STARBRIGHT: Study of Idalopirdine in Patients With Mild - Moderate Alzheimer's Disease Treated With an Acetylcholinesterase Inhibitor

• Sponsor: H. Lundbeck A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02006654
• Collaborator: Otsuka Pharmaceutical Co., Ltd. (Industry)
• Enrollment: 734
• Locations: 107
• Arms: 2
• Duration (Months): 34.1
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To establish efficacy of idalopirdine as adjunctive therapy to acetylcholinesterase inhibitors (AChEIs) for symptomatic treatment of patients with mild-moderate Alzheimer's disease (AD).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Placebo; Drug: Idalopirdine	Phase 3

Detailed Description

The study consisted of a screening period (up to 2-week period from screening to randomization), a 24-week double-blind treatment period with placebo or idalopirdine 60mg/day as adjunctive therapy to an acetylcholinesterase inhibitor (donepezil 10mg/day, rivastigmine at the patient's individual maintenance dose, or galantamine at the patient's individual maintenance dose), and a 4-week safety follow-up period following study completion or withdrawal from treatment. The dose could be decreased once during the study to 30mg/day if 60mg/day was not well tolerated in the opinion of the investigator. The dose could be increased again to 60mg/day, after which the dose was kept fixed for the remainder of the study. Dose changes were permitted until Week 12 (Visit 5).

Study Design

• Study Type: Interventional
• Actual Enrollment: 734 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Randomised, Double-blind, Parallel-group, Placebo-controlled Study of Idalopirdine in Patients With Mild - Moderate Alzheimer's Disease Treated With an Acetylcholinesterase Inhibitor
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Jan 1, 2017
• Actual Study Completion Date: Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo adjunct to base treatment with an AChEI	Drug: Placebo; Once daily, matching placebo capsules, orally
Experimental: Idalopirdine 60 mg (or 30 mg) Idalopirdine adjunct to base treatment with an AChEI	Drug: Idalopirdine; Once daily, encapsulated tablets, orally; Other Names: Lu AE58054

Outcome Measures

Primary Outcome Measures

1. Change in Cognition [Baseline and Week 24]

   Change from baseline to Week 24 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) total score. The Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-cog) is a 11-item neuropsychological test that assess the severity of cognitive impairment. The items determine the patient's orientation, memory, language, and praxis. Total score of the 11 items range from 0 to 70 (lower score indicates lower cognitive impairment).

Secondary Outcome Measures

1. Change in Global Impression [Baseline and Week 24]

   Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) score at Week 24. The Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change is a semi-structured interview to assess clinically relevant changes in patients with AD. The items determine cognition, behavior, social and daily functioning. Severity at baseline is rated on a 7-point scale from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). The clinically relevant change from baseline is rated on a 7-point scale from 1 (marked improvement) to 7 (marked worsening).

2. Change in Daily Functioning [Baseline and Week 24]

   Change from baseline to Week 24 in Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL23) total score. The Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) is a 23-item clinician-rated inventory to assess activities of daily living (conducted with a caregiver or informant). Each item comprises a series of hierarchical sub-questions, ranging from the highest level of independent performance to a complete loss for each activity. Total score of the 23 items ranges from 0 to 78 (higher score indicates lower disability).

3. Change in Behavioural Disturbance [Baseline and Week 24]

   Change from baseline to Week 24 in Neuropsychiatric Inventory (NPI) total score The Neuropsychiatric Inventory is a 12-item structured interview with a caregiver to assess behavioural disturbances. The NPI comprises 10 behavioural and 2 neurovegetative items. Each item consists of a screening question and several sub-questions that are rated no (not present) or yes (present). Each item is then rated for frequency (a 4-point scale from 1 [occasionally] to 4 [very frequent]) and severity (a 3-point scale from 1 [mild] to 3 [marked]). The total NPI score is the frequency ratings multiplied by the severity ratings and ranges from 0 to 144 (higher score indicates worse outcome).

4. Change in Individual Behavioural Disturbance Items [Baseline and Week 24]

   Change in single NPI item scores at Week 24. The Neuropsychiatric Inventory is a 12-item structured interview with a caregiver to assess behavioural disturbances. The NPI comprises 10 behavioural and 2 neurovegetative items. Each item consists of a screening question and several sub-questions that are rated no (not present) or yes (present). Each item is then rated for frequency (a 4-point scale from 1 [occasionally] to 4 [very frequent]) and severity (a 3-point scale from 1 [mild] to 3 [marked]). Total score for each single NPI item ranges from 0-12 (frequency multiplied by severity), where higher scores represent worse outcome.

5. Change in NPI Anxiety Item Score in Patients With an NPI Anxiety Item Score of at Least 2 at Baseline [Baseline and Week 24]

   Change from baseline to Week 24 in NPI anxiety item score in patients with an NPI anxiety item score of at least 2 at baseline The Neuropsychiatric Inventory is a 12-item structured interview with a caregiver to assess behavioural disturbances. The NPI comprises 10 behavioural and 2 neurovegetative items. Each item consists of a screening question and several sub-questions that are rated no (not present) or yes (present). Each item is then rated for frequency (a 4-point scale from 1 [occasionally] to 4 [very frequent]) and severity (a 3-point scale from 1 [mild] to 3 [marked]). The total score for the NPI anxiety item ranges from 0-12 (frequency multiplied by severity), where a higher score represents a worse outcome.

6. Clinical Improvement [Week 24]

   Clinical response at Week 24 (based on pre-specified ADAS-cog, ADCS-ADL23, and ADCS-CGIC changes [change in ADAS-cog below or equal to -4, change in ADCS-ADL23 at least 0, and ADCS-CGIC below or equal to 4])

7. Clinical Worsening [Week 24]

   Clinical worsening at Week 24 (Based on pre-specified ADAS-cog, ADCS-ADL23, and ADCS-CGIC changes [change in ADAS-cog above or equal to 4, change in ADCS-ADL23 below 0, and ADCS-CGIC above 4])

8. Change in Cognitive Aspects of Mental Function [Baseline and Week 24]

   Change from baseline to Week 24 in Mini Mental State Examination (MMSE). The Mini Mental State Examination (MMSE) is an 11-item test to assess the cognitive aspects of mental function. The subtests assess orientation, memory, attention, language, and visual construction. The scores for each item is dichotomous (1 = response is correct, 0 = response is incorrect). Total score of the 11 items ranges from 0 to 30 (higher score indicates lower deficit).

9. Change in Health-related Quality of Life (EQ-5D) Utility Score [Baseline and Week 24]

   Change from baseline to Week 24 in EuroQol 5-dimensional (EQ-5D) utility score The EQ-5D is a patient-reported assessment that measures the patient's well-being. It consists of an utility score based on 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety) and a Visual Analogue Scale (VAS). Each descriptive item is rated on a 3-point index ranging from 1 (no problems) to 3 (extreme problems) that is used for calculating a single summary index (from 0 to 1). A higher EQ-5D score indicates a worse outcome.

10. Change in Health-related Quality of Life (EQ-5D VAS) [Baseline and Week 24]

    Change from baseline to Week 24 in EQ-5D Visual Analogue Scale (EQ-5D VAS). The EQ-5D is a patient-reported assessment that measures the patient's well-being. It consists of an utility score based on 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety) and a Visual Analogue Scale (VAS). The VAS ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The patient has a knowledgeable and reliable caregiver.

• The patient is an outpatient.

• The patient has probable AD.

• The patient has mild to moderate AD.

• Stable treatment with an AChEI.

• The patient, if a woman, must have had her last natural menstruation ≥24 months prior to baseline, OR be surgically sterile.

• The patient, if a man, agrees to protocol-defined use of effective contraception if his female partner is of childbearing potential, OR must have been surgically sterilised prior to the screening visit.

Exclusion Criteria:

• The patient has evidence of any clinically significant neurodegenerative disease, or other serious neurological disorders other than AD.

• The patient has a Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) Axis I disorder other than AD.

• The patient has evidence of clinically significant disease.

• The patient's current AChEI therapy is likely to be interrupted or discontinued during the study.

• The patient is currently receiving memantine or has taken memantine within 2 months prior to screening.

Other inclusion and exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	US612	Mesa	Arizona	United States
2	US625	Bellflower	California	United States
3	US626	Costa Mesa	California	United States
4	US604	Oxnard	California	United States
5	US627	Santa Ana	California	United States
6	US609	Danbury	Connecticut	United States
7	US614	Norwalk	Connecticut	United States
8	US608	Deerfield Beach	Florida	United States
9	US616	Hialeah	Florida	United States
10	US620	Miami	Florida	United States
11	US603	North Palm Beach	Florida	United States
12	US631	Port Charlotte	Florida	United States
13	US622	Elk Grove Village	Illinois	United States
14	US611	Elkhart	Indiana	United States
15	US606	Prairie Village	Kansas	United States
16	US601	Farmington Hills	Michigan	United States
17	US607	Saint Louis	Missouri	United States
18	US613	Lawrenceville	New Jersey	United States
19	US635	Manchester	New Jersey	United States
20	US630	Toms River	New Jersey	United States
21	US621	Albany	New York	United States
22	US632	Staten Island	New York	United States
23	US633	Charlotte	North Carolina	United States
24	US623	Oklahoma City	Oklahoma	United States
25	US618	Norristown	Pennsylvania	United States
26	US619	Houston	Texas	United States
27	AU603	Caulfield		Australia
28	AU609	Glen Iris		Australia
29	AU602	Heidelberg West		Australia
30	AU604	Kanwal		Australia
31	AU606	Newcastle		Australia
32	AU601	West Perth		Australia
33	AU610	Woodville south		Australia
34	BR608	Belo Horizonte		Brazil
35	BR609	Itapira		Brazil
36	BR607	Rio de Janeiro		Brazil
37	CZ602	Chocen		Czechia
38	CZ608	Chocen		Czechia
39	CZ605	Havlickuv Brod		Czechia
40	CZ606	Kladno		Czechia
41	CZ603	Plzen		Czechia
42	CZ601	Prague		Czechia
43	CZ607	Praha 10 - Strasnice		Czechia
44	CZ604	Praha 6		Czechia
45	DE612	Bad Homburg		Germany
46	DE610	Bad Honnef		Germany
47	DE609	Berlin		Germany
48	DE617	Berlin		Germany
49	DE604	Erbach		Germany
50	DE611	Freiburg		Germany
51	DE607	Gelsenkirchen		Germany
52	DE605	Homburg		Germany
53	DE608	Karlstadt		Germany
54	DE602	Mittweida		Germany
55	DE601	Munich		Germany
56	DE606	Rostock		Germany
57	DE603	Ulm		Germany
58	DE616	Unterhaching		Germany
59	IL605	Bat Yam		Israel
60	IL601	Haifa		Israel
61	IL604	Holon		Israel
62	IL602	Ramat Gan		Israel
63	IL603	Tel Aviv		Israel
64	KR601	Seongnam-si		Korea, Republic of
65	KR602	Seoul		Korea, Republic of
66	KR603	Seoul		Korea, Republic of
67	KR604	Seoul		Korea, Republic of
68	MX602	Mexico		Mexico
69	MX601	Monterrey		Mexico
70	MX603	Monterrey		Mexico
71	MX604	Monterrey		Mexico
72	MX605	Monterrey		Mexico
73	MX606	Saltillo		Mexico
74	RS602	Belgrade		Serbia
75	RS603	Kragujevac		Serbia
76	RS601	Novi Sad		Serbia
77	SG601	Singapore		Singapore
78	SG602	Singapore		Singapore
79	SK601	Banska Bystrica		Slovakia
80	SK603	Bratislava		Slovakia
81	SK605	Bratislava		Slovakia
82	SK604	Rimavska Sobota		Slovakia
83	SK602	Svidnik		Slovakia
84	ES601	Barcelona		Spain
85	ES603	Barcelona		Spain
86	ES604	Barcelona		Spain
87	ES608	Barcelona		Spain
88	ES611	Bilbao		Spain
89	ES612	Burgos		Spain
90	ES602	Lleida		Spain
91	ES613	Madrid		Spain
92	ES610	Sant Cugat del Vallès		Spain
93	ES606	Sevilla		Spain
94	ES605	Terrassa		Spain
95	ES607	Valencia		Spain
96	CH603	Biel		Switzerland
97	CH605	Lausanne		Switzerland
98	CH602	Les Acacias		Switzerland
99	CH601	Schlieren		Switzerland
100	TR602	Balova		Turkey
101	TR601	Istanbul		Turkey
102	TR603	İstanbul		Turkey
103	TR605	Istanbul		Turkey
104	TR606	Izmir		Turkey
105	TR607	Samsun		Turkey
106	GB601	Brentford		United Kingdom
107	GB603	Northampton		United Kingdom

Sponsors and Collaborators

• H. Lundbeck A/S
• Otsuka Pharmaceutical Co., Ltd.

Investigators

• Study Director: Email contact via H. Lundbeck A/S, [e-mail]

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: H. Lundbeck A/S
• ClinicalTrials.gov Identifier: NCT02006654
• Other Study ID Numbers: 14863A; 2012-004765-40
• First Posted: Dec 10, 2013
• Last Update Posted: Feb 7, 2018
• Last Verified: Jan 1, 2018

• Additional relevant MeSH terms: Alzheimer Disease

Study Results

Participant Flow

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an ACHEI Idalopirdine: Once daily, encapsulated tablets, orally
Period Title: Overall Study
STARTED	369	365
Treated	365	363
COMPLETED	324	321
NOT COMPLETED	45	44

Baseline Characteristics

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)	Total
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally	Total of all reporting groups
Overall Participants	365	363	728
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.2 (8.0)	73.6 (8.6)	73.9 (8.3)
Sex: Female, Male (Count of Participants)
Female	131 35.9%	135 37.2%	266 36.5%
Male	234 64.1%	228 62.8%	462 63.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 2.2%	6 1.7%	14 1.9%
Not Hispanic or Latino	33 9%	33 9.1%	66 9.1%
Unknown or Not Reported	324 88.8%	324 89.3%	648 89%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	NA NaN	NA NaN	NA NaN
Asian	40 11%	39 10.7%	79 10.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	12 3.3%	7 1.9%	19 2.6%
White	292 80%	299 82.4%	591 81.2%
More than one race	NA NaN	NA NaN	NA NaN
Unknown or Not Reported	21 5.8%	18 5%	39 5.4%
Region of Enrollment (Count of Participants)
Singapore	17 4.7%	15 4.1%	32 4.4%
United States	41 11.2%	39 10.7%	80 11%
Czechia	42 11.5%	37 10.2%	79 10.9%
United Kingdom	7 1.9%	4 1.1%	11 1.5%
Switzerland	2 0.5%	2 0.6%	4 0.5%
Spain	65 17.8%	62 17.1%	127 17.4%
South Korea	19 5.2%	20 5.5%	39 5.4%
Turkey	15 4.1%	14 3.9%	29 4%
Brazil	23 6.3%	21 5.8%	44 6%
Mexico	25 6.8%	23 6.3%	48 6.6%
Slovakia	27 7.4%	29 8%	56 7.7%
Israel	7 1.9%	9 2.5%	16 2.2%
Australia	19 5.2%	23 6.3%	42 5.8%
Germany	37 10.1%	43 11.8%	80 11%
France	9 2.5%	11 3%	20 2.7%
MMSE total score at screening (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	17.5 (3.0)	17.2 (2.9)	17.3 (2.9)

Outcome Measures

1. Primary Outcome

Title	Change in Cognition
Description	Change from baseline to Week 24 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) total score. The Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-cog) is a 11-item neuropsychological test that assess the severity of cognitive impairment. The items determine the patient's orientation, memory, language, and praxis. Total score of the 11 items range from 0 to 70 (lower score indicates lower cognitive impairment).
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an ACHEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	356	361
Least Squares Mean (Standard Error) [units on a scale]	0.68 (0.37)	0.13 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Idalopirdine 60 mg (or 30 mg)
	Comments	For demonstrating efficacy, change in cognition (ADAS-cog) and either change in daily functioning (ADCS-ADL23) or change in global clinical impression (ADCS-CGIC) had to show statistically significant favourable differences compared to placebo at Week 24. Multiple testing procedures were used to control the overall type 1 error at 5%. The null hypothesis of no difference in mean change from baseline in ADAS-cog total score at Week 24 was tested for idalopirdine at significance level 5%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2365
	Comments	Corrected for multiplicity
	Method	Mixed Models Analysis
	Comments	Adjusted for effects of country, MMSE stratum-by-week, treatment-by-week, base treatment stratum-by-week, and baseline score-by-week interactions
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 95%; -1.45 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.46
	Estimation Comments	A negative mean difference indicates a treatment effect in favor of idalopirdine

2. Secondary Outcome

Title	Change in Global Impression
Description	Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) score at Week 24. The Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change is a semi-structured interview to assess clinically relevant changes in patients with AD. The items determine cognition, behavior, social and daily functioning. Severity at baseline is rated on a 7-point scale from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). The clinically relevant change from baseline is rated on a 7-point scale from 1 (marked improvement) to 7 (marked worsening).
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an ACHEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	353	357
Least Squares Mean (Standard Error) [units on a scale]	4.32 (0.07)	4.39 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Idalopirdine 60 mg (or 30 mg)
	Comments	For demonstrating efficacy, change in cognition (ADAS-cog) and either change in daily functioning (ADCS-ADL23) or change in global clinical impression (ADCS-CGIC) had to show statistically significant favourable differences compared to placebo at Week 24. Multiple testing procedures were used to control the overall type 1 error at 5%. The null hypothesis of no difference in mean change from baseline in ADAS-cog total score at Week 24 was tested at significance level 5%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4064
	Comments	Corrected for multiplicity according to the multiple testing procedure
	Method	Mixed Models Analysis
	Comments	Adjusted for effects of country, MMSE stratum-by-week, treatment-by-week, base treatment stratum-by-week, and baseline score-by-week interactions
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.08
	Estimation Comments	A negative mean difference indicates a treatment effect in favor of idalopirdine

3. Secondary Outcome

Title	Change in Daily Functioning
Description	Change from baseline to Week 24 in Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL23) total score. The Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) is a 23-item clinician-rated inventory to assess activities of daily living (conducted with a caregiver or informant). Each item comprises a series of hierarchical sub-questions, ranging from the highest level of independent performance to a complete loss for each activity. Total score of the 23 items ranges from 0 to 78 (higher score indicates lower disability).
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an ACHEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	356	361
Least Squares Mean (Standard Error) [units on a scale]	-1.72 (0.50)	-1.05 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Idalopirdine 60 mg (or 30 mg)
	Comments	For demonstrating efficacy, change in cognition (ADAS-cog) and either change in daily functioning (ADCS-ADL23) or change in global clinical impression (ADCS-CGIC) had to show statistically significant favourable differences compared to placebo at Week 24. Multiple testing procedures were used to control the overall type 1 error at 5%. The null hypothesis of no difference in mean change from baseline in ADAS-cog total score at Week 24 was tested at significance level 5%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4064
	Comments	Corrected for multiplicity according to the multiple testing procedure
	Method	Mixed Models Analysis
	Comments	Adjusted for effects of country, MMSE stratum-by-week, treatment-by-week, base treatment stratum-by-week, and baseline score-by-week interactions
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; -0.57 to 1.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.63
	Estimation Comments	A positive mean difference indicates a treatment effect in favour of idalopirdine

4. Secondary Outcome

Title	Change in Behavioural Disturbance
Description	Change from baseline to Week 24 in Neuropsychiatric Inventory (NPI) total score The Neuropsychiatric Inventory is a 12-item structured interview with a caregiver to assess behavioural disturbances. The NPI comprises 10 behavioural and 2 neurovegetative items. Each item consists of a screening question and several sub-questions that are rated no (not present) or yes (present). Each item is then rated for frequency (a 4-point scale from 1 [occasionally] to 4 [very frequent]) and severity (a 3-point scale from 1 [mild] to 3 [marked]). The total NPI score is the frequency ratings multiplied by the severity ratings and ranges from 0 to 144 (higher score indicates worse outcome).
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	356	361
Least Squares Mean (Standard Error) [units on a scale]	-0.46 (0.53)	-0.74 (0.54)

5. Secondary Outcome

Title	Change in Individual Behavioural Disturbance Items
Description	Change in single NPI item scores at Week 24. The Neuropsychiatric Inventory is a 12-item structured interview with a caregiver to assess behavioural disturbances. The NPI comprises 10 behavioural and 2 neurovegetative items. Each item consists of a screening question and several sub-questions that are rated no (not present) or yes (present). Each item is then rated for frequency (a 4-point scale from 1 [occasionally] to 4 [very frequent]) and severity (a 3-point scale from 1 [mild] to 3 [marked]). Total score for each single NPI item ranges from 0-12 (frequency multiplied by severity), where higher scores represent worse outcome.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure/item assessed

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	356	361
Delusions	-0.00 (0.10)	0.03 (0.10)
Hallucinations	0.05 (0.06)	0.08 (0.06)
Agitation/aggression	0.15 (0.11)	0.03 (0.11)
Depression/dysphoria	-0.28 (0.09)	-0.18 (0.09)
Anxiety	-0.16 (0.09)	-0.07 (0.09)
Elation/euphoria	0.02 (0.04)	0.03 (0.04)
Apathy/indifference	-0.06 (0.15)	-0.19 (0.15)
Disinhibition	0.12 (0.08)	-0.00 (0.08)
Irritability/lability	0.10 (0.12)	-0.04 (0.12)
Aberrant motor behaviour	0.08 (0.11)	0.11 (0.11)
Sleep	-0.13 (0.11)	-0.12 (0.11)
Appetite/eating disorder	-0.25 (0.12)	-0.21 (0.12)

6. Secondary Outcome

Title	Change in NPI Anxiety Item Score in Patients With an NPI Anxiety Item Score of at Least 2 at Baseline
Description	Change from baseline to Week 24 in NPI anxiety item score in patients with an NPI anxiety item score of at least 2 at baseline The Neuropsychiatric Inventory is a 12-item structured interview with a caregiver to assess behavioural disturbances. The NPI comprises 10 behavioural and 2 neurovegetative items. Each item consists of a screening question and several sub-questions that are rated no (not present) or yes (present). Each item is then rated for frequency (a 4-point scale from 1 [occasionally] to 4 [very frequent]) and severity (a 3-point scale from 1 [mild] to 3 [marked]). The total score for the NPI anxiety item ranges from 0-12 (frequency multiplied by severity), where a higher score represents a worse outcome.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome/item measure assessed

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	86	83
Least Squares Mean (Standard Error) [units on a scale]	-1.93 (0.32)	-1.52 (0.33)

7. Secondary Outcome

Title	Clinical Improvement
Description	Clinical response at Week 24 (based on pre-specified ADAS-cog, ADCS-ADL23, and ADCS-CGIC changes [change in ADAS-cog below or equal to -4, change in ADCS-ADL23 at least 0, and ADCS-CGIC below or equal to 4])
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	324	321
Count of Participants [Participants]	32 8.8%	35 9.6%

8. Secondary Outcome

Title	Clinical Worsening
Description	Clinical worsening at Week 24 (Based on pre-specified ADAS-cog, ADCS-ADL23, and ADCS-CGIC changes [change in ADAS-cog above or equal to 4, change in ADCS-ADL23 below 0, and ADCS-CGIC above 4])
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	324	321
Count of Participants [Participants]	37 10.1%	40 11%

9. Secondary Outcome

Title	Change in Cognitive Aspects of Mental Function
Description	Change from baseline to Week 24 in Mini Mental State Examination (MMSE). The Mini Mental State Examination (MMSE) is an 11-item test to assess the cognitive aspects of mental function. The subtests assess orientation, memory, attention, language, and visual construction. The scores for each item is dichotomous (1 = response is correct, 0 = response is incorrect). Total score of the 11 items ranges from 0 to 30 (higher score indicates lower deficit).
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	323	320
Least Squares Mean (Standard Error) [units on a scale]	-0.64 (0.20)	-0.35 (0.20)

10. Secondary Outcome

Title	Change in Health-related Quality of Life (EQ-5D) Utility Score
Description	Change from baseline to Week 24 in EuroQol 5-dimensional (EQ-5D) utility score The EQ-5D is a patient-reported assessment that measures the patient's well-being. It consists of an utility score based on 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety) and a Visual Analogue Scale (VAS). Each descriptive item is rated on a 3-point index ranging from 1 (no problems) to 3 (extreme problems) that is used for calculating a single summary index (from 0 to 1). A higher EQ-5D score indicates a worse outcome.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	351	354
Least Squares Mean (Standard Error) [units on a scale]	-0.01 (0.01)	-0.00 (0.01)

11. Secondary Outcome

Title	Change in Health-related Quality of Life (EQ-5D VAS)
Description	Change from baseline to Week 24 in EQ-5D Visual Analogue Scale (EQ-5D VAS). The EQ-5D is a patient-reported assessment that measures the patient's well-being. It consists of an utility score based on 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety) and a Visual Analogue Scale (VAS). The VAS ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

All patients who took at least one dose of placebo or idalopirdine, and who had a valid baseline assessment and at least one valid post-baseline assessment of the primary outcome measure in the 24-week treatment period (Full-analysis Set). For secondary outcome measures, the number of participants who had the respective outcome measure assessed.

Arm/Group Title	Placebo	Idalopirdine 60 mg (or 30 mg)
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally	Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
Measure Participants	351	353
Least Squares Mean (Standard Error) [units on a scale]	-0.40 (1.00)	0.51 (1.02)

Adverse Events

Time Frame	Baseline to end of study
Adverse Event Reporting Description	Treatment-Emergent Adverse Events are reported in this section
Arm/Group Title	Placebo		Idalopirdine 60 mg
Arm/Group Description	Placebo adjunct to base treatment with an AChEI Placebo: Once daily, matching placebo capsules, orally		Idalopirdine adjunct to base treatment with an AChEI Idalopirdine: Once daily, encapsulated tablets, orally
All Cause Mortality
	Placebo		Idalopirdine 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/365 (0.3%)		0/363 (0%)
Serious Adverse Events
	Placebo		Idalopirdine 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/365 (6%)		28/363 (7.7%)
Cardiac disorders
Bradycardia	0/365 (0%)		2/363 (0.6%)
Left ventricular failure	0/365 (0%)		1/363 (0.3%)
Myocardial infarction	2/365 (0.5%)		1/363 (0.3%)
Eye disorders
Retinal detachment	0/365 (0%)		1/363 (0.3%)
Gastrointestinal disorders
Colitis ulcerative	0/365 (0%)		1/363 (0.3%)
Gastrointestinal inflammation	1/365 (0.3%)		0/363 (0%)
Nausea	0/365 (0%)		1/363 (0.3%)
Pancreatitis acute	0/365 (0%)		1/363 (0.3%)
Vomiting	0/365 (0%)		1/363 (0.3%)
General disorders
Chest pain	0/365 (0%)		1/363 (0.3%)
Hepatobiliary disorders
Cholelithiasis	0/365 (0%)		1/363 (0.3%)
Drug-induced liver injury	0/365 (0%)		1/363 (0.3%)
Infections and infestations
Diverticulitis	1/365 (0.3%)		0/363 (0%)
Erysipelas	1/365 (0.3%)		0/363 (0%)
Gastroenteritis viral	0/365 (0%)		1/363 (0.3%)
Pneumonia bacterial	0/365 (0%)		1/363 (0.3%)
Urinary tract infection bacterial	1/365 (0.3%)		1/363 (0.3%)
Injury, poisoning and procedural complications
Acetabulum fracture	0/365 (0%)		1/363 (0.3%)
Clavicle fracture	1/365 (0.3%)		0/363 (0%)
Concussion	0/365 (0%)		1/363 (0.3%)
Fall	1/365 (0.3%)		5/363 (1.4%)
Femoral neck fracture	0/365 (0%)		1/363 (0.3%)
Femur fracture	0/365 (0%)		1/363 (0.3%)
Head injury	1/365 (0.3%)		0/363 (0%)
Hip fracture	0/365 (0%)		1/363 (0.3%)
Laceration	2/365 (0.5%)		0/363 (0%)
Lumbar vertebral fracture	0/365 (0%)		2/363 (0.6%)
Pubis fracture	1/365 (0.3%)		0/363 (0%)
Rib fracture	1/365 (0.3%)		0/363 (0%)
Road traffic accident	1/365 (0.3%)		0/363 (0%)
Subdural haematoma	1/365 (0.3%)		0/363 (0%)
Traumatic intracranial haemorrhage	1/365 (0.3%)		0/363 (0%)
Investigations
Electrocardiogram st segment depression	1/365 (0.3%)		0/363 (0%)
Metabolism and nutrition disorders
Gout	0/365 (0%)		1/363 (0.3%)
Hypokalaemia	1/365 (0.3%)		0/363 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/365 (0.3%)		1/363 (0.3%)
Cervix carcinoma	0/234 (0%)		1/228 (0.4%)
Glioblastoma multiforme	0/365 (0%)		1/363 (0.3%)
Nervous system disorders
Cerebral haematoma	1/365 (0.3%)		0/363 (0%)
Cerebral haemorrhage	1/365 (0.3%)		0/363 (0%)
Dizziness	1/365 (0.3%)		0/363 (0%)
Generalised tonic-clonic seizure	1/365 (0.3%)		0/363 (0%)
Intracranial haematoma	1/365 (0.3%)		0/363 (0%)
Ischaemic stroke	1/365 (0.3%)		0/363 (0%)
Lethargy	0/365 (0%)		1/363 (0.3%)
Loss of consciousness	0/365 (0%)		1/363 (0.3%)
Partial seizures	0/365 (0%)		1/363 (0.3%)
Syncope	1/365 (0.3%)		1/363 (0.3%)
Psychiatric disorders
Agitation	1/365 (0.3%)		0/363 (0%)
Behavioural and psychiatric symptoms of dementia	0/365 (0%)		1/363 (0.3%)
Personality disorder	1/365 (0.3%)		0/363 (0%)
Renal and urinary disorders
Azotaemia	1/365 (0.3%)		0/363 (0%)
Skin and subcutaneous tissue disorders
Subcutaneous emphysema	1/365 (0.3%)		0/363 (0%)
Vascular disorders
Hypertension	2/365 (0.5%)		0/363 (0%)
Hypertensive emergency	0/365 (0%)		1/363 (0.3%)
Internal haemorrhage	0/365 (0%)		1/363 (0.3%)
Peripheral vascular disorder	1/365 (0.3%)		0/363 (0%)
Peripheral venous disease	0/365 (0%)		1/363 (0.3%)
Other (Not Including Serious) Adverse Events
	Placebo		Idalopirdine 60 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/365 (17.5%)		82/363 (22.6%)
Injury, poisoning and procedural complications
Accidental overdose	43/365 (11.8%)		40/363 (11%)
Fall	21/365 (5.8%)		19/363 (5.2%)
Investigations
Aspartate aminotransferase increased	3/365 (0.8%)		19/363 (5.2%)
Gamma-glutamyltransferase increased	2/365 (0.5%)		22/363 (6.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.