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Clinical Trial Results:
A 26-Week Extension Study of the Safety and Clinical Effects of EVP-6124 in Subjects with Alzheimer's Disease Currently or Previously Receiving an Acetylcholinesterase Inhibitor Medication

Summary
EudraCT number	2013-002654-75
Trial protocol	DE BE GB ES IT NL CZ
Global end of trial date	23 Dec 2015

Results information
Results version number	v1(current)
This version publication date	05 Feb 2017
First version publication date	05 Feb 2017
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

EVP-6124-026

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

IND Number: 102623

Sponsor organisation name

FORUM Pharmaceuticals Inc.

Sponsor organisation address

225 Second Avenue, Waltham, MA, United States, 02451

Public contact

Franz Buchholzer, inVentiv Health Clinical UK Ltd, Regopseurope@inventivhealth.com

Scientific contact

Franz Buchholzer, inVentiv Health Clinical UK Ltd, Regopseurope@inventivhealth.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

14 Jun 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Dec 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

To assess the safety of 2 fixed doses of EVP-6124 (2 or 3 mg daily) for up to 52 weeks in subjects with Alzheimer's disease (AD) who complete (Day 182) studies EVP-6124-024 or EVP-6124-025

Protection of trial subjects

There were no invasive or potentially pain-inducing procedures in this study except blood sampling. If patients experience pain, analgesic treatment was allowed per the physician discretion.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Jun 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

Netherlands: 8

Country: Number of subjects enrolled

Poland: 11

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

Czech Republic: 8

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Australia: 6

Country: Number of subjects enrolled

Canada: 14

Country: Number of subjects enrolled

Japan: 7

Country: Number of subjects enrolled

South Africa: 43

Country: Number of subjects enrolled

Korea, Republic of: 22

Country: Number of subjects enrolled

United States: 204

Worldwide total number of subjects

348

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

274

85 years and over

Subject disposition

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Recruitment details

Screening details

In this extension study, subjects who complete study EVP-6124-024 or EVP-6124-025 (Day 182) and fulfill all entry criteria will be randomized. Assessments performed at the final double-blind study visit (Day 182) will serve as the baseline for this extension study for all subjects.

Period 1 title

Double-blind period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer

Are arms mutually exclusive

Yes

EVP-6124, 2 mg

Arm description

Previously treated with EVP-6124 will receive the same dose during this study as received in the previous study and subjects previously treated with placebo will be randomized to EVP-6124 2 or 3 mg daily (1:1 ratio).

Arm type

Experimental

Investigational medicinal product name

Encenicline

Investigational medicinal product code

EVP-6124

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects will be instructed to take 1 tablet once daily at the same time each day, preferably between 8 and 10 AM, with or without food, and with an adequate amount of water.

EVP-6124, 3 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Encenicline

Investigational medicinal product code

EVP-6124

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects will be instructed to take 1 tablet once daily at the same time each day, preferably between 8 and 10 AM, with or without food, and with an adequate amount of water.

Pbo-EVP-6124, 2 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Encenicline

Investigational medicinal product code

EVP-6124

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects will be instructed to take 1 tablet once daily at the same time each day, preferably between 8 and 10 AM, with or without food, and with an adequate amount of water.

Pbo-EVP-6124, 3 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Encenicline

Investigational medicinal product code

EVP-6124

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects will be instructed to take 1 tablet once daily at the same time each day, preferably between 8 and 10 AM, with or without food, and with an adequate amount of water.

Number of subjects in period 1	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Started	111	114	61	62
Completed	37	36	20	12
Not completed	74	78	41	50
Consent withdrawn by subject	2	1	1	3
Adverse event, non-fatal	5	5	4	3
Other	3	2	5	3
Withdrawal by Subject/Caregiver	2	2	-	2
Due to Clinical hold	60	67	31	39
Lost to follow-up	2	1	-	-

Baseline characteristics

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Reporting group title

EVP-6124, 2 mg

Reporting group description

Reporting group title

EVP-6124, 3 mg

Reporting group description

Reporting group title

Pbo-EVP-6124, 2 mg

Reporting group description

Reporting group title

Pbo-EVP-6124, 3 mg

Reporting group description

Reporting group values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg	Total
Number of subjects	111	114	61	62	348
Age categorical
Units: Subjects
Adults (18-64 years)	21	26	7	6	60
From 65-84 years	85	86	51	52	274
85 years and over	5	2	3	4	14
Age continuous
Units: years
arithmetic mean (full range (min-max))	72.8 (57 to 85)	71.7 (55 to 85)	74.3 (55 to 85)	75.4 (57 to 85)	-
Gender categorical
Units: Subjects
Female	49	62	40	37	188
Male	62	52	21	25	160

End points

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Reporting group title

EVP-6124, 2 mg

Reporting group description

Reporting group title

EVP-6124, 3 mg

Reporting group description

Reporting group title

Pbo-EVP-6124, 2 mg

Reporting group description

Reporting group title

Pbo-EVP-6124, 3 mg

Reporting group description

Primary: Albumin (Change from baseline)

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End point title

Albumin (Change from baseline) ^[1]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: (g/L)
arithmetic mean (full range (min-max))	-1 (-7 to 2)	-0.7 (-7 to 3)	-0.3 (-6 to 6)	-1.2 (-6 to 3)

No statistical analyses for this end point

Primary: Alkaline Phosphatase (Change from baseline)

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End point title

Alkaline Phosphatase (Change from baseline) ^[2]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: U/L
arithmetic mean (full range (min-max))	-1.1 (-29 to 12)	2.6 (-25 to 29)	-2.9 (-31 to 19)	9.1 (-15 to 104)

No statistical analyses for this end point

Primary: Alanine Aminotransferase (Change from baseline)

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End point title

Alanine Aminotransferase (Change from baseline) ^[3]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: U/L
arithmetic mean (full range (min-max))	-2.5 (-18 to 7)	-1.7 (-17 to 16)	1.2 (-7 to 12)	0.2 (-5 to 17)

No statistical analyses for this end point

Primary: Aspartate Aminotransferase (Change from baseline)

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End point title

Aspartate Aminotransferase (Change from baseline) ^[4]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: U/L
arithmetic mean (full range (min-max))	-2.9 (-35 to 3)	-1.7 (-18 to 10)	0.7 (-5 to 8)	0 (-15 to 10)

No statistical analyses for this end point

Primary: Bicarbonate (Change from baseline)

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End point title

Bicarbonate (Change from baseline) ^[5]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	-0.75 (-5.7 to 3.6)	-0.22 (-8.1 to 8.2)	0.29 (-4.4 to 5.2)	0.59 (-2.4 to 7.9)

No statistical analyses for this end point

Primary: Bilirubin (Change from baseline)

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End point title

Bilirubin (Change from baseline) ^[6]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: umol/L
arithmetic mean (full range (min-max))	0.77 (-3.9 to 9.4)	0 (-8 to 7.1)	-0.07 (-6.9 to 8)	0.03 (-3.4 to 4.4)

No statistical analyses for this end point

Primary: Blood Urea Nitrogen (Change from baseline)

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End point title

Blood Urea Nitrogen (Change from baseline) ^[7]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: MMOL UREA/L
arithmetic mean (full range (min-max))	-0.29 (-5 to 2.5)	-0.09 (-4.7 to 2.1)	-0.31 (-5 to 2.5)	0.38 (-5.4 to 5.4)

No statistical analyses for this end point

Primary: Calcium (Change from baseline)

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End point title

Calcium (Change from baseline) ^[8]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	-0.024 (-0.22 to 0.16)	-0.023 (-0.28 to 0.13)	0.006 (-0.15 to 0.16)	-0.028 (-0.23 to 0.14)

No statistical analyses for this end point

Primary: Creatine Kinase (Change from baseline)

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End point title

Creatine Kinase (Change from baseline) ^[9]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: U/L
arithmetic mean (full range (min-max))	-26.8 (-344 to 61)	-11.6 (-210 to 106)	10.2 (-36 to 123)	-4.6 (-142 to 257)

No statistical analyses for this end point

Primary: Chloride (Change from baseline)

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End point title

Chloride (Change from baseline) ^[10]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	0.5 (-5 to 6)	-0.2 (-5 to 6)	0.5 (-6 to 8)	-0.4 (-12 to 6)

No statistical analyses for this end point

Primary: Creatinine (Change from baseline)

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End point title

Creatinine (Change from baseline) ^[11]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: umol/L
arithmetic mean (full range (min-max))	2.51 (-15.9 to 19.5)	2.08 (-15.9 to 23.9)	2.98 (-124.6 to 41.5)	0.52 (-23.9 to 31.8)

No statistical analyses for this end point

Primary: Gamma Glutamyl Transferase (Change from baseline)

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End point title

Gamma Glutamyl Transferase (Change from baseline) ^[12]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: U/L
arithmetic mean (full range (min-max))	-0.7 (-14 to 12)	0.9 (-17 to 24)	1 (-4 to 11)	8.6 (-12 to 129)

No statistical analyses for this end point

Primary: Glucose (Change from baseline)

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End point title

Glucose (Change from baseline) ^[13]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	-0.27 (-9.04 to 2.94)	0.408 (-5.94 to 13.77)	0.309 (-1.5 to 3.44)	-0.382 (-4.11 to 4.49)

No statistical analyses for this end point

Primary: Potassium (Change from baseline)

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End point title

Potassium (Change from baseline) ^[14]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	0.06 (-1.6 to 1.1)	-0.07 (-0.8 to 1)	0.16 (-0.5 to 1.6)	0.15 (-0.7 to 0.9)

No statistical analyses for this end point

Primary: Magnesium (Change from baseline)

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End point title

Magnesium (Change from baseline) ^[15]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	-0.0079 (-0.123 to 0.164)	-0.0253 (-0.124 to 0.083)	-0.0057 (-0.214 to 0.205)	-0.0213 (-0.164 to 0.185)

No statistical analyses for this end point

Primary: Inorganic Phosphate (Change from baseline)

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End point title

Inorganic Phosphate (Change from baseline) ^[16]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	-0.0291 (-0.394 to 0.339)	-0.017 (-0.419 to 0.368)	0.0025 (-0.362 to 0.649)	0.0199 (-0.294 to 0.62)

No statistical analyses for this end point

Primary: Protein (Change from baseline)

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End point title

Protein (Change from baseline) ^[17]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: g/L
arithmetic mean (full range (min-max))	-1.5 (-12 to 4)	-0.9 (-10 to 6)	-0.4 (-6 to 6)	-0.2 (-5 to 8)

No statistical analyses for this end point

Primary: Sodium (Change from baseline)

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End point title

Sodium (Change from baseline) ^[18]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	0.8 (-4 to 8)	0.1 (-8 to 5)	1 (-4 to 6)	0.2 (-11 to 9)

No statistical analyses for this end point

Primary: Urate (Change from baseline)

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End point title

Urate (Change from baseline) ^[19]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmol/L
arithmetic mean (full range (min-max))	-0.004 (-0.12 to 0.13)	0 (-0.08 to 0.1)	0.008 (-0.08 to 0.12)	0.014 (-0.1 to 0.1)

No statistical analyses for this end point

Primary: Leukocytes (Change from baseline)

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End point title

Leukocytes (Change from baseline) ^[20]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: 10^9/L
arithmetic mean (full range (min-max))	0.016 (-2.28 to 8.25)	-0.219 (-3.58 to 1.74)	-0.245 (-5.27 to 2.66)	-0.013 (-10.64 to 4.29)

No statistical analyses for this end point

Primary: Erythrocytes (Change from baseline)

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End point title

Erythrocytes (Change from baseline) ^[21]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: 10^12/L
arithmetic mean (full range (min-max))	-0.054 (-0.63 to 0.75)	-0.085 (-0.65 to 0.42)	-0.065 (-1.74 to 0.45)	-0.075 (-0.51 to 0.55)

No statistical analyses for this end point

Primary: Hemoglobin (Change from baseline)

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End point title

Hemoglobin (Change from baseline) ^[22]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: g/L
arithmetic mean (full range (min-max))	-2.1 (-35 to 13)	-1.7 (-20 to 11)	-1.1 (-42 to 23)	-2.7 (-21 to 11)

No statistical analyses for this end point

Primary: Hematocrit (change from baseline)

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End point title

Hematocrit (change from baseline) ^[23]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: %(v/v)
arithmetic mean (full range (min-max))	0.004 (-0.091 to 0.074)	-0.0038 (-0.058 to 0.061)	0.0006 (-0.144 to 0.059)	-0.0023 (-0.073 to 0.049)

No statistical analyses for this end point

Primary: Platelets (Change from baseline)

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End point title

Platelets (Change from baseline) ^[24]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: 10^9/L
arithmetic mean (full range (min-max))	-13.1 (-84 to 47)	-6.3 (-65 to 135)	2.7 (-71 to 236)	9.7 (-141 to 329)

No statistical analyses for this end point

Primary: Basophils (Change from baseline)

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End point title

Basophils (Change from baseline) ^[25]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: 10^9/L
arithmetic mean (full range (min-max))	-0.001 (-0.06 to 0.05)	0 (-0.03 to 0.08)	0.003 (-0.11 to 0.11)	0.001 (-0.02 to 0.03)

No statistical analyses for this end point

Primary: Eosinophils (Change from baseline)

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End point title

Eosinophils (Change from baseline) ^[26]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: 10^9/L
arithmetic mean (full range (min-max))	-0.01 (-0.31 to 0.25)	-0.017 (-0.6 to 0.28)	-0.009 (-0.38 to 0.32)	0.04 (-0.15 to 0.44)

No statistical analyses for this end point

Primary: Lymphocytes (Change from baseline)

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End point title

Lymphocytes (Change from baseline) ^[27]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: 10^9/L
arithmetic mean (full range (min-max))	2.116 (0.64 to 19.97)	1.725 (0.58 to 3.97)	2.364 (0.81 to 19.09)	1.502 (0.7 to 3.33)

No statistical analyses for this end point

Primary: Monocytes (Change from baseline)

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End point title

Monocytes (Change from baseline) ^[28]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: 10^9/L
arithmetic mean (full range (min-max))	-0.006 (-0.39 to 0.45)	-0.002 (-0.64 to 1.03)	-0.002 (-0.62 to 0.76)	0.034 (-0.59 to 0.5)

No statistical analyses for this end point

Primary: Neutrophils (Change from baseline)

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End point title

Neutrophils (Change from baseline) ^[29]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: 10^9/L
arithmetic mean (full range (min-max))	0.011 (-2.05 to 5.16)	-0.012 (-3.07 to 2.3)	-0.418 (-5.57 to 2.47)	-0.015 (-9.83 to 3.26)

No statistical analyses for this end point

Primary: Urinalysis - pH

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End point title

Urinalysis - pH ^[30]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[30] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: N/A
arithmetic mean (full range (min-max))	-0.1 (-3 to 2)	-0.5 (-3 to 1)	0.1 (-2 to 2)	-0.3 (-3 to 1)

No statistical analyses for this end point

Primary: Urinalysis - Specific Gravity

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End point title

Urinalysis - Specific Gravity ^[31]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182. Performed non-fasting at each clinic visit.

Notes
[31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: N/A
arithmetic mean (full range (min-max))	0.001 (-0.025 to 0.02)	0.0019 (-0.02 to 0.025)	0 (-0.02 to 0.015)	0 (-0.015 to 0.01)

No statistical analyses for this end point

Primary: Heart Rate (Change from baseline)

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End point title

Heart Rate (Change from baseline) ^[32]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182

Notes
[32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: beats/min
arithmetic mean (full range (min-max))	1.5 (-22 to 26)	2.5 (-17 to 27)	-0.6 (-40 to 13)	2.5 (-19 to 19)

No statistical analyses for this end point

Primary: QT Duration (Change from baseline)

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End point title

QT Duration (Change from baseline) ^[33]

End point description

End point type

Primary

End point timeframe

12-lead electrocardiogram (ECG): Days 28, 56, 112, 140, and 182

Notes
[33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: msec
arithmetic mean (full range (min-max))	-6 (-50 to 52)	-4.9 (-86 to 42)	-1.8 (-40 to 126)	-7.3 (-64 to 38)

No statistical analyses for this end point

Primary: QRS Duration (Change from baseline)

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End point title

QRS Duration (Change from baseline) ^[34]

End point description

End point type

Primary

End point timeframe

12-lead electrocardiogram (ECG): Days 28, 56, 112, 140, and 182

Notes
[34] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: msec
arithmetic mean (full range (min-max))	-1.8 (-12 to 8)	0.5 (-14 to 46)	1.2 (-12 to 14)	-0.7 (-12 to 6)

No statistical analyses for this end point

Primary: PR Duration (Change from baseline)

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End point title

PR Duration (Change from baseline) ^[35]

End point description

End point type

Primary

End point timeframe

12-lead electrocardiogram (ECG): Days 28, 56, 112, 140, and 182

Notes
[35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: msec
arithmetic mean (full range (min-max))	2 (-22 to 24)	2 (-50 to 44)	0.3 (-28 to 24)	-3 (-30 to 18)

No statistical analyses for this end point

Primary: QTcF - Fridericia's Correction Formula (Change from baseline)

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End point title

QTcF - Fridericia's Correction Formula (Change from baseline) ^[36]

End point description

End point type

Primary

End point timeframe

12-lead electrocardiogram (ECG): Days 28, 56, 112, 140, and 182

Notes
[36] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: msec
arithmetic mean (full range (min-max))	-2.9 (-37 to 23)	0.7 (-25 to 29)	-4.4 (-30 to 31)	-1.5 (-34 to 58)

No statistical analyses for this end point

Primary: Temperature (Change from baseline)

Top of page

End point title

Temperature (Change from baseline) ^[37]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182

Notes
[37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: celsius
arithmetic mean (full range (min-max))	4 (-60 to 62)	6.9 (-2 to 62)	2.3 (-57 to 61)	-0.1 (-2 to 1)

No statistical analyses for this end point

Primary: Systolic Blood Pressure (Change from baseline)

Top of page

End point title

Systolic Blood Pressure (Change from baseline) ^[38]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182

Notes
[38] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmHg
arithmetic mean (full range (min-max))	-1 (-25 to 40)	-8.2 (-63 to 30)	-4.8 (-37 to 19)	-2.7 (-46 to 38)

No statistical analyses for this end point

Primary: Diastolic Blood Pressure (Change from baseline)

Top of page

End point title

Diastolic Blood Pressure (Change from baseline) ^[39]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182

Notes
[39] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: mmHg
arithmetic mean (full range (min-max))	-0.7 (-26 to 47)	-1.9 (-22 to 28)	0.7 (-20 to 19)	-3.1 (-22 to 30)

No statistical analyses for this end point

Primary: Heart Rate (Change from baseline)

Top of page

End point title

Heart Rate (Change from baseline) ^[40]

End point description

End point type

Primary

End point timeframe

12-lead electrocardiogram (ECG): Days 28, 56, 112, 140, and 182

Notes
[40] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: bpm
arithmetic mean (full range (min-max))	0.8 (-22 to 19)	1.3 (-21 to 26)	-0.7 (-20 to 15)	1.4 (-18 to 17)

No statistical analyses for this end point

Primary: Respiratory Rate (Change from baseline)

Top of page

End point title

Respiratory Rate (Change from baseline) ^[41]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182

Notes
[41] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: breaths/min
arithmetic mean (full range (min-max))	0.7 (-6 to 8)	-0.1 (-7 to 6)	0.1 (-4 to 6)	-0.1 (-5 to 2)

No statistical analyses for this end point

Primary: Weight (Change from baseline)

Top of page

End point title

Weight (Change from baseline) ^[42]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182

Notes
[42] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: kg
arithmetic mean (full range (min-max))	8.1 (-11 to 101)	7.3 (-91 to 103)	7.7 (-3 to 107)	-0.7 (-18 to 8)

No statistical analyses for this end point

Primary: Columbia Suicide Severity Rating Scale (C-SSRS) (Change from baseline)

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End point title

Columbia Suicide Severity Rating Scale (C-SSRS) (Change from baseline) ^[43]

End point description

End point type

Primary

End point timeframe

Days 28, 56, 84, 112, 140, and 182

Notes
[43] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the premature termination of the studies, a full statistical analysis could not be performed.

End point values	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Number of subjects analysed	106	110	61	59
Units: Subjects wishing to be dead	0	1	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events observed at any time after the ICF is signed through the safety follow-up telephone contact (Day 189 or early termination, as applicable) will be recorded.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

EVP-6124, 2 mg

Reporting group description

Reporting group title

EVP-6124, 3 mg

Reporting group description

Reporting group title

Pbo-EVP-6124, 2 mg

Reporting group description

Reporting group title

Pbo-EVP-6124, 3 mg

Reporting group description

Serious adverse events	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 106 (3.77%)	7 / 110 (6.36%)	4 / 61 (6.56%)	4 / 59 (6.78%)
number of deaths (all causes)	0	0	0	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer recurrent
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder cancer recurrent
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cancer
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sick sinus syndrome
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Dementia Alzheimer's type
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Gastrointestinal disorders
Colitis ulcerative
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	1 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mesenteric occlusion
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal colic
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Diverticulitis
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 7	1 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	EVP-6124, 2 mg	EVP-6124, 3 mg	Pbo-EVP-6124, 2 mg	Pbo-EVP-6124, 3 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	42 / 106 (39.62%)	42 / 110 (38.18%)	23 / 61 (37.70%)	30 / 59 (50.85%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer recurrent
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Gastric cancer recurrent
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Ovarian cancer
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Thyroid neoplasm
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Vascular disorders
Hypertension
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Hypotension
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
General disorders and administration site conditions
Gait disturbance
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Oedema peripheral
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Asthenia
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Fatigue
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Irritability
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Non-cardiac chest pain
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Pain
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Rhinorrhoea
subjects affected / exposed	2 / 106 (1.89%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Asthma
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 106 (0.94%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Confusional state
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Delirium
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	2 / 61 (3.28%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Hallucination
subjects affected / exposed	1 / 106 (0.94%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Insomnia
subjects affected / exposed	2 / 106 (1.89%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Abnormal behaviour
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Anxiety
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Depression
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Depressive symptom
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Hypersexuality
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Panic attack
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Investigations
Specific gravity urine increased
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Blood pressure decreased
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Blood urine present
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Eosinophil count increased
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Heart rate irregular
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Protein urine
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Specific gravity urine abnormal
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Weight decreased
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Weight increased
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
White blood cells urine
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	2 / 61 (3.28%)	3 / 59 (5.08%)
occurrences all number	42	42	23	30
Laceration
subjects affected / exposed	1 / 106 (0.94%)	1 / 110 (0.91%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Contusion
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Ankle fracture
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Arthropod bite
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Confusion postoperative
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Excoriation
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Femoral neck fracture
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Procedural pain
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Spinal fracture
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Thoracic vertebral fracture
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Acute myocardial infarction
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Angina pectoris
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Bradyarrhythmia
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Bundle branch block left
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Cardiac failure
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Palpitations
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Sick sinus syndrome
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	2 / 61 (3.28%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Syncope
subjects affected / exposed	1 / 106 (0.94%)	2 / 110 (1.82%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Cognitive disorder
subjects affected / exposed	1 / 106 (0.94%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Headache
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Altered state of consciousness
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Cerebral haemorrhage
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Dementia
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Dementia Alzheimer's type
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Migraine
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Neuralgia
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Parkinsonism
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Postural reflex impairment
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Presyncope
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Psychomotor skills impaired
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Eosinophilia
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Lymphopenia
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Neutrophilia
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Eye disorders
Cataract
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Conjunctivitis
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Retinal detachment
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Gastrointestinal disorders
Constipation
subjects affected / exposed	9 / 106 (8.49%)	12 / 110 (10.91%)	11 / 61 (18.03%)	9 / 59 (15.25%)
occurrences all number	42	42	23	30
Diarrhoea
subjects affected / exposed	9 / 106 (8.49%)	7 / 110 (6.36%)	4 / 61 (6.56%)	3 / 59 (5.08%)
occurrences all number	42	42	23	30
Nausea
subjects affected / exposed	5 / 106 (4.72%)	5 / 110 (4.55%)	4 / 61 (6.56%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Abdominal pain
subjects affected / exposed	3 / 106 (2.83%)	1 / 110 (0.91%)	3 / 61 (4.92%)	2 / 59 (3.39%)
occurrences all number	42	42	23	30
Vomiting
subjects affected / exposed	3 / 106 (2.83%)	2 / 110 (1.82%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Faecal incontinence
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Faeces hard
subjects affected / exposed	1 / 106 (0.94%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Haematochezia
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Rectal tenesmus
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Toothache
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Colitis ulcerative
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Diverticular perforation
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Dyschezia
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Gastrointestinal motility disorder
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Mesenteric occlusion
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Oesophagitis
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Periodontal disease
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Salivary gland mass
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 106 (0.94%)	1 / 110 (0.91%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Psoriasis
subjects affected / exposed	2 / 106 (1.89%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Dermatitis contact
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Pruritus
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Rash pruritic
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Skin lesion
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	2 / 59 (3.39%)
occurrences all number	42	42	23	30
Urinary incontinence
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Enuresis
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Glycosuria
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Proteinuria
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Renal colic
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Renal failure
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Renal failure acute
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Renal impairment
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Urinary retention
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 106 (0.94%)	1 / 110 (0.91%)	3 / 61 (4.92%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Arthralgia
subjects affected / exposed	3 / 106 (2.83%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Musculoskeletal stiffness
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Arthritis
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Costochondritis
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Foot deformity
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Osteoarthritis
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Pain in extremity
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Rotator cuff syndrome
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Temporomandibular joint syndrome
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Infections and infestations
Urinary tract infection
subjects affected / exposed	2 / 106 (1.89%)	2 / 110 (1.82%)	1 / 61 (1.64%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Upper respiratory tract infection
subjects affected / exposed	2 / 106 (1.89%)	1 / 110 (0.91%)	0 / 61 (0.00%)	2 / 59 (3.39%)
occurrences all number	42	42	23	30
Nasopharyngitis
subjects affected / exposed	0 / 106 (0.00%)	3 / 110 (2.73%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Bacteriuria
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Cellulitis
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Diverticulitis
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Herpes zoster
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Pharyngitis
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Pneumonia
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Sepsis
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Staphylococcal infection
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Tonsillitis
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	0 / 61 (0.00%)	1 / 59 (1.69%)
occurrences all number	42	42	23	30
Vulvovaginal candidiasis
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Wound sepsis
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	1 / 106 (0.94%)	1 / 110 (0.91%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Hypokalaemia
subjects affected / exposed	0 / 106 (0.00%)	1 / 110 (0.91%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Dehydration
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Gout
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Hypernatraemia
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Hyponatraemia
subjects affected / exposed	0 / 106 (0.00%)	0 / 110 (0.00%)	1 / 61 (1.64%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30
Type 2 diabetes mellitus
subjects affected / exposed	1 / 106 (0.94%)	0 / 110 (0.00%)	0 / 61 (0.00%)	0 / 59 (0.00%)
occurrences all number	42	42	23	30

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
23 Dec 2015	The Phase 3 Alzheimer's disease studies (EVP-6124-024, EVP-6124-025 and EVP-6124-026) were placed on complete clinical hold by the FDA due to potential gastrointestinal safety concern(s) around September 1st, 2015. Subsequent to this time, they were terminated to analyze the available data around January 1st, 2016.	-

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 26-Week Extension Study of the Safety and Clinical Effects of EVP-6124 in Subjects with Alzheimer's Disease Currently or Previously Receiving an Acetylcholinesterase Inhibitor Medication

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Albumin (Change from baseline)

Primary: Albumin (Change from baseline)

Primary: Alkaline Phosphatase (Change from baseline)

Primary: Alkaline Phosphatase (Change from baseline)

Primary: Alanine Aminotransferase (Change from baseline)

Primary: Alanine Aminotransferase (Change from baseline)

Primary: Aspartate Aminotransferase (Change from baseline)

Primary: Aspartate Aminotransferase (Change from baseline)

Primary: Bicarbonate (Change from baseline)

Primary: Bicarbonate (Change from baseline)

Primary: Bilirubin (Change from baseline)

Primary: Bilirubin (Change from baseline)

Primary: Blood Urea Nitrogen (Change from baseline)

Primary: Blood Urea Nitrogen (Change from baseline)

Primary: Calcium (Change from baseline)

Primary: Calcium (Change from baseline)

Primary: Creatine Kinase (Change from baseline)

Primary: Creatine Kinase (Change from baseline)

Primary: Chloride (Change from baseline)

Primary: Chloride (Change from baseline)

Primary: Creatinine (Change from baseline)

Primary: Creatinine (Change from baseline)

Primary: Gamma Glutamyl Transferase (Change from baseline)

Primary: Gamma Glutamyl Transferase (Change from baseline)

Primary: Glucose (Change from baseline)

Primary: Glucose (Change from baseline)

Primary: Potassium (Change from baseline)

Primary: Potassium (Change from baseline)

Primary: Magnesium (Change from baseline)

Primary: Magnesium (Change from baseline)

Primary: Inorganic Phosphate (Change from baseline)

Primary: Inorganic Phosphate (Change from baseline)

Primary: Protein (Change from baseline)

Primary: Protein (Change from baseline)

Primary: Sodium (Change from baseline)

Primary: Sodium (Change from baseline)

Primary: Urate (Change from baseline)

Primary: Urate (Change from baseline)

Primary: Leukocytes (Change from baseline)

Primary: Leukocytes (Change from baseline)

Primary: Erythrocytes (Change from baseline)

Primary: Erythrocytes (Change from baseline)

Primary: Hemoglobin (Change from baseline)

Primary: Hemoglobin (Change from baseline)

Primary: Hematocrit (change from baseline)

Primary: Hematocrit (change from baseline)

Primary: Platelets (Change from baseline)

Primary: Platelets (Change from baseline)

Primary: Basophils (Change from baseline)

Primary: Basophils (Change from baseline)

Primary: Eosinophils (Change from baseline)

Primary: Eosinophils (Change from baseline)

Primary: Lymphocytes (Change from baseline)

Primary: Lymphocytes (Change from baseline)

Primary: Monocytes (Change from baseline)

Primary: Monocytes (Change from baseline)

Primary: Neutrophils (Change from baseline)

Primary: Neutrophils (Change from baseline)

Primary: Urinalysis - pH

Primary: Urinalysis - pH

Primary: Urinalysis - Specific Gravity

Primary: Urinalysis - Specific Gravity

Primary: Heart Rate (Change from baseline)

Primary: Heart Rate (Change from baseline)

Primary: QT Duration (Change from baseline)

Primary: QT Duration (Change from baseline)

Primary: QRS Duration (Change from baseline)

Primary: QRS Duration (Change from baseline)

Primary: PR Duration (Change from baseline)

Primary: PR Duration (Change from baseline)

Clinical Trial Results:
A 26-Week Extension Study of the Safety and Clinical Effects of EVP-6124 in Subjects with Alzheimer's Disease Currently or Previously Receiving an Acetylcholinesterase Inhibitor Medication