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Clinical Trial Results:
A Prospective, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Efficacy and Safety Study of Oral ELND005 for Treatment of Agitation and Aggression in Patients With Moderate to Severe Alzheimer's Disease.

Summary
EudraCT number	2012-004299-20
Trial protocol	GB ES
Global end of trial date	20 May 2015

Results information
Results version number	v1(current)
This version publication date	30 Apr 2016
First version publication date	30 Apr 2016
Other versions

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

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Trial information

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Sponsor protocol code

ELND005-AG201

ISRCTN number

US NCT number

NCT01735630

WHO universal trial number (UTN)

Sponsor organisation name

Transition Therapeutics Ireland Limited

Sponsor organisation address

Arthur Cox Building Earlsfort Centre, Earlsfort Terrace, Dublin, Ireland, Dublin 2

Public contact

Aleksandra Pastrak,MD, PhD, VP, Transition Therapeutics Ireland Limited, 001 416 263 1227, apastrak@transitiontherapeutics.com

Scientific contact

Aleksandra Pastrak,MD, PhD, VP of Clinical Development and Medical Officer, Transition Therapeutics Ireland Limited, 001 416 263 1227, apastrak@transitiontherapeutics.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

30 Oct 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 May 2015

Global end of trial reached?

Yes

Global end of trial date

20 May 2015

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of ELND005 treatment compared with placebo in reducing the severity of agitation and aggression at 12 weeks; To evaluate the safety and tolerability of the ELND005 dosing regimen in Moderate to Severe AD patients

Protection of trial subjects

400 subjects planned The study was conducted according to /ICH/ guidelines concerning Good Clinical Practice (GCP)

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Nov 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

9 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

United States: 304

Country: Number of subjects enrolled

Spain: 23

Country: Number of subjects enrolled

United Kingdom: 6

Worldwide total number of subjects

350

EEA total number of subjects

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

280

85 years and over

Subject disposition

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Recruitment details

Patients recruited between Nov 2012 and Feb 2015.

Screening details

Patients with moderate to severe Alzheimer’s Disease who had clinically significant agitation and aggression.

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo matching ELND005

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PlaceboTablet - BID for 4 weeks followed by Placebo BID for 8 weeks

Test

Arm description

ELND005 250 mg

Arm type

Experimental

Investigational medicinal product name

Scyllo Inositol

Investigational medicinal product code

ELND005

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

250mg Tablet -1000mg BID for 4 weeks followed by 250 mg BID for 8 weeks

Number of subjects in period 1	Placebo	Test
Started	175	175
Completed	157	157
Not completed	18	18
Consent withdrawn by subject	9	7
Physician decision	1	-
Adverse event, non-fatal	7	8
Sponsor desicion	-	2
Sponsor decision	1	-
Lost to follow-up	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo matching ELND005

Reporting group title

Test

Reporting group description

ELND005 250 mg

Reporting group values	Placebo	Test	Total
Number of subjects	175	175	350
Age categorical
Units: Subjects
Adults (18-64 years)	20	13	33
From 65-84 years	132	142	274
85 years and over	23	20	43
Age continuous
Units: years
arithmetic mean (standard deviation)	75.9 ± 8.51	76.2 ± 7.89	-
Gender categorical
Units: Subjects
Female	100	95	195
Male	75	80	155
race
Units: Subjects
White	151	155	306
Black	22	17	39
Asian	1	2	3
Other	1	1	2

Subject analysis set title

modified Intent-to-Treat (mITT)

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects in the safety set (patients that were randomized and received at least one dose of study drug) that had a valid baseline NPI-C A+A assessment and at least one valid post-baseline NPI-C A+A assessment.

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who were enrolled in the study and received at least one dose of study drug were included in safety analyses.

Subject analysis sets values	modified Intent-to-Treat (mITT)	Safety Analysis Set
Number of subjects	334	350
Age categorical
Units: Subjects
Adults (18-64 years)	30	33
From 65-84 years	262	274
85 years and over	42	43
Age continuous
Units: years
arithmetic mean (standard deviation)	±	±
Gender categorical
Units: Subjects
Female	187	195
Male	147	155
race
Units: Subjects
White	290	306
Black	39	39
Asian	3	3
Other	2	2

End points

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Reporting group title

Placebo

Reporting group description

Placebo matching ELND005

Reporting group title

Test

Reporting group description

ELND005 250 mg

Subject analysis set title

modified Intent-to-Treat (mITT)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who were enrolled in the study and received at least one dose of study drug were included in safety analyses.

Primary: Change from Baseline in NPI-C A+A Score

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End point title

Change from Baseline in NPI-C A+A Score

End point description

Change from Baseline to Week 12 in NPI-C A+A scored between the ELND005 and placebo treatment groups

End point type

Primary

End point timeframe

12 weeks

End point values	Placebo	Test
Number of subjects analysed	155	157
Units: Change from Baseline Score
least squares mean (standard error)
NPI-C A+A	-4.2 ± 0.7	-4.3 ± 0.7

Mixed Model Repeated Measured Analyses

Statistical analysis description

Mixed Model Repeated Measured Analyses of Change from Baseline in NPI-C A+A Score

Comparison groups

Placebo v Test

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8982

Method

t-test, 2-sided

Confidence interval

Adverse events

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Timeframe for reporting adverse events

Mean duration on study for subjects in the ELND005 group was 83.6 days and for subjects in the placebo group was 83.8 days.

Adverse event reporting additional description

All subjects who were enrolled in the study and received at least one dose of study drug were included in safety analyses.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Placebo Safety

Reporting group description

All subjects who were randomized into the study and received at least one dose of study drug.

Reporting group title

ELND005 250 mg (Safety)

Reporting group description

All subjects who were randomized into the study and received at least one dose of study drug.

Serious adverse events	Placebo Safety	ELND005 250 mg (Safety)
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 175 (2.86%)	17 / 175 (9.71%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer
subjects affected / exposed	1 / 175 (0.57%)	0 / 175 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 175 (0.57%)	2 / 175 (1.14%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Acetabulum fracture
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 175 (0.57%)	0 / 175 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 175 (0.57%)	0 / 175 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac Failure congestive
subjects affected / exposed	1 / 175 (0.57%)	0 / 175 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 175 (0.00%)	2 / 175 (1.14%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar infarction
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	0 / 175 (0.00%)	2 / 175 (1.14%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 175 (0.00%)	2 / 175 (1.14%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Homocidal ideation
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infections Infestations Sepsis
subjects affected / exposed	0 / 175 (0.00%)	3 / 175 (1.71%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 175 (0.00%)	3 / 175 (1.71%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 2 diabetes mellitus
subjects affected / exposed	0 / 175 (0.00%)	1 / 175 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 17
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Placebo Safety	ELND005 250 mg (Safety)
Total subjects affected by non serious adverse events
subjects affected / exposed	82 / 175 (46.86%)	97 / 175 (55.43%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	9 / 175 (5.14%)	11 / 175 (6.29%)
occurrences all number	82	97
Contusion
subjects affected / exposed	7 / 175 (4.00%)	1 / 175 (0.57%)
occurrences all number	82	97
Nervous system disorders
Dizziness
subjects affected / exposed	7 / 175 (4.00%)	2 / 175 (1.14%)
occurrences all number	82	97
Lethargy
subjects affected / exposed	2 / 175 (1.14%)	6 / 175 (3.43%)
occurrences all number	82	97
Somnolence
subjects affected / exposed	4 / 175 (2.29%)	3 / 175 (1.71%)
occurrences all number	82	97
Headache
subjects affected / exposed	2 / 175 (1.14%)	4 / 175 (2.29%)
occurrences all number	82	97
General disorders and administration site conditions
Gait disturbance
subjects affected / exposed	1 / 175 (0.57%)	4 / 175 (2.29%)
occurrences all number	82	97
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	5 / 175 (2.86%)	14 / 175 (8.00%)
occurrences all number	82	97
Vomiting
subjects affected / exposed	5 / 175 (2.86%)	5 / 175 (2.86%)
occurrences all number	82	97
Constipation
subjects affected / exposed	2 / 175 (1.14%)	4 / 175 (2.29%)
occurrences all number	82	97
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 175 (1.14%)	7 / 175 (4.00%)
occurrences all number	82	97
Psychiatric disorders
Agitation
subjects affected / exposed	13 / 175 (7.43%)	14 / 175 (8.00%)
occurrences all number	82	97
Insomnia
subjects affected / exposed	7 / 175 (4.00%)	5 / 175 (2.86%)
occurrences all number	82	97
Infections and infestations
Urinary Tract Infection
subjects affected / exposed	7 / 175 (4.00%)	12 / 175 (6.86%)
occurrences all number	82	97
Bronchitis
subjects affected / exposed	5 / 175 (2.86%)	2 / 175 (1.14%)
occurrences all number	82	97
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 175 (2.29%)	3 / 175 (1.71%)
occurrences all number	82	97

More information

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Were there any global substantial amendments to the protocol? No

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 Prospective, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Efficacy and Safety Study of Oral ELND005 for Treatment of Agitation and Aggression in Patients With Moderate to Severe Alzheimer's Disease.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in NPI-C A+A Score

Primary: Change from Baseline in NPI-C A+A Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Prospective, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Efficacy and Safety Study of Oral ELND005 for Treatment of Agitation and Aggression in Patients With Moderate to Severe Alzheimer's Disease.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in NPI-C A+A Score

Primary: Change from Baseline in NPI-C A+A Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Prospective, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Efficacy and Safety Study of Oral ELND005 for Treatment of Agitation and Aggression in Patients With Moderate to Severe Alzheimer's Disease.