BI 425809 in Patients With Cognitive Impairment Due to Alzheimer's Disease.

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02788513
• Collaborator: (none)
• Enrollment: 611
• Locations: 95
• Arms: 5
• Actual Duration (Months): 38
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The study is designed to compare the effects of BI 425809 compared to placebo in patients with cognitive impairment due to Alzheimer's Disease.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Drug: BI 425809 dose 1; Drug: BI 425809 dose 2; Drug: BI 425809 dose 3; Drug: BI 425809 dose 4; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 611 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Multi-centre, Double-blind, Parallel-group, Randomised Controlled Study to Investigate Efficacy and Safety of Orally Administered BI 425809 During a 12-week Treatment Period Compared to Placebo in Patients With Cognitive Impairment Due to Alzheimer's Disease.
• Actual Study Start Date: Aug 11, 2016
• Actual Primary Completion Date: Sep 12, 2019
• Actual Study Completion Date: Oct 11, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 425809 dose 1	Drug: BI 425809 dose 1; Drug: Placebo
Experimental: BI 425809 dose 2	Drug: BI 425809 dose 2; Drug: Placebo
Experimental: BI 425809 dose 3	Drug: BI 425809 dose 3; Drug: Placebo
Experimental: BI 425809 dose 4	Drug: BI 425809 dose 4; Drug: Placebo
Placebo Comparator: Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment [On day 1 (visit 2, baseline) and day 85 (end of trial)]

   The ADAS-Cog11 is an 11-item cognitive subscale that objectively measures memory, language, orientation and praxis with a total score range of 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. Multiple comparison procedures and modelling (MCPmod) in combination with mixed model repeated measures (MMRM) is used for primary analysis of the primary endpoint. MMRM included fixed, categorical covariates of treatment, visit, baseline Mini Mental State Examination MMSE (>=20, <20) and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. Patient was considered as random effect. The unstructured covariance structure was used to model the within patient measurements. The same MMRM model used in the primary analysis is used for the secondary analysis of the primary endpoint.

Secondary Outcome Measures

1. Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment [On day 1 (visit 2, baseline) and day 85 (end of trial)]

   Change from baseline in the ADCS-ADL score after 12 weeks of treatment is presented. The ADCS-ADL is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum score could range from 0 to 78, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline. Abbreviation: MMSE = Mini Mental State Examination

2. Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment [On day 1 (visit 2, baseline) and day 85 (end of trial)]

   Clinician's Interview-Based Impression of Change (CIBIC+) score is based on semi-structured interview covering domains of function and cognition. It additionally requires the assessment of psychiatric signs and symptoms. The patient and their caregiver are interviewed and questioned by the clinician. Change rate is based on an unanchored 7-point scale (with 0 being not assessed, 1-3 being very much improved to minimally improved, 4 being no change, and 5-7 being minimally worse to very much worse). For the ANCOVA model, the baseline value for CIBIC+ is represented by CIBIS which is clinician's interview-based impression of severity score (scores range from 0-7, with 0 being not assessed, 1 being normal, and 7 being most extremely ill) in order to adjust for potential baseline heterogeneity. Abbreviation: MMSE = Mini Mental State Examination

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Patients with early signs of dementia of Alzheimer Type

• Male and female patients with an age of at least 55 years

• Concomitant use of acetylcholinesterase inhibitors (AChEIs) is allowed but not required. Patients who are currently taking AChEIs are eligible as long as they have been using a stable dose for at least 3 months prior to screening and no change is foreseen for the duration of the study. This dose must be consistent with the product label in the concerned country. Patients who are not currently taking AChEIs but have taken them in the past are also eligible if AChEIs were stopped at least 3 months prior to screening.

• Patients must have at least 6 years of formal education and fluency in the test language as verbally confirmed by the patient and documented by the study investigator.

• Patients must have a reliable study partner (per investigator judgement, for instance a family member, partner etc., guardian)

• Further inclusion criteria apply

Exclusion criteria:

• Cognitive impairment or dementia with any etiology other than Alzheimer's Dementia (AD)

• Substantial concomitant cerebrovascular disease (defined by a history of a stroke / intracranial haemorrhagia) temporally related to the onset of worsening of cognitive impairment per investigator judgement

• Medical history or diagnosis of any of symptomatic and unstable/uncontrolled conditions per investigator judgement

• Patients receiving prescribed drugs for treatment of dementia of Alzheimer Type (other than Acetylcholine Esterase Inhibitors) at screening or within 3 months prior to screening

• Previous participation in investigational drug studies of dementia of Alzheimer's Type within three months prior to screening. Patients having received any active treatment in studies targeting disease modification of AD are excluded. Previous participation in studies with non-prescription medications, vitamins or other nutritional formulations is allowed.

• Clinically significant uncompensated hearing loss in the judgment of the investigator. Use of hearing aids is allowed.

• Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Axiom Research LLC	Colton	California	United States	92324
2	Alliance for Wellness	Long Beach	California	United States	90807
3	Anderson Clinical Research	Redlands	California	United States	92374
4	CITrials	Santa Ana	California	United States	92705
5	MD Clinical	Hallandale Beach	Florida	United States	33009
6	Galiz Research	Miami	Florida	United States	33016
7	Premier Clinical Research Institute	Miami	Florida	United States	33122
8	Miami Jewish Health System	Miami	Florida	United States	33137
9	Stedman Clinical Trials	Tampa	Florida	United States	33613
10	Bioclinica Research	The Villages	Florida	United States	32162
11	Neuro Trials Research Incorporated	Atlanta	Georgia	United States	30342
12	Millennium Psychiatric Associates LLC	Saint Louis	Missouri	United States	63132
13	ANI Neurology, PLLC, dba Alzheimer's Memory Center	Charlotte	North Carolina	United States	28270
14	Tulsa Clinical Research, LLC	Tulsa	Oklahoma	United States	74104
15	Northeastern Pennsylvania Memory and Alzheimer Center	Plains	Pennsylvania	United States	18705
16	Roper St. Francis Healthcare	Charleston	South Carolina	United States	29401
17	The Memory Clinic	Bennington	Vermont	United States	05201
18	LKH-Univ. Hospital Graz	Graz		Austria	8036
19	Medical University of Innsbruck	Innsbruck		Austria	6020
20	SALK Christian-Doppler-Klinik,Paracel.Med.Privatuni.f.Neurol	Salzburg		Austria	5020
21	Private Practice for Psychiatry and Neurology	Vienna		Austria	1130
22	The Medical Arts Health Research Group	Kelowna	British Columbia	Canada	V1Y 4N7
23	True North Clinical Research Halifax, Inc.	Halifax	Nova Scotia	Canada	B3S 1M7
24	True North Clinical Research Kentville, Inc.	Kentville	Nova Scotia	Canada	B4N 4K9
25	Bluewater Clinical Research	Sarnia	Ontario	Canada	N7T 4X3
26	Clinique Neuro-Outaouais	Gatineau	Quebec	Canada	J8Y 1W2
27	Diex Recherche	Sherbrooke	Quebec	Canada	J1H 0H8
28	Orton	Helsinki		Finland	FI-00280
29	University of Eastern Finland, Brain Research Unit	Kuopio		Finland	70210
30	Terveystalo Lahti	Lahti		Finland	15110
31	OYS, Neurologian tutkimusyksikkö	Oulu		Finland	90220
32	CRST - Clinical Research Services Turku	Turku		Finland	20520
33	HOP Pellegrin	Bordeaux		France	33076
34	HOP Pierre Wertheimer	Bron		France	69677
35	HOP Roger Salengro	Lille		France	59037
36	HOP Gui de Chauliac	Montpellier		France	34295
37	HOP Nord Laënnec	Nantes		France	44093
38	HOP La Pitié Salpêtrière	Paris		France	75651
39	CHU La Grave-Casselardit - Cité de la Santé	Toulouse		France	31052
40	HOP Brabois	Vandoeuvre les Nancy		France	54500
41	HOP des Charpennes	Villeurbanne		France	69100
42	Zentrum für klinische Forschung Dr. med. Irma Schöll & Kollegen	Bad Homburg		Germany	61348
43	Praxis Dr. med. Volker Schumann	Berlin		Germany	10245
44	Charité - Universitätsmedizin Berlin	Berlin		Germany	12200
45	Charité - Universitätsmedizin Berlin	Berlin		Germany	13125
46	Praxis Dr. Oehlwein	Gera		Germany	07551
47	Universitätsklinikum Köln (AöR)	Köln		Germany	50937
48	Pharmakologisches Studienzentrum Chemnitz	Mittweida		Germany	09648
49	Institut für Psychogerontologie	Nürnberg		Germany	90408
50	Neuropraxis München Süd, Unterhaching	Unterhaching		Germany	82008
51	Naval Hospital of Athens	Athens		Greece	11521
52	Eginition Hospital	Athens		Greece	11528
53	University General Hospital Attikon	Athens		Greece	124 62
54	Athens Medical Center	Athens		Greece	15125
55	University General Hospital of Thessaloniki AHEPA	Thessaloniki		Greece	54621
56	University General Hospital of Thessaloniki AHEPA	Thessaloniki		Greece	54636
57	Semmelweis University	Budapest		Hungary	1083
58	CRU Ltd, Neurology Dept., Miskolc	Miskolc		Hungary	3526
59	University of Szeged	Szeged		Hungary	6725
60	IRCCS Fondazione Ospedale Maggiore	Milano		Italy	20122
61	A.O. San Gerardo di Monza	Monza (MB)		Italy	20900
62	Azienda Ospedaliera Universitaria di Padova	Padova		Italy	35128
63	Azienda Ospedaliera Universitaria Pisana	Pisa		Italy	56126
64	Fujita Health University Hospital	Aichi, Toyoake		Japan	470-1192
65	Inage Neurology and Memory Clinic	Chiba, Chiba		Japan	263-0043
66	Sapporo Medical University Hospital	Hokkaido, Sapporo		Japan	060-8543
67	Kagawa University Hospital	Kagawa, Kita-gun		Japan	761-0793
68	Kawashima Neurology Clinic	Kanagawa, Fujisawa		Japan	251-0038
69	Ishikawa Clinic	Kyoto, Kyoto		Japan	606-0851
70	Nara Medical University Hospital	Nara, Kashihara		Japan	634-8522
71	Katayama Medical Clinic	Okayama, Kurashiki		Japan	710-0813
72	National Hospital Organization Hizen Psychiatric Center	Saga, Kanzaki-gun		Japan	842-0192
73	National Center Neurology and Psychiatry	Tokyo, Kodaira		Japan	187-8551
74	Nozomi Memory Clinic	Tokyo, Mitaka		Japan	181-0013
75	Showa University East Hospital	Tokyo, Shinagawa		Japan	142-0054
76	Oslo Universitetssykehus HF, Hukommelsesklinikken	Oslo		Norway	N-0450
77	St. Olavs Hospital, Universitetssykehuset i Trondheim	Trondheim		Norway	N-7030
78	Podlassian Center of Psychogeriatry, Bialystok	Bialystok		Poland	15-732
79	Non-Public Outpat. Clinic "Dom Sue Ryder", PALLMED Sp. z o.o	Bydgoszcz		Poland	85-023
80	Non-Public Outpatient Clinic Neuro-Kard Ilkowski & Partners	Poznan		Poland	61-853
81	EUROMEDIS Sp. z o.o., Szczecin	Szczecin		Poland	70-111
82	Clin.Research Centre Clinsante SC Ewa Galczak-Nowak,Torun	Torun		Poland	87-100
83	Hospital del Mar	Barcelona		Spain	08003
84	Hospital Vall d'Hebron	Barcelona		Spain	08035
85	Hospital Sant Joan de Deu de Manresa	Manresa		Spain	08423
86	Hospital Universitari General de Catalunya	Sant Cugat del Vallès		Spain	08190
87	Hospital Universitario Marqués de Valdecilla	Santander		Spain	39008
88	Hospital Viamed Montecanal	Zaragoza		Spain	50012
89	Royal Cornhill Hospital	Aberdeen		United Kingdom	AB25 2ZH
90	Fulbourn Hospital	Cambridge		United Kingdom	CB21 5EF
91	Ninewells Hospital & Medical School	Dundee		United Kingdom	DD2 1SY
92	Western General Hospital	Edinburgh		United Kingdom	EH4 2XU
93	Queen Elizabeth University Hospital	Glasgow		United Kingdom	G51 4TF
94	Warneford Hospital	Oxford		United Kingdom	OX3 7JX
95	Sheffield Memory Service	Sheffield		United Kingdom	S10 3TH

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Jul 12, 2018
• Statistical Analysis Plan - Oct 4, 2019

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02788513
• Other Study ID Numbers: 1346.23; 2015-005438-24
• First Posted: Jun 2, 2016
• Last Update Posted: Nov 6, 2020
• Last Verified: Oct 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Alzheimer Disease; Cognitive Dysfunction; BI 425809

Study Results

Participant Flow

Recruitment Details	This is a multi-centre, double-blind, parallel-group, randomised controlled study to investigate efficacy and safety of orally administered BI 425809 during a 12-week treatment period compared to placebo in patients with cognitive impairment due to Alzheimer's Disease.
Pre-assignment Detail	Subjects were screened prior to participation and attended a specialist site which ensured that they strictly met all inclusion/exclusion criteria. Subjects were not to be allocated to a treatment group if any of the criteria were violated. One subject was randomized by error via Interactive Response Technology (IRT) but never took a drug.

Arm/Group Title	2 mg BI 425809	5 mg BI 425809	10 mg BI 425809	25 mg BI 425809	Placebo Group
Arm/Group Description	Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Period Title: Overall Study
STARTED	123	122	122	123	120
COMPLETED	114	114	114	117	115
NOT COMPLETED	9	8	8	6	5

Baseline Characteristics

Arm/Group Title	2 mg BI 425809	5 mg BI 425809	10 mg BI 425809	25 mg BI 425809	Placebo Group	Total
Arm/Group Description	Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Total of all reporting groups
Overall Participants	123	122	122	123	120	610
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	72.3 (7.5)	72.5 (8.2)	74.4 (6.9)	72.9 (7.7)	72.4 (7.9)	72.9 (7.7)
Sex: Female, Male (Count of Participants)
Female	68 55.3%	62 50.8%	66 54.1%	64 52%	64 53.3%	324 53.1%
Male	55 44.7%	60 49.2%	56 45.9%	59 48%	56 46.7%	286 46.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 13.8%	22 18%	11 9%	16 13%	20 16.7%	86 14.1%
Not Hispanic or Latino	101 82.1%	98 80.3%	106 86.9%	103 83.7%	94 78.3%	502 82.3%
Unknown or Not Reported	5 4.1%	2 1.6%	5 4.1%	4 3.3%	6 5%	22 3.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	11 8.9%	10 8.2%	12 9.8%	14 11.4%	11 9.2%	58 9.5%
Native Hawaiian or Other Pacific Islander	0 0%	2 1.6%	1 0.8%	1 0.8%	2 1.7%	6 1%
Black or African American	10 8.1%	5 4.1%	4 3.3%	3 2.4%	8 6.7%	30 4.9%
White	97 78.9%	103 84.4%	100 82%	102 82.9%	93 77.5%	495 81.1%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	5 4.1%	2 1.6%	5 4.1%	3 2.4%	6 5%	21 3.4%
ADASCOG baseline cognitive assessment data (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	18.8 (7.9)	18.8 (7.4)	19.6 (7.8)	19.6 (7.3)	18.2 (8.0)	19.0 (7.7)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment
Description	The ADAS-Cog11 is an 11-item cognitive subscale that objectively measures memory, language, orientation and praxis with a total score range of 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. Multiple comparison procedures and modelling (MCPmod) in combination with mixed model repeated measures (MMRM) is used for primary analysis of the primary endpoint. MMRM included fixed, categorical covariates of treatment, visit, baseline Mini Mental State Examination MMSE (>=20, <20) and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. Patient was considered as random effect. The unstructured covariance structure was used to model the within patient measurements. The same MMRM model used in the primary analysis is used for the secondary analysis of the primary endpoint.
Time Frame	On day 1 (visit 2, baseline) and day 85 (end of trial)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.

Arm/Group Title	2 mg BI 425809	5 mg BI 425809	10 mg BI 425809	25 mg BI 425809	Placebo Group
Arm/Group Description	Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Measure Participants	121	120	121	119	118
Mean (Standard Deviation) [score on a scale]	0.026 (4.864)	0.175 (4.471)	0.699 (4.313)	-0.174 (4.044)	0.138 (4.939)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, 5 mg BI 425809, 10 mg BI 425809, 25 mg BI 425809, Placebo Group
	Comments	Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9931
	Comments	An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
	Method	MCPMod Beta model fit.
	Comments	Model assumption: 75% of max effect is achieved at 2 mg, 87.5% at 5 mg, 25% at 25 mg, max effect achieved at 10 mg of BI 425809, scalar parameter = 26

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, 5 mg BI 425809, 10 mg BI 425809, 25 mg BI 425809, Placebo Group
	Comments	Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9225
	Comments	An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
	Method	MCPMod Emax model fit.
	Comments	Model assumption: 20% of the maximum effect is achieved at 2 mg

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, 5 mg BI 425809, 10 mg BI 425809, 25 mg BI 425809, Placebo Group
	Comments	Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9287
	Comments	An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
	Method	MCPMod Sigmoidal Emax model fit.
	Comments	Model assumption: 25% of max effect achieved at 5 mg and 75% of max effect achieved at 10 mg of BI 425809.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, 5 mg BI 425809, 10 mg BI 425809, 25 mg BI 425809, Placebo Group
	Comments	Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7646
	Comments	An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
	Method	MCPMod linear model fit.
	Comments	No assumption needed.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, 5 mg BI 425809, 10 mg BI 425809, 25 mg BI 425809, Placebo Group
	Comments	Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9335
	Comments	An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
	Method	MCPMod linear in log model fit.
	Comments	No assumption needed.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, 5 mg BI 425809, 10 mg BI 425809, 25 mg BI 425809, Placebo Group
	Comments	Multiple comparison procedures and modelling (MCPmod) techniques for mixed model repeated measures (MMRM) was used.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8199
	Comments	An alpha of 0.05 was used for one-sided test. The MCPMod procedure adjusts for multiplicity.
	Method	MCPMod logistic model fit.
	Comments	Model assumption: 10% of max effect achieved at 5 mg and 50% of max effect achieved at 10 mg of BI 425809.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, Placebo Group
	Comments	Mixed model repeated measures (MMRM)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9340
	Comments	p-values are nominal without multiplicity adjustment.
	Method	MMRM
	Comments	MMRM information is described in the description section.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -1.09 to 1.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.58
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	5 mg BI 425809, Placebo Group
	Comments	Mixed model repeated measures (MMRM)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6041
	Comments	p-values are nominal without multiplicity adjustment.
	Method	MMRM
	Comments	MMRM information is described in the description section.
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; -0.84 to 1.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.58
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	10 mg BI 425809, Placebo Group
	Comments	Mixed model repeated measures (MMRM)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1926
	Comments	p-values are nominal without multiplicity adjustment.
	Method	MMRM
	Comments	MMRM information is described in the description section.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; -0.38 to 1.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.58
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	25 mg BI 425809, Placebo Group
	Comments	Mixed model repeated measures (MMRM)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9739
	Comments	p-values are nominal without multiplicity adjustment.
	Method	MMRM
	Comments	MMRM information is described in the description section.
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -1.16 to 1.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.58
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment
Description	Change from baseline in the ADCS-ADL score after 12 weeks of treatment is presented. The ADCS-ADL is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum score could range from 0 to 78, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline. Abbreviation: MMSE = Mini Mental State Examination
Time Frame	On day 1 (visit 2, baseline) and day 85 (end of trial)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.

Arm/Group Title	2 mg BI 425809	5 mg BI 425809	10 mg BI 425809	25 mg BI 425809	Placebo Group
Arm/Group Description	Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Measure Participants	113	111	110	116	111
Mean (Standard Deviation) [score on a scale]	0.283 (6.805)	0.577 (5.852)	-1.145 (4.764)	-1.828 (7.034)	0.261 (4.842)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, Placebo Group
	Comments	Analysis of Covariance (ANCOVA)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.979
	Comments	p-values are nominal without multiplicity adjustment.
	Method	ANCOVA
	Comments	Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -1.48 to 1.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.76
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	5 mg BI 425809, Placebo Group
	Comments	Analysis of Covariance (ANCOVA)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.521
	Comments	p-values are nominal without multiplicity adjustment.
	Method	ANCOVA
	Comments	Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; -1.01 to 2.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.77
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	10 mg BI 425809, Placebo Group
	Comments	Analysis of Covariance (ANCOVA)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments	p-values are nominal without multiplicity adjustment.
	Method	ANCOVA
	Comments	Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.53
	Confidence Interval	(2-Sided) 95%; -3.04 to -0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.77
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	25 mg BI 425809, Placebo Group
	Comments	Analysis of Covariance (ANCOVA)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-values are nominal without multiplicity adjustment.
	Method	ANCOVA
	Comments	Analysis of Covariance model included baseline value for the secondary endpoint measure, MMSE stratification (>=20, <20) at baseline and treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.16
	Confidence Interval	(2-Sided) 95%; -3.65 to -0.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.76
	Estimation Comments

3. Secondary Outcome

Title	Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment
Description	Clinician's Interview-Based Impression of Change (CIBIC+) score is based on semi-structured interview covering domains of function and cognition. It additionally requires the assessment of psychiatric signs and symptoms. The patient and their caregiver are interviewed and questioned by the clinician. Change rate is based on an unanchored 7-point scale (with 0 being not assessed, 1-3 being very much improved to minimally improved, 4 being no change, and 5-7 being minimally worse to very much worse). For the ANCOVA model, the baseline value for CIBIC+ is represented by CIBIS which is clinician's interview-based impression of severity score (scores range from 0-7, with 0 being not assessed, 1 being normal, and 7 being most extremely ill) in order to adjust for potential baseline heterogeneity. Abbreviation: MMSE = Mini Mental State Examination
Time Frame	On day 1 (visit 2, baseline) and day 85 (end of trial)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.

Arm/Group Title	2 mg BI 425809	5 mg BI 425809	10 mg BI 425809	25 mg BI 425809	Placebo Group
Arm/Group Description	Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Measure Participants	114	112	110	116	112
Mean (Standard Deviation) [score on a scale]	4.000 (0.941)	4.080 (0.773)	4.209 (0.679)	4.224 (0.781)	4.080 (0.829)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	2 mg BI 425809, Placebo Group
	Comments	Analysis of Covariance (ANCOVA)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.343
	Comments	p-values are nominal without multiplicity adjustment.
	Method	ANCOVA
	Comments	ANCOVA included MMSE stratification (>=20, <20) at baseline (BL) and treatment, CIBIS is included as BL adjustment term.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	5 mg BI 425809, Placebo Group
	Comments	Analysis of Covariance (ANCOVA)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.645
	Comments	p-values are nominal without multiplicity adjustment.
	Method	ANCOVA
	Comments	ANCOVA included MMSE stratification (>=20, <20) at baseline (BL) and treatment, CIBIS is included as BL adjustment term.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	10 mg BI 425809, Placebo Group
	Comments	Analysis of Covariance (ANCOVA)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.448
	Comments	p-values are nominal without multiplicity adjustment.
	Method	ANCOVA
	Comments	ANCOVA included MMSE stratification (>=20, <20) at baseline (BL) and treatment, CIBIS is included as BL adjustment term.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	25 mg BI 425809, Placebo Group
	Comments	Analysis of Covariance (ANCOVA)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.340
	Comments	p-values are nominal without multiplicity adjustment.
	Method	ANCOVA
	Comments	ANCOVA included MMSE stratification (>=20, <20) at baseline (BL) and treatment, CIBIS is included as BL adjustment term.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Adverse Events

Time Frame	From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks.
Adverse Event Reporting Description	Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Arm/Group Title	2 mg BI 425809		5 mg BI 425809		10 mg BI 425809		25 mg BI 425809		Placebo Group
Arm/Group Description	Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.		Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.		Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.		Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.		Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
All Cause Mortality
	2 mg BI 425809		5 mg BI 425809		10 mg BI 425809		25 mg BI 425809		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/123 (0%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		0/120 (0%)
Serious Adverse Events
	2 mg BI 425809		5 mg BI 425809		10 mg BI 425809		25 mg BI 425809		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/123 (4.1%)		4/122 (3.3%)		4/122 (3.3%)		4/123 (3.3%)		5/120 (4.2%)
Cardiac disorders
Atrial flutter	1/123 (0.8%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		0/120 (0%)
Eye disorders
Cataract	0/123 (0%)		0/122 (0%)		1/122 (0.8%)		0/123 (0%)		0/120 (0%)
Glaucoma	0/123 (0%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		1/120 (0.8%)
Gastrointestinal disorders
Pancreatitis acute	1/123 (0.8%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		0/120 (0%)
Hepatobiliary disorders
Cholecystitis acute	0/123 (0%)		0/122 (0%)		0/122 (0%)		1/123 (0.8%)		0/120 (0%)
Drug-induced liver injury	0/123 (0%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		1/120 (0.8%)
Infections and infestations
Bronchitis	0/123 (0%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		1/120 (0.8%)
Gingivitis	0/123 (0%)		0/122 (0%)		0/122 (0%)		1/123 (0.8%)		0/120 (0%)
Pneumonia	1/123 (0.8%)		0/122 (0%)		1/122 (0.8%)		0/123 (0%)		0/120 (0%)
Sepsis	0/123 (0%)		0/122 (0%)		1/122 (0.8%)		1/123 (0.8%)		0/120 (0%)
Urinary tract infection bacterial	0/123 (0%)		1/122 (0.8%)		0/122 (0%)		0/123 (0%)		0/120 (0%)
Injury, poisoning and procedural complications
Fall	2/123 (1.6%)		1/122 (0.8%)		0/122 (0%)		1/123 (0.8%)		0/120 (0%)
Head injury	0/123 (0%)		1/122 (0.8%)		0/122 (0%)		0/123 (0%)		0/120 (0%)
Skin laceration	0/123 (0%)		0/122 (0%)		0/122 (0%)		1/123 (0.8%)		0/120 (0%)
Metabolism and nutrition disorders
Dehydration	0/123 (0%)		0/122 (0%)		0/122 (0%)		1/123 (0.8%)		0/120 (0%)
Hypoglycaemia	0/123 (0%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		1/120 (0.8%)
Musculoskeletal and connective tissue disorders
Torticollis	0/123 (0%)		0/122 (0%)		1/122 (0.8%)		0/123 (0%)		0/120 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic neoplasm	0/123 (0%)		1/122 (0.8%)		0/122 (0%)		0/123 (0%)		0/120 (0%)
Nervous system disorders
Dementia	0/123 (0%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		1/120 (0.8%)
Syncope	0/123 (0%)		1/122 (0.8%)		0/122 (0%)		1/123 (0.8%)		0/120 (0%)
Transient ischaemic attack	1/123 (0.8%)		0/122 (0%)		1/122 (0.8%)		0/123 (0%)		0/120 (0%)
Psychiatric disorders
Depression	0/123 (0%)		1/122 (0.8%)		0/122 (0%)		0/123 (0%)		0/120 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory distress	0/123 (0%)		0/122 (0%)		0/122 (0%)		0/123 (0%)		1/120 (0.8%)
Other (Not Including Serious) Adverse Events
	2 mg BI 425809		5 mg BI 425809		10 mg BI 425809		25 mg BI 425809		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/123 (13.8%)		22/122 (18%)		14/122 (11.5%)		19/123 (15.4%)		12/120 (10%)
Gastrointestinal disorders
Nausea	6/123 (4.9%)		1/122 (0.8%)		2/122 (1.6%)		8/123 (6.5%)		2/120 (1.7%)
Infections and infestations
Nasopharyngitis	3/123 (2.4%)		7/122 (5.7%)		3/122 (2.5%)		3/123 (2.4%)		3/120 (2.5%)
Nervous system disorders
Dizziness	4/123 (3.3%)		9/122 (7.4%)		3/122 (2.5%)		6/123 (4.9%)		2/120 (1.7%)
Headache	6/123 (4.9%)		10/122 (8.2%)		7/122 (5.7%)		5/123 (4.1%)		5/120 (4.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.