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Clinical Trial Results:
A Randomized, Double-Blind, Placebo- and Active-Controlled Phase 2 Dose-Ranging Study to Evaluate the Efficacy and Safety of ABT-126 in Subjects with Mild to Moderate Alzheimer's Disease

Summary
EudraCT number	2011-002004-32
Trial protocol	GB PL
Global end of trial date	10 Dec 2013

Results information
Results version number	v2(current)
This version publication date	18 May 2016
First version publication date	11 Jul 2015
Other versions	v1
Version creation reason	Correction of full data set new version being created so writer can re-gain access to the published study to re-confirm that study has no errors.

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

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Trial information

Top of page

Sponsor protocol code

M10-985

ISRCTN number

US NCT number

NCT01527916

WHO universal trial number (UTN)

Sponsor organisation name

Abbvie Deutschland GmbH & Co.KG

Sponsor organisation address

Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4XE

Public contact

Global Medical Information, AbbVie, 001 800-633-9110,

Scientific contact

Laura Gault MD PhD, AbbVie, laura.gault@abbvie.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

10 Dec 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Dec 2013

Was the trial ended prematurely?

Main objective of the trial

Evaluate the dose-response relationship with respect to the efficacy of symptomatic treatment and safety of three doses of ABT-126 in subjects with mild to moderate Alzheimer's disease (AD). The primary efficacy measure is the Alzheimer's Disease Assessment Scale – cognitive subscale (ADAS-Cog).

Protection of trial subjects

Participant and/or legal guardian read and understood the information provided about the study and gave written permission.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Feb 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

7 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 39

Country: Number of subjects enrolled

United Kingdom: 65

Country: Number of subjects enrolled

Russian Federation: 153

Country: Number of subjects enrolled

Ukraine: 50

Country: Number of subjects enrolled

South Africa: 95

Country: Number of subjects enrolled

United States: 36

Worldwide total number of subjects

438

EEA total number of subjects

104

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

336

85 years and over

Subject disposition

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Recruitment details

Screening details

Subjects were to undergo screening procedures within 28 days prior to enrollment.

Number of subjects started

438

Number of subjects completed

436

Reason: Number of subjects

Randomized but not treated: 2

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer

Blinding implementation details

The study was designed to have 2 parts with different randomization schemes for each part. In Part 1, 350 subjects were randomized to 5 treatment groups using a Bayesian response adaptive randomization scheme. In Part 2 of the study, approximately 80 subjects were randomized in equal ratio to placebo and an ABT-126 dose (50 mg) selected by an independent data monitoring committee based on an interim evaluation of the data from Part 1. The treatment duration for Parts 1 and 2 was 24 weeks.

Are arms mutually exclusive

Yes

Placebo

Arm description

Three placebo capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

All investigational products were made to appear identical in order to maintain the blind.

ABT-126 25 mg

Arm description

One ABT-126 25 mg capsule and 2 placebo capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Arm type

Experimental

Investigational medicinal product name

ABT-126

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

All investigational products were made to appear identical in order to maintain the blind.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

All investigational products were made to appear identical in order to maintain the blind.

ABT-126 50 mg

Arm description

Two ABT-126 25 mg capsules and 1 placebo capsule taken orally once daily in the morning for 24 weeks beginning on Day 1.

Arm type

Experimental

Investigational medicinal product name

ABT-126

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

All investigational products were made to appear identical in order to maintain the blind.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

All investigational products were made to appear identical in order to maintain the blind.

ABT-126 75 mg

Arm description

Three ABT-126 25 mg capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Arm type

Experimental

Investigational medicinal product name

ABT-126

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

All investigational products were made to appear identical in order to maintain the blind.

Donepezil

Arm description

One 5 mg donepezil capsule and 2 placebo capsules taken orally once daily in the morning for 4 weeks beginning on Day 1, and one 10 mg donepezil capsule and 2 placebo capsules taken orally once daily in the morning for 20 weeks thereafter.

Arm type

Active comparator

Investigational medicinal product name

Donepezil

Investigational medicinal product code

Other name

Aricept®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

All investigational products were made to appear identical in order to maintain the blind.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

All investigational products were made to appear identical in order to maintain the blind.

Number of subjects in period 1 ^[1]	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Started	104	77	107	73	75
Completed	89	64	92	62	60
Not completed	15	13	15	11	15
Consent withdrawn by subject	9	4	9	8	5
Not specified	2	2	1	1	1
Adverse event	3	5	3	2	7
Lost to follow-up	-	-	-	-	1
Noncompliance	1	2	1	-	1
Lack of efficacy	-	-	1	-	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Two subjects were randomized but not treated, and are not included in the baseline period.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Three placebo capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

ABT-126 25 mg

Reporting group description

One ABT-126 25 mg capsule and 2 placebo capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

ABT-126 50 mg

Reporting group description

Two ABT-126 25 mg capsules and 1 placebo capsule taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

ABT-126 75 mg

Reporting group description

Three ABT-126 25 mg capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

Donepezil

Reporting group description

Reporting group values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil	Total
Number of subjects	104	77	107	73	75	436
Age categorical
Data are provided for the Intent-to-treat population (subjects who received at least 1 dose of study drug).
Units: Subjects
< 75 years	59	37	50	30	30	206
≥ 75 years	45	40	57	43	45	230
Age continuous
Data are provided for the Intent-to-treat population (subjects who received at least 1 dose of study drug).
Units: years
arithmetic mean (standard deviation)	73.2 ± 7.39	73 ± 7.62	73.9 ± 8.26	76.2 ± 8.14	75.1 ± 7.75	-
Gender categorical
Data are provided for the Intent-to-treat population (subjects who received at least 1 dose of study drug).
Units: Subjects
Female	65	40	68	52	40	265
Male	39	37	39	21	35	171

End points

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Reporting group title

Placebo

Reporting group description

Three placebo capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

ABT-126 25 mg

Reporting group description

One ABT-126 25 mg capsule and 2 placebo capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

ABT-126 50 mg

Reporting group description

Two ABT-126 25 mg capsules and 1 placebo capsule taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

ABT-126 75 mg

Reporting group description

Three ABT-126 25 mg capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

Donepezil

Reporting group description

Primary: Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) 11-item Total Score: Change from Baseline to Week 24

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End point title

Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) 11-item Total Score: Change from Baseline to Week 24

End point description

From repeated measures analysis. The ADAS-Cog 11-item total score is the sum of the following 11 items: Word Recall, Commands, Constructional Praxis, Naming Objects and Fingers, Ideational Praxis, Orientation, Word Recognition, Remembering Test Instructions, Comprehension of Spoken Language, Spoken Language Ability, and Word Finding Difficulty. The ADAS-Cog 11-item total score ranges from 0 to 70 with a lower score being desirable. A decrease in the total score indicates improvement, with a higher score indicating greater cognitive impairment.

End point type

Primary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	88 ^[1]	63 ^[2]	90 ^[3]	62 ^[4]	59 ^[5]
Units: units on a scale
least squares mean (standard error)	-0.31 ± 0.61	-0.77 ± 0.73	-1.18 ± 0.61	-1.38 ± 0.73	-2.6 ± 0.76

Notes
[1] - Subjects with a baseline and at least one post baseline assessment
[2] - Subjects with a baseline and at least one post baseline assessment
[3] - Subjects with a baseline and at least one post baseline assessment
[4] - Subjects with a baseline and at least one post baseline assessment
[5] - Subjects with a baseline and at least one post baseline assessment

ABT-126 25 mg v. Placebo

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.309 ^[6]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.47

Confidence interval

level

90%

sides

2-sided

lower limit

-2.02

upper limit

1.08

Variability estimate

Standard error of the mean

Dispersion value

0.94

Notes
[6] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

ABT-126 50 mg v. Placebo

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.153 ^[7]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.87

Confidence interval

level

90%

sides

2-sided

lower limit

-2.27

upper limit

0.53

Variability estimate

Standard error of the mean

Dispersion value

0.85

Notes
[7] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

ABT-126 75 mg v. Placebo

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.127 ^[8]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-1.08

Confidence interval

level

90%

sides

2-sided

lower limit

-2.63

upper limit

0.48

Variability estimate

Standard error of the mean

Dispersion value

0.94

Notes
[8] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Donepezil v. Placebo

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008 ^[9]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-2.29

Confidence interval

level

90%

sides

2-sided

lower limit

-3.87

upper limit

-0.72

Variability estimate

Standard error of the mean

Dispersion value

0.95

Notes
[9] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.05 level.

Secondary: ADAS-Cog 13-Item Total Score: Change from Baseline to Week 24

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End point title

ADAS-Cog 13-Item Total Score: Change from Baseline to Week 24

End point description

The ADAS-Cog 13-item total score differs from the primary efficacy measure (ADAS-Cog 11-item total score) by 2 additional items of Delayed Word Recall and Number Cancellation Test. The ADAS-Cog 13-item total score ranges from 0 to 85. A decrease in the total score indicates improvement, with a higher score indicating greater cognitive impairment.

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	88 ^[10]	63 ^[11]	87 ^[12]	61 ^[13]	59 ^[14]
Units: units on a scale
least squares mean (standard error)	-0.67 ± 0.71	-1.14 ± 0.84	-1.7 ± 0.71	-1.87 ± 0.84	-3.54 ± 0.87

Notes
[10] - Subjects with a baseline and at least one post baseline assessment
[11] - Subjects with a baseline and at least one post baseline assessment
[12] - Subjects with a baseline and at least one post baseline assessment
[13] - Subjects with a baseline and at least one post baseline assessment
[14] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

ABT-126 25 mg v Placebo

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.333 ^[15]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.47

Confidence interval

level

90%

sides

2-sided

lower limit

-2.25

upper limit

1.31

Variability estimate

Standard error of the mean

Dispersion value

1.08

Notes
[15] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.149 ^[16]

Method

mixed-effects model for repeated measure

Parameter type

Least Squares Mean of Difference

Point estimate

-1.03

Confidence interval

level

90%

sides

2-sided

lower limit

-2.65

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.98

Notes
[16] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.137 ^[17]

Method

mixed-effects model for repeated measure

Parameter type

Least Squares Mean of Difference

Point estimate

-1.19

Confidence interval

level

90%

sides

2-sided

lower limit

-2.98

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

1.09

Notes
[17] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

147

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[18]

Method

mixed-effects model for repeated measure

Parameter type

Least Squares Mean of Difference

Point estimate

-2.86

Confidence interval

level

90%

sides

2-sided

lower limit

-4.67

upper limit

-1.05

Variability estimate

Standard error of the mean

Dispersion value

1.1

Notes
[18] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.01 level.

Secondary: Mini-Mental Status Exam (MMSE): Change from Baseline to Week 24

Top of page

End point title

Mini-Mental Status Exam (MMSE): Change from Baseline to Week 24

End point description

The MMSE is a brief questionnaire that provides a quantitative measure of cognitive status and was used to estimate the severity of cognitive impairment. The MMSE total score ranges from 0 to 30 with a higher score being desirable. An increase in the total score indicates improvement, with a lower score indicating greater cognitive impairment.

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	89 ^[19]	64 ^[20]	92 ^[21]	62 ^[22]	59 ^[23]
Units: units on a scale
least squares mean (standard error)	0.39 ± 0.32	-0.16 ± 0.38	0.78 ± 0.32	0.53 ± 0.38	1.19 ± 0.39

Notes
[19] - Subjects with a baseline and at least one post baseline assessment
[20] - Subjects with a baseline and at least one post baseline assessment
[21] - Subjects with a baseline and at least one post baseline assessment
[22] - Subjects with a baseline and at least one post baseline assessment
[23] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.866 ^[24]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.55

Confidence interval

level

90%

sides

2-sided

lower limit

-1.36

upper limit

0.27

Variability estimate

Standard error of the mean

Dispersion value

0.49

Notes
[24] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.191 ^[25]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.39

Confidence interval

level

90%

sides

2-sided

lower limit

-0.34

upper limit

1.12

Variability estimate

Standard error of the mean

Dispersion value

0.44

Notes
[25] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.39 ^[26]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-0.68

upper limit

0.95

Variability estimate

Standard error of the mean

Dispersion value

0.49

Notes
[26] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.055 ^[27]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.8

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

1.62

Variability estimate

Standard error of the mean

Dispersion value

0.5

Notes
[27] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.10 level.

Secondary: Neuropsychiatric Inventory (NPI) 12-item Total Score: Change from Baseline to Week 24

Top of page

End point title

Neuropsychiatric Inventory (NPI) 12-item Total Score: Change from Baseline to Week 24

End point description

The NPI is used to assess changes in the subject's behavior that have occurred in a defined period of time. The NPI assesses 10 behavioral domains and 2 neurovegetative domains on the dimensions of frequency and severity. Frequency is rated on a scale where 0 = absent, 1 = occasionally, 2 = often, 3 = frequently, and 4 = very frequently. Severity is rated on a scale where 0 = absent, 1 = mild, 2 = moderate, and 3 = marked. Distress is rated on a scale where 0 = not at all, 1 = minimally, 2 = mildly, 3 = moderately, 4 = severely, and 5 = very severely or extremely. For each of the behavioral domains, 4 scores were obtained: frequency, severity, distress, and total (product of frequency and severity; ranges from 0 to 12). A 12-item NPI total score was calculated by also including the domain total scores for the 2 neurovegetative domains (ranges from 0 to 144 with a lower score desirable).

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	89 ^[28]	64 ^[29]	93 ^[30]	62 ^[31]	59 ^[32]
Units: units on a scale
least squares mean (standard error)	-0.11 ± 0.95	-0.92 ± 1.11	0.05 ± 0.94	-0.54 ± 1.12	-2.67 ± 1.15

Notes
[28] - Subjects with a baseline and at least one post baseline assessment
[29] - Subjects with a baseline and at least one post baseline assessment
[30] - Subjects with a baseline and at least one post baseline assessment
[31] - Subjects with a baseline and at least one post baseline assessment
[32] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.287 ^[33]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.81

Confidence interval

level

90%

sides

2-sided

lower limit

-3.17

upper limit

1.56

Variability estimate

Standard error of the mean

Dispersion value

1.44

Notes
[33] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.549 ^[34]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.16

Confidence interval

level

90%

sides

2-sided

lower limit

-1.98

upper limit

2.3

Variability estimate

Standard error of the mean

Dispersion value

1.3

Notes
[34] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.383 ^[35]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.43

Confidence interval

level

90%

sides

2-sided

lower limit

-2.82

upper limit

1.96

Variability estimate

Standard error of the mean

Dispersion value

1.45

Notes
[35] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.041 ^[36]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-2.55

Confidence interval

level

90%

sides

2-sided

lower limit

-4.96

upper limit

-0.15

Variability estimate

Standard error of the mean

Dispersion value

1.46

Notes
[36] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.10 level.

Secondary: Neuropsychiatric Inventory (NPI) 10-item Total Score: Change from Baseline to Week 24

Top of page

End point title

Neuropsychiatric Inventory (NPI) 10-item Total Score: Change from Baseline to Week 24

End point description

The NPI is used to assess changes in the subject's behavior that have occurred in a defined period of time. The NPI assesses 10 behavioral domains and 2 neurovegetative domains on the dimensions of frequency and severity. Frequency is rated on a scale where 0 = absent, 1 = occasionally, 2 = often, 3 = frequently, and 4 = very frequently. Severity is rated on a scale where 0 = absent, 1 = mild, 2 = moderate, and 3 = marked. Distress is rated on a scale where 0 = not at all, 1 = minimally, 2 = mildly, 3 = moderately, 4 = severely, and 5 = very severely or extremely. For each of the behavioral domains, 4 scores were obtained: frequency, severity, distress, and total (product of frequency and severity; ranges from 0 to 12). A 10-item NPI total score was calculated by summing the domain total scores for the 10 behavioral domains (ranges from 0 to 120 with a lower score desirable).

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	89 ^[37]	64 ^[38]	93 ^[39]	62 ^[40]	59 ^[41]
Units: units on a scale
least squares mean (standard error)	-0.26 ± 0.82	-1.09 ± 0.96	-0.5 ± 0.81	-0.13 ± 0.96	-2.72 ± 0.99

Notes
[37] - Subjects with a baseline and at least one post baseline assessment
[38] - Subjects with a baseline and at least one post baseline assessment
[39] - Subjects with a baseline and at least one post baseline assessment
[40] - Subjects with a baseline and at least one post baseline assessment
[41] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.252 ^[42]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.82

Confidence interval

level

90%

sides

2-sided

lower limit

-2.86

upper limit

1.21

Variability estimate

Standard error of the mean

Dispersion value

1.23

Notes
[42] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.416 ^[43]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.24

Confidence interval

level

90%

sides

2-sided

lower limit

-2.07

upper limit

1.6

Variability estimate

Standard error of the mean

Dispersion value

1.11

Notes
[43] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.544 ^[44]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-1.92

upper limit

2.19

Variability estimate

Standard error of the mean

Dispersion value

1.25

Notes
[44] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026 ^[45]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-2.45

Confidence interval

level

90%

sides

2-sided

lower limit

-4.53

upper limit

-0.38

Variability estimate

Standard error of the mean

Dispersion value

1.26

Notes
[45] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.10 level.

Secondary: Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL): Change from Baseline to Week 24

Top of page

End point title

Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL): Change from Baseline to Week 24

End point description

The ADCS-ADL is a 23-item, caregiver-based assessment of activities of daily living designed specifically for AD patients and is completed by a trained rater. The scale assesses functional activities such as eating, bathing, grooming, cooking, household chores, shopping, keeping appointments, social interactions and hobbies. Items are assessed according to whether they were performed in the past 4 weeks and, if so, some items are further assessed as to whether they were performed independently, with supervision, or with physical help. The ADCS-ADL total score ranges from 0 to 78 with a higher score being desirable. An increase in the total score indicates improvement, with a lower score indicating more severe impairment.

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	89 ^[46]	64 ^[47]	93 ^[48]	62 ^[49]	59 ^[50]
Units: units on a scale
least squares mean (standard error)	-2.3 ± 0.76	-0.44 ± 0.89	0 ± 0.75	-0.44 ± 0.9	1.71 ± 0.92

Notes
[46] - Subjects with a baseline and at least one post baseline assessment
[47] - Subjects with a baseline and at least one post baseline assessment
[48] - Subjects with a baseline and at least one post baseline assessment
[49] - Subjects with a baseline and at least one post baseline assessment
[50] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.053 ^[51]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

1.86

Confidence interval

level

90%

sides

2-sided

lower limit

-0.03

upper limit

3.74

Variability estimate

Standard error of the mean

Dispersion value

1.14

Notes
[51] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.10 level.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013 ^[52]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

2.3

Confidence interval

level

90%

sides

2-sided

lower limit

0.6

upper limit

4.01

Variability estimate

Standard error of the mean

Dispersion value

1.04

Notes
[52] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.05 level.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.054 ^[53]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

1.86

Confidence interval

level

90%

sides

2-sided

lower limit

-0.04

upper limit

3.76

Variability estimate

Standard error of the mean

Dispersion value

1.15

Notes
[53] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.10 level.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[54]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

4.01

Confidence interval

level

90%

sides

2-sided

lower limit

2.09

upper limit

5.93

Variability estimate

Standard error of the mean

Dispersion value

1.16

Notes
[54] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P = 0.001 level.

Secondary: DEMentia Quality of Life (DEMQOL) Global Score: Change from Baseline to Week 24

Top of page

End point title

DEMentia Quality of Life (DEMQOL) Global Score: Change from Baseline to Week 24

End point description

The DEMQOL is a measure of health-related quality of life in dementia and is appropriate for use in mild-to-moderate stages of dementia severity. The DEMQOL contains 28-items and covers 4 domains: daily activities and looking after oneself, health and well-being, cognitive functioning, and social relationships. The recall period is 1 week. Items are scored on a 4-point Likert scale, resulting in a global score ranging from 28 to 112. Higher scores indicate better health-related quality of life.

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	88 ^[55]	64 ^[56]	92 ^[57]	62 ^[58]	60 ^[59]
Units: units on a scale
least squares mean (standard error)	0.86 ± 0.88	2.56 ± 1.04	2.21 ± 0.89	1.82 ± 1.03	2.7 ± 1.07

Notes
[55] - Subjects with a baseline and at least one post baseline assessment
[56] - Subjects with a baseline and at least one post baseline assessment
[57] - Subjects with a baseline and at least one post baseline assessment
[58] - Subjects with a baseline and at least one post baseline assessment
[59] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1 ^[60]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

1.69

Confidence interval

level

90%

sides

2-sided

lower limit

-0.48

upper limit

3.87

Variability estimate

Standard error of the mean

Dispersion value

1.32

Notes
[60] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P=0.10 level.

Statistical Analysis 2

Comparison groups

ABT-126 50 mg v Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.13 ^[61]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

1.34

Confidence interval

level

90%

sides

2-sided

lower limit

-0.62

upper limit

3.31

Variability estimate

Standard error of the mean

Dispersion value

1.19

Notes
[61] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.235 ^[62]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.96

Confidence interval

level

90%

sides

2-sided

lower limit

-1.23

upper limit

3.15

Variability estimate

Standard error of the mean

Dispersion value

1.33

Notes
[62] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.084 ^[63]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

1.84

Confidence interval

level

90%

sides

2-sided

lower limit

-0.35

upper limit

4.02

Variability estimate

Standard error of the mean

Dispersion value

1.33

Notes
[63] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the 0.10 level.

Secondary: DEMQOL-Proxy Global Score: Change from Baseline to Week 24

Top of page

End point title

DEMQOL-Proxy Global Score: Change from Baseline to Week 24

End point description

The DEMQOL-Proxy is a measure of health-related quality of life in dementia and is appropriate for use in mild-to-moderate stages of dementia severity. The DEMQOL contains 28 items and covers 4 domains: daily activities and looking after oneself, health and well-being, cognitive functioning, and social relationships. The Proxy contains 31 items and has similar content to the patient-report version, and also includes a self-concept item. The recall period for both versions is 1 week. Items are scored on a 4-point Likert scale, resulting in a global score ranging from 31 to 124. Higher scores indicate better health-related quality of life.

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	88 ^[64]	63 ^[65]	92 ^[66]	62 ^[67]	60 ^[68]
Units: units on a scale
least squares mean (standard error)	1.95 ± 0.92	1.58 ± 1.1	1.99 ± 0.93	1.49 ± 1.07	3.64 ± 1.11

Notes
[64] - Subjects with a baseline and at least one post baseline assessment
[65] - Subjects with a baseline and at least one post baseline assessment
[66] - Subjects with a baseline and at least one post baseline assessment
[67] - Subjects with a baseline and at least one post baseline assessment
[68] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.607 ^[69]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.37

Confidence interval

level

90%

sides

2-sided

lower limit

-2.64

upper limit

1.89

Variability estimate

Standard error of the mean

Dispersion value

1.37

Notes
[69] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.489 ^[70]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.03

Confidence interval

level

90%

sides

2-sided

lower limit

-2.01

upper limit

2.08

Variability estimate

Standard error of the mean

Dispersion value

1.24

Notes
[70] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.631 ^[71]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.46

Confidence interval

level

90%

sides

2-sided

lower limit

-2.74

upper limit

1.81

Variability estimate

Standard error of the mean

Dispersion value

1.38

Notes
[71] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

148

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.111 ^[72]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

1.69

Confidence interval

level

90%

sides

2-sided

lower limit

-0.59

upper limit

3.96

Variability estimate

Standard error of the mean

Dispersion value

1.38

Notes
[72] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Secondary: Partner-Patient Questionnaire for Shared Activities (PPQSA) Average Score: Change from Baseline to Week 24

Top of page

End point title

Partner-Patient Questionnaire for Shared Activities (PPQSA) Average Score: Change from Baseline to Week 24

End point description

The PPQSA is a caregiver-completed assessment constructed to measure the extent to which the AD patient's mood and mental state interferes with the patient-partner (i.e., patient-caregiver, patient-spouse or patient-non-spouse partner) relationship. The scale consists of 17 shared activity items, a global interference item, and a ranking of the 5 most important activities. Interference is scored on a 5-point scale ranging from 0 ("not at all") to 4 ("extremely"), with higher scores indicating greater interference in the past week. The PPQSA average score ranges from 0 to 5 with a higher score desirable.

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	89 ^[73]	64 ^[74]	92 ^[75]	62 ^[76]	60 ^[77]
Units: units on a scale
least squares mean (standard error)	-0.07 ± 0.07	-0.04 ± 0.08	-0.08 ± 0.07	-0.24 ± 0.08	-0.21 ± 0.08

Notes
[73] - Subjects with a baseline and at least one post baseline assessment
[74] - Subjects with a baseline and at least one post baseline assessment
[75] - Subjects with a baseline and at least one post baseline assessment
[76] - Subjects with a baseline and at least one post baseline assessment
[77] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.382 ^[78]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.03

Confidence interval

level

90%

sides

2-sided

lower limit

-0.14

upper limit

0.2

Variability estimate

Standard error of the mean

Dispersion value

0.1

Notes
[78] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.553 ^[79]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.16

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.09

Notes
[79] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.954 ^[80]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.17

Confidence interval

level

90%

sides

2-sided

lower limit

-0.34

upper limit

Variability estimate

Standard error of the mean

Dispersion value

0.1

Notes
[80] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.905 ^[81]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-0.31

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.1

Notes
[81] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Secondary: The Wechsler Memory Scale-III (WMS-III) Working Memory Index: Change from Baseline to Week 18

Top of page

End point title

The Wechsler Memory Scale-III (WMS-III) Working Memory Index: Change from Baseline to Week 18

End point description

The Wechsler Memory Scale-III (WMS-III) Working Memory Index includes the Letter Number Sequencing (LNS) and Spatial Span (SS) tests. The range of scores from the LNS is 0 to 21 points. The score range for the total of the 2 SS tests ranges from 0 to 32. Raw scores from both LNS and SS were converted to scale scores using the WMS-III Administration and Scoring Manual and an overall Working Memory Index was derived from these scaled scores. The WMS-III Index score ranges from 49 to 155 with a higher score desirable.

End point type

Secondary

End point timeframe

Baseline through Week 18

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	91 ^[82]	65 ^[83]	93 ^[84]	64 ^[85]	61 ^[86]
Units: units on a scale
least squares mean (standard error)	1.17 ± 1.11	0.24 ± 1.31	-1.73 ± 1.1	-2.34 ± 1.27	1.31 ± 1.35

Notes
[82] - Subjects with a baseline and at least one post baseline assessment
[83] - Subjects with a baseline and at least one post baseline assessment
[84] - Subjects with a baseline and at least one post baseline assessment
[85] - Subjects with a baseline and at least one post baseline assessment
[86] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.715 ^[87]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.93

Confidence interval

level

90%

sides

2-sided

lower limit

-3.63

upper limit

1.77

Variability estimate

Standard error of the mean

Dispersion value

1.64

Notes
[87] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

184

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.975 ^[88]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-2.91

Confidence interval

level

90%

sides

2-sided

lower limit

-5.34

upper limit

-0.47

Variability estimate

Standard error of the mean

Dispersion value

1.48

Notes
[88] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.983 ^[89]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-3.52

Confidence interval

level

90%

sides

2-sided

lower limit

-6.23

upper limit

-0.8

Variability estimate

Standard error of the mean

Dispersion value

1.65

Notes
[89] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.468 ^[90]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

0.13

Confidence interval

level

90%

sides

2-sided

lower limit

-2.6

upper limit

2.86

Variability estimate

Standard error of the mean

Dispersion value

1.65

Notes
[90] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Secondary: Resource Utilization in Dementia (RUD)-Lite Caregiver Time: Change from Baseline to Final Evaluation (up to Week 24)

Top of page

End point title

Resource Utilization in Dementia (RUD)-Lite Caregiver Time: Change from Baseline to Final Evaluation (up to Week 24)

End point description

RUD-Lite assesses the healthcare resource utilization of participants and their caregivers to determine the level of formal and informal care attributable to Alzheimer's Disease (AD). Components of the RUD-Lite include living accommodations and long-term care, use of respite, home nursing and day care. Outpatient, hospital and social services visits, as well as caregiver informal care time is collected from the baseline and follow-up interviews. The change from baseline to Week 24 in caregiver time is reported.

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	86 ^[91]	56 ^[92]	81 ^[93]	55 ^[94]	58 ^[95]
Units: units on a scale
least squares mean (standard error)	68.96 ± 22.7	9.95 ± 28.45	-14.02 ± 24.36	-14.9 ± 27.56	-21.5 ± 28.05

Notes
[91] - Subjects with a baseline and at least one post baseline assessment
[92] - Subjects with a baseline and at least one post baseline assessment
[93] - Subjects with a baseline and at least one post baseline assessment
[94] - Subjects with a baseline and at least one post baseline assessment
[95] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

ABT-126 25 mg v Placebo

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044 ^[96]

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-59.01

Confidence interval

level

90%

sides

2-sided

lower limit

-115.97

upper limit

-2.05

Variability estimate

Standard error of the mean

Dispersion value

34.52

Notes
[96] - Statistically significant at the P=0.05 level.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[97]

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-82.98

Confidence interval

level

90%

sides

2-sided

lower limit

-134.26

upper limit

-31.71

Variability estimate

Standard error of the mean

Dispersion value

31.08

Notes
[97] - Statistically significant at the P=0.01 level.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

141

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009 ^[98]

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-83.86

Confidence interval

level

90%

sides

2-sided

lower limit

-141.6

upper limit

-26.11

Variability estimate

Standard error of the mean

Dispersion value

Notes
[98] - Statistically significant at the P=0.01 level.

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[99]

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-90.46

Confidence interval

level

90%

sides

2-sided

lower limit

-145.97

upper limit

-34.95

Variability estimate

Standard error of the mean

Dispersion value

33.64

Notes
[99] - Statistically significant at the P=0.01 level.

Secondary: EuroQol-5D (EQ-5D)-5L Index Score: Change from Baseline to Final Evaluation (up to Week 24)

Top of page

End point title

EuroQol-5D (EQ-5D)-5L Index Score: Change from Baseline to Final Evaluation (up to Week 24)

End point description

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	92 ^[100]	65 ^[101]	93 ^[102]	63 ^[103]	62 ^[104]
Units: units on a scale
least squares mean (standard error)	0 ± 0.01	0 ± 0.01	0.01 ± 0.01	0.01 ± 0.01	0.01 ± 0.01

Notes
[100] - Subjects with a baseline and at least one post baseline assessment
[101] - Subjects with a baseline and at least one post baseline assessment
[102] - Subjects with a baseline and at least one post baseline assessment
[103] - Subjects with a baseline and at least one post baseline assessment
[104] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.516

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-0.03

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.02

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.365

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.01

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.338

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.03

Variability estimate

Standard error of the mean

Dispersion value

0.02

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.222

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.01

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.02

Secondary: EQ-5D-5L Health State Score: Change from Baseline to Final Evaluation (up to Week 24)

Top of page

End point title

EQ-5D-5L Health State Score: Change from Baseline to Final Evaluation (up to Week 24)

End point description

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	92 ^[105]	65 ^[106]	93 ^[107]	61 ^[108]	62 ^[109]
Units: units on a scale
least squares mean (standard error)	4.18 ± 1.7	3.11 ± 2.05	1.34 ± 1.76	1.94 ± 2.06	3.58 ± 2.09

Notes
[105] - Subjects with a baseline and Week 24 assessment
[106] - Subjects with a baseline and at least one post baseline assessment
[107] - Subjects with a baseline and at least one post baseline assessment
[108] - Subjects with a baseline and at least one post baseline assessment
[109] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.662

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-1.07

Confidence interval

level

90%

sides

2-sided

lower limit

-5.3

upper limit

3.16

Variability estimate

Standard error of the mean

Dispersion value

2.56

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.889

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-2.84

Confidence interval

level

90%

sides

2-sided

lower limit

-6.65

upper limit

0.98

Variability estimate

Standard error of the mean

Dispersion value

2.31

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.807

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-2.24

Confidence interval

level

90%

sides

2-sided

lower limit

-6.52

upper limit

2.03

Variability estimate

Standard error of the mean

Dispersion value

2.59

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.593

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-0.6

Confidence interval

level

90%

sides

2-sided

lower limit

-4.81

upper limit

3.61

Variability estimate

Standard error of the mean

Dispersion value

2.55

Secondary: EQ-5D-3L-Proxy Index Score: Change from Baseline to Final Evaluation (up to Week 24)

Top of page

End point title

EQ-5D-3L-Proxy Index Score: Change from Baseline to Final Evaluation (up to Week 24)

End point description

The EQ-5D-5L is a 5 dimensional tool capturing subjects' mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Subjects rate each dimension using a scale with 5 levels: no problem, slight problem, moderate problem, severe problem and extreme problem. Similar to the EQ-5D-5L, the EQ-5D-3L proxy is also a 5 dimensional tool. However, proxies (e.g., caregivers) rate each dimension using a scale with 3 levels: no problem, some problem, extreme problem. Proxies are asked to rate how he/she (the proxy) believes the patient would rate his/her own Health Related Quality of Life (HRQoL) if he/she (the subject) was able to communicate it. Proxies also rate the overall health of the subject on a VAS scale. The index score ranges from best health (+1) to worst health (-0.59).

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	92 ^[110]	65 ^[111]	94 ^[112]	63 ^[113]	63 ^[114]
Units: units on a scale
least squares mean (standard error)	0 ± 0.01	-0.02 ± 0.02	0.01 ± 0.01	0.02 ± 0.02	0.01 ± 0.02

Notes
[110] - Subjects with a baseline and at least one post baseline assessment
[111] - Subjects with a baseline and at least one post baseline assessment
[112] - Subjects with a baseline and at least one post baseline assessment
[113] - Subjects with a baseline and at least one post baseline assessment
[114] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

ABT-126 25 mg v Placebo

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.803

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-0.02

Confidence interval

level

90%

sides

2-sided

lower limit

-0.05

upper limit

0.02

Variability estimate

Standard error of the mean

Dispersion value

0.02

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.285

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.02

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.109

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

0.02

Confidence interval

level

90%

sides

2-sided

lower limit

-0.01

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.02

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.306

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.02

Secondary: EQ-5D-3L-Proxy Health State Score: Change from Baseline to Final Evaluation (up to Week 24)

Top of page

End point title

EQ-5D-3L-Proxy Health State Score: Change from Baseline to Final Evaluation (up to Week 24)

End point description

The EQ-5D-5L is a 5 dimensional tool capturing subjects' mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Subjects rate each dimension using a scale with 5 levels: no problem, slight problem, moderate problem, severe problem and extreme problem. Similar to the EQ-5D-5L, the EQ-5D-3L proxy is also a 5 dimensional tool. However, proxies (e.g., caregivers) rate each dimension using a scale with 3 levels: no problem, some problem, extreme problem. Proxies are asked to rate how he/she (the proxy) believes the patient would rate his/her own Health Related Quality of Life (HRQoL) if he/she (the subject) was able to communicate it. Proxies also rate the overall health of the subject on a vertical graduated VAS ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	92 ^[115]	65 ^[116]	94 ^[117]	63 ^[118]	63 ^[119]
Units: units on a scale
least squares mean (standard error)	1.51 ± 1.64	-1.04 ± 1.97	1.78 ± 1.67	3.48 ± 1.93	4.69 ± 1.97

Notes
[115] - Subjects with a baseline and at least one post baseline assessment
[116] - Subjects with a baseline and at least one post baseline assessment
[117] - Subjects with a baseline and at least one post-baseline assessment
[118] - Subjects with a baseline and at least one post baseline assessment
[119] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.852

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

-2.56

Confidence interval

level

90%

sides

2-sided

lower limit

-6.59

upper limit

1.47

Variability estimate

Standard error of the mean

Dispersion value

2.44

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.452

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

0.27

Confidence interval

level

90%

sides

2-sided

lower limit

-3.38

upper limit

3.91

Variability estimate

Standard error of the mean

Dispersion value

2.21

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.213

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

1.97

Confidence interval

level

90%

sides

2-sided

lower limit

-2.1

upper limit

6.03

Variability estimate

Standard error of the mean

Dispersion value

2.46

Statistical Analysis 4

Comparison groups

Placebo v Donepezil

Number of subjects included in analysis

155

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.097 ^[120]

Method

ANCOVA

Parameter type

least squares mean of difference

Point estimate

3.17

Confidence interval

level

90%

sides

2-sided

lower limit

-0.84

upper limit

7.19

Variability estimate

Standard error of the mean

Dispersion value

2.44

Notes
[120] - Statistically significant at the P=0.10 level.

Secondary: Clinician Interview-Based Impression of Change – Plus (CIBIC-Plus): Change from Baseline to Week 24

Top of page

End point title

Clinician Interview-Based Impression of Change – Plus (CIBIC-Plus): Change from Baseline to Week 24

End point description

The CIBIC-plus is designed to capture a global impression of change in severity of dementia. The 4 major areas assessed by the CIBIC-plus are general functioning, cognitive functioning, behavioral functioning and activities of daily living. The interview with the caregiver assesses the functional activities and behavior of the subject. The subject interview primarily assesses cognition. The CIBIC-plus score ranges from 1 to 7 with a lower score being desirable. A decrease in the total score indicates improvement, with a higher score indicating greater impairment.

End point type

Secondary

End point timeframe

Baseline through Week 24

End point values	Placebo	ABT-126 25 mg	ABT-126 50 mg	ABT-126 75 mg	Donepezil
Number of subjects analysed	89 ^[121]	64 ^[122]	92 ^[123]	61 ^[124]	59 ^[125]
Units: units on a scale
least squares mean (standard error)	4.18 ± 0.09	4.06 ± 0.1	4.03 ± 0.08	3.8 ± 0.1	3.75 ± 0.1

Notes
[121] - Subjects with a baseline and at least one post baseline assessment
[122] - Subjects with a baseline and at least one post baseline assessment
[123] - Subjects with a baseline and at least one post baseline assessment
[124] - Subjects with a baseline and at least one post baseline assessment
[125] - Subjects with a baseline and at least one post baseline assessment

Statistical Analysis 1

Comparison groups

Placebo v ABT-126 25 mg

Number of subjects included in analysis

153

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.184 ^[126]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.12

Confidence interval

level

90%

sides

2-sided

lower limit

-0.33

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.13

Notes
[126] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 2

Comparison groups

Placebo v ABT-126 50 mg

Number of subjects included in analysis

181

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.105 ^[127]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.15

Confidence interval

level

90%

sides

2-sided

lower limit

-0.34

upper limit

0.05

Variability estimate

Standard error of the mean

Dispersion value

0.12

Notes
[127] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured.

Statistical Analysis 3

Comparison groups

Placebo v ABT-126 75 mg

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[128]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.38

Confidence interval

level

90%

sides

2-sided

lower limit

-0.59

upper limit

-0.16

Variability estimate

Standard error of the mean

Dispersion value

0.13

Notes
[128] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P=0.01 level.

Statistical Analysis 4

Comparison groups

Placebo v ABT-126 75 mg v Donepezil

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[129]

Method

mixed-effects model for repeated measure

Parameter type

least squares mean of difference

Point estimate

-0.43

Confidence interval

level

90%

sides

2-sided

lower limit

-0.65

upper limit

-0.21

Variability estimate

Standard error of the mean

Dispersion value

0.13

Notes
[129] - One-sided P value from repeated measures model with treatment, site, visit, baseline score, interactions of treatment and visit; baseline score and visit; covariance structure is unstructured. Statistically significant at the P=0.001 level.

Adverse events

Top of page

Timeframe for reporting adverse events

From Screening up to 2 weeks (± 3 days) after the last dose of study drug (at Week 24 or premature discontinuation).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Placebo

Reporting group description

Three placebo capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

ABT-126 50 mg

Reporting group description

Two ABT-126 25 mg capsules and 1 placebo capsule taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

ABT-126 25 mg

Reporting group description

One ABT-126 25 mg capsule and 2 placebo capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Reporting group title

Donepezil

Reporting group description

One 5 mg capsule taken orally once daily in the morning for 4 weeks beginning on Day 1, and 1 10 mg capsule taken orally once daily in the morning for 20 weeks thereafter.

Reporting group title

ABT-126 75 mg

Reporting group description

Three ABT-126 25 mg capsules taken orally once daily in the morning for 24 weeks beginning on Day 1.

Serious adverse events	Placebo	ABT-126 50 mg	ABT-126 25 mg	Donepezil	ABT-126 75 mg
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 104 (4.81%)	7 / 107 (6.54%)	6 / 77 (7.79%)	3 / 75 (4.00%)	2 / 73 (2.74%)
number of deaths (all causes)	0	0	0	2	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma
subjects affected / exposed	0 / 104 (0.00%)	1 / 107 (0.93%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Uterine prolapse
subjects affected / exposed	1 / 104 (0.96%)	0 / 107 (0.00%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 104 (0.00%)	1 / 107 (0.93%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Aggression
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Insomnia
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Weight decreased
subjects affected / exposed	0 / 104 (0.00%)	1 / 107 (0.93%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Brain contusion
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 104 (0.96%)	0 / 107 (0.00%)	0 / 77 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Complex partial seizures
subjects affected / exposed	1 / 104 (0.96%)	0 / 107 (0.00%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 104 (0.96%)	0 / 107 (0.00%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiplegia
subjects affected / exposed	1 / 104 (0.96%)	0 / 107 (0.00%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 104 (0.96%)	0 / 107 (0.00%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 104 (0.00%)	1 / 107 (0.93%)	0 / 77 (0.00%)	0 / 75 (0.00%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenitis
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	0 / 77 (0.00%)	0 / 75 (0.00%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	0 / 77 (0.00%)	0 / 75 (0.00%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	1 / 77 (1.30%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	0 / 77 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Urethral stenosis
subjects affected / exposed	0 / 104 (0.00%)	1 / 107 (0.93%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 104 (0.00%)	1 / 107 (0.93%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	0 / 77 (0.00%)	1 / 75 (1.33%)	1 / 73 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 104 (0.00%)	0 / 107 (0.00%)	0 / 77 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 104 (0.96%)	2 / 107 (1.87%)	0 / 77 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	ABT-126 50 mg	ABT-126 25 mg	Donepezil	ABT-126 75 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	19 / 104 (18.27%)	31 / 107 (28.97%)	17 / 77 (22.08%)	24 / 75 (32.00%)	15 / 73 (20.55%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	4 / 104 (3.85%)	5 / 107 (4.67%)	3 / 77 (3.90%)	5 / 75 (6.67%)	3 / 73 (4.11%)
occurrences all number	4	6	3	5	4
Nervous system disorders
Headache
subjects affected / exposed	7 / 104 (6.73%)	4 / 107 (3.74%)	5 / 77 (6.49%)	8 / 75 (10.67%)	5 / 73 (6.85%)
occurrences all number	10	7	7	9	6
Gastrointestinal disorders
Constipation
subjects affected / exposed	3 / 104 (2.88%)	15 / 107 (14.02%)	7 / 77 (9.09%)	2 / 75 (2.67%)	2 / 73 (2.74%)
occurrences all number	3	15	10	2	2
Diarrhoea
subjects affected / exposed	2 / 104 (1.92%)	4 / 107 (3.74%)	2 / 77 (2.60%)	4 / 75 (5.33%)	2 / 73 (2.74%)
occurrences all number	2	4	2	4	3
Nausea
subjects affected / exposed	3 / 104 (2.88%)	4 / 107 (3.74%)	1 / 77 (1.30%)	6 / 75 (8.00%)	2 / 73 (2.74%)
occurrences all number	3	4	1	6	3
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 104 (0.96%)	7 / 107 (6.54%)	1 / 77 (1.30%)	0 / 75 (0.00%)	2 / 73 (2.74%)
occurrences all number	1	7	1	0	2
Depressed mood
subjects affected / exposed	1 / 104 (0.96%)	0 / 107 (0.00%)	1 / 77 (1.30%)	4 / 75 (5.33%)	0 / 73 (0.00%)
occurrences all number	1	0	1	4	0

More information

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Were there any global substantial amendments to the protocol? Yes

13 Sep 2011

Significant changes implemented by Amendment 1 included: ● Updated Section 3.0 and Section 5.6.4 to incorporate preliminary pharmacokinetic and safety data from the Phase 1 multiple-dose Study M12-843. ● Updated exclusion criterion number 3 to clarify that subjects and caregivers may participate in counseling to provide additional information about AD if it is clinically indicated. ● Replaced the formula nomenclature used in the synopsis with ABT-126 to maintain proprietary information in a document that will be used in the public domain. ● Moved PPQSA assessment from Week 18 to Week 24 to obtain a more appropriate final assessment. ● Clarified QTcB interval calculation to determine the QTcB interval that should be used for subject's eligibility. ● Added language for subject rescreening to specify terms in which subjects may re-screen for study. ● Updated Figure 1, Figure 2, and Figure 3 to better clarify study design. ● Updated Section 10.1 Source Documents to clarify specific items being used as source documents.

14 Dec 2011

Significant changes implemented by Amendment 2 included: ● Included preliminary data from 2 recently conducted ABT-126 Phase 1 studies in Section 3.0, Introduction and Section 5.6.4, Selection of Doses in the Study; included an additional electrocardiogram (ECG) assessment; excluded subjects with risk factors for Torsades de Pointes; excluded concomitant medications associated with Torsades de Pointes. An increase in the group mean QTcF interval was observed in healthy volunteers in Phase 1 studies evaluating doses of 100 mg, 125 mg and 150 mg doses of ABT-126, which were higher than those under evaluation in this study. ● Updated inclusion criterion 12 to clarify level of education required for subject eligibility to ensure ability to complete assessments accurately. ● Added the Wechsler Memory Scale-III Working Memory Index to obtain additional data regarding the effects of ABT-126 on working memory to complement the cognition data obtained from the other outcome measures. ● Added the EuroQol-5D-5L and the EuroQol-5D-3L proxy to obtain additional Health Economics and Outcomes Research (HEOR) data. ● Clarified circumstances for individual subject withdrawal. Subjects may be discontinued from the study in the event they show pronounced clinical symptom progression. ● Updated language in Section 6.0 to comply with the latest sponsor standards. ● Updated contact information in Section 7.0, Protocol Deviations since there was a change in personnel.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind, Placebo- and Active-Controlled Phase 2 Dose-Ranging Study to Evaluate the Efficacy and Safety of ABT-126 in Subjects with Mild to Moderate Alzheimer's Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) 11-item Total Score: Change from Baseline to Week 24

Primary: Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) 11-item Total Score: Change from Baseline to Week 24

Secondary: ADAS-Cog 13-Item Total Score: Change from Baseline to Week 24

Secondary: ADAS-Cog 13-Item Total Score: Change from Baseline to Week 24

Secondary: Mini-Mental Status Exam (MMSE): Change from Baseline to Week 24

Secondary: Mini-Mental Status Exam (MMSE): Change from Baseline to Week 24

Secondary: Neuropsychiatric Inventory (NPI) 12-item Total Score: Change from Baseline to Week 24

Secondary: Neuropsychiatric Inventory (NPI) 12-item Total Score: Change from Baseline to Week 24

Secondary: Neuropsychiatric Inventory (NPI) 10-item Total Score: Change from Baseline to Week 24

Secondary: Neuropsychiatric Inventory (NPI) 10-item Total Score: Change from Baseline to Week 24

Secondary: Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL): Change from Baseline to Week 24

Secondary: Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL): Change from Baseline to Week 24

Secondary: DEMentia Quality of Life (DEMQOL) Global Score: Change from Baseline to Week 24

Secondary: DEMentia Quality of Life (DEMQOL) Global Score: Change from Baseline to Week 24

Secondary: DEMQOL-Proxy Global Score: Change from Baseline to Week 24

Secondary: DEMQOL-Proxy Global Score: Change from Baseline to Week 24

Secondary: Partner-Patient Questionnaire for Shared Activities (PPQSA) Average Score: Change from Baseline to Week 24

Secondary: Partner-Patient Questionnaire for Shared Activities (PPQSA) Average Score: Change from Baseline to Week 24

Secondary: The Wechsler Memory Scale-III (WMS-III) Working Memory Index: Change from Baseline to Week 18

Secondary: The Wechsler Memory Scale-III (WMS-III) Working Memory Index: Change from Baseline to Week 18

Secondary: Resource Utilization in Dementia (RUD)-Lite Caregiver Time: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: Resource Utilization in Dementia (RUD)-Lite Caregiver Time: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: EuroQol-5D (EQ-5D)-5L Index Score: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: EuroQol-5D (EQ-5D)-5L Index Score: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: EQ-5D-5L Health State Score: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: EQ-5D-5L Health State Score: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: EQ-5D-3L-Proxy Index Score: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: EQ-5D-3L-Proxy Index Score: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: EQ-5D-3L-Proxy Health State Score: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: EQ-5D-3L-Proxy Health State Score: Change from Baseline to Final Evaluation (up to Week 24)

Secondary: Clinician Interview-Based Impression of Change – Plus (CIBIC-Plus): Change from Baseline to Week 24

Secondary: Clinician Interview-Based Impression of Change – Plus (CIBIC-Plus): Change from Baseline to Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-Blind, Placebo- and Active-Controlled Phase 2 Dose-Ranging Study to Evaluate the Efficacy and Safety of ABT-126 in Subjects with Mild to Moderate Alzheimer's Disease