	95	-0.77	3.01	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
OG002 OG004	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.	ANCOVA	0.1732	p-value was nominal and not adjusted.	Mean Difference (Final Values)	1.28	Standard Error of the Mean	0.940	2-Sided	95	-0.57	3.13	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.
OG003 OG004	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.	ANCOVA	0.0088	p-value was nominal and not adjusted.	Mean Difference (Final Values)	2.47	Standard Error of the Mean	0.936	2-Sided	95	0.63	4.31	The mean difference is actually adjusted mean of difference and the dispersion value is standard error of differences.	Superiority	Analyses of covariance (ANCOVA) were used to assess between-group differences in the modelled changes from baseline to Week 12.