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Clinical Trial Results:
Efficacy and safety of 2 doses of agomelatine (10mg, 25mg) given orally in children (from 7 to less than 12 years) and adolescents (from 12 to less than 18 years) with moderate to severe Major Depressive Disorder. A 12-week, randomized, double-blind, active (fluoxetine 10 mg/day with potential adjustment to 20 mg/day) and placebo-controlled, parallel groups, international, multicentre study followed by an optional open-labelled 21-month safety extension period.

Summary
EudraCT number	2015-002181-23
Trial protocol	FI HU DE BG PL
Global end of trial date	27 Oct 2021

Results information
Results version number	v2(current)
This version publication date	11 May 2022
First version publication date	24 Jul 2020
Other versions	v1
Version creation reason	New data added to full data set Final results

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

CL3-20098-076

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Institut de Recherches Internationales Servier

Sponsor organisation address

50 rue Carnot, Suresnes, France, 92284

Public contact

Clinical Studies Department, Institut de Recherche International Servier, 33 155724366, clinicaltrials@servier.com

Scientific contact

Clinical Studies Department, Institut de Recherche International Servier, 33 155724366, clinicaltrials@servier.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001181-PIP01-11

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?

Yes

Analysis stage

Final

Date of interim/final analysis

27 Oct 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Oct 2021

Global end of trial reached?

Yes

Global end of trial date

27 Oct 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective is to demonstrate the antidepressant short-term efficacy of at least one of the two doses of agomelatine compared to placebo after 12 weeks of treatment in children (from 7 to less than 12 years of age) and adolescents (from 12 to less than 18 years of age) suffering from moderate to severe Major Depressive Disorder using Children Depression Rating Scale – Revised (CDRS-R).

Protection of trial subjects

This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Feb 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

21 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

South Africa: 17

Country: Number of subjects enrolled

Ukraine: 72

Country: Number of subjects enrolled

Bulgaria: 9

Country: Number of subjects enrolled

Finland: 6

Country: Number of subjects enrolled

Hungary: 74

Country: Number of subjects enrolled

Poland: 31

Country: Number of subjects enrolled

Romania: 61

Country: Number of subjects enrolled

Russian Federation: 120

Country: Number of subjects enrolled

Serbia: 10

Worldwide total number of subjects

400

EEA total number of subjects

181

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)

320

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Male or female, in-or-out patients: children (from 7 to less than 12 years old) and adolescents (from 12 to less than 18 years old). Primary diagnosis of Major Depressive Disorder (MDD), single or recurrent episode, of moderate to severe intensity, fulfilling DSM-IV-TR, CDRS-R Raw score > or = 45, CGI-S score > or = 4.

Period 1 title

Double-blind period - Total population

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Agomelatine 10 mg - Total population

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg in the evening at bedtime.

Agomelatine 25 mg - Total population

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 25 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 25 mg in the evening at bedtime.

Placebo - Total population

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of placebo in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of placebo in the evening at bedtime.

Fluoxetine - Total population

Arm description

Arm type

Active comparator

Investigational medicinal product name

Fluoxetine

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

From W0 to W2: 2.5 mL (10 mg) of oral solution of fluoxetine in the morning at wake-up, 1 tablet of placebo in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double leading to an increased dose: 5 mL (20 mg) of oral solution of fluoxetine in the morning at wake-up, 1 tablet of placebo in the evening at bedtime.

Number of subjects in period 1	Agomelatine 10 mg - Total population	Agomelatine 25 mg - Total population	Placebo - Total population	Fluoxetine - Total population
Started	102	95	103	100
Completed	94	84	87	87
Not completed	8	11	16	13
Non medical reason	3	7	12	9
Adverse event, non-fatal	2	3	2	3
Lack of efficacy	3	1	2	-
Protocol deviation	-	-	-	1

Period 2 title

Double-blind period - Adolescents

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Agomelatine 10 mg - Adolescents

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Agomelatine 25 mg - Adolescents

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo - Adolescents

Arm description

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Fluoxetine - Adolescents

Arm description

Arm type

Experimental

Investigational medicinal product name

Fluoxetine

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 2	Agomelatine 10 mg - Adolescents	Agomelatine 25 mg - Adolescents	Placebo - Adolescents	Fluoxetine - Adolescents
Started	81	76	82	81
Completed	73	68	71	71
Not completed	8	8	11	10
Non medical reason	3	5	8	6
Adverse event, non-fatal	2	2	1	3
Lack of efficacy	3	1	2	-
Protocol deviation	-	-	-	1

Period 3 title

Double-blind period - Children

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Agomelatine 10 mg - Children

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Agomelatine 25 mg - Children

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo - Children

Arm description

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution, Tablet

Routes of administration

Oral use

Dosage and administration details

Fluoxetine - Children

Arm description

Arm type

Experimental

Investigational medicinal product name

Fluoxetine

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 3	Agomelatine 10 mg - Children	Agomelatine 25 mg - Children	Placebo - Children	Fluoxetine - Children
Started	21	19	21	19
Completed	21	16	16	16
Not completed	0	3	5	3
Non medical reason	-	2	4	3
Adverse event, non-fatal	-	1	1	-

Period 4 title

Open-label Period - Total population

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

From W12 to W14, patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were in the agomelatine 10 mg or agomelatine 25 mg groups.

Placebo / Agomelatine 10-25 mg - W012-W104 period

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

From W12 to W14, all patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were on placebo.

Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

All - W012-W104 period

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 4	Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period	Placebo / Agomelatine 10-25 mg - W012-W104 period	Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period	All - W012-W104 period
Started	170	85	84	339
Completed	93	48	46	187
Not completed	77	37	38	152
Recovery	40	14	15	69
Non medical reason	25	12	17	54
Adverse event, non-fatal	6	5	3	14
Lost to follow-up	1	1	-	2
Lack of efficacy	4	2	2	8
Protocol deviation	1	3	1	5

Period 5 title

Open-label Period - Adolescents

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

From W12 to W14, adolescent patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were in the agomelatine 10 mg or agomelatine 25 mg groups.

Placebo / Agomelatine 10-25 mg - Ado - W012-W104

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

From W12 to W14, adolescents took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient. During the double-blind period (W0-W12), those patients were on placebo.

Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012-W104

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

All - Adolescents - W012-W104

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 5	Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104	Placebo / Agomelatine 10-25 mg - Ado - W012-W104	Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012-W104	All - Adolescents - W012-W104
Started	134	69	68	271
Completed	71	38	36	145
Not completed	63	31	32	126
Recovery	31	11	13	55
Non medical reason	23	9	14	46
Adverse event, non-fatal	3	5	3	11
Lost to follow-up	1	1	-	2
Protocol deviation	1	3	1	5
Lack of efficacy	4	2	1	7

Period 6 title

Study period W000-W104

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg or agomelatine 25 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg or agomelatine 25 mg in the evening at bedtime. From W12 to W14, patients took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient.

Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104

Arm description

Arm type

Experimental

Investigational medicinal product name

Agomelatine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

From W0 to W2: 2.5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg or agomelatine 25 mg in the evening at bedtime. From W2 to W12, patients with a sufficient improvement remained on the initial dose. In case of insufficient improvement according to the investigator’s clinical judgement, the volume of oral solution could double: 5 mL of oral solution of placebo in the morning at wake-up, 1 tablet of agomelatine 10 mg or agomelatine 25 mg in the evening at bedtime. From W12 to W14, adolescents took 1 tablet of agomelatine 10 mg in the evening at bedtime. From W14 to W104, the dose of agomelatine could be adjusted (flexible dose, either to increase to 25 mg or to decrease again to 10 mg) at each visit by investigator based on the clinical picture of patient.

Number of subjects in period 6	Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period	Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104
Started	170	134
Completed	93	71
Not completed	77	63
Recovery	40	31
Non medical reason	25	23
Adverse event, non-fatal	6	3
Lost to follow-up	1	1
Lack of efficacy	4	4
Protocol deviation	1	1

Baseline characteristics

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Reporting group title

Agomelatine 10 mg - Total population

Reporting group description

Reporting group title

Agomelatine 25 mg - Total population

Reporting group description

Reporting group title

Placebo - Total population

Reporting group description

Reporting group title

Fluoxetine - Total population

Reporting group description

Reporting group values	Agomelatine 10 mg - Total population	Agomelatine 25 mg - Total population	Placebo - Total population	Fluoxetine - Total population	Total
Number of subjects	102	95	103	100	400
Age categorical
Units: Subjects
Children (2-11 years)	21	19	21	19	80
Adolescents (12-17 years)	81	76	82	81	320
Age continuous
Units: years
arithmetic mean (standard deviation)	13.6 ± 2.9	13.4 ± 2.7	13.8 ± 2.6	13.8 ± 2.7	-
Gender categorical
Units: Subjects
Female	68	61	64	57	250
Male	34	34	39	43	150

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all patients of the Modified Randomised Set (MRS) having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint. MRS: All included and randomised patients (i.e. all included patients to whom a therapeutic unit was randomly assigned using IRS).

Subject analysis set title

Adolescents of the Full Analysis Set (FAS_ADO)

Subject analysis set type

Full analysis

Subject analysis set description

In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all adolescents patients of the MRS having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint.

Subject analysis set title

Children of the Full Analysis Set (FAS_CHILD)

Subject analysis set type

Full analysis

Subject analysis set description

In accordance with the intention-to-treat principle and the section 5.2.1 of ICH E9 guideline, all children patients of the MRS having taken at least one dose of IMP and having a value at baseline and at least one post-baseline value for the primary efficacy endpoint.

Subject analysis sets values	Full Analysis Set (FAS)	Adolescents of the Full Analysis Set (FAS_ADO)	Children of the Full Analysis Set (FAS_CHILD)
Number of subjects	396	317	79
Age categorical
Units: Subjects
Children (2-11 years)	79
Adolescents (12-17 years)	317
Age continuous
Units: years
arithmetic mean (standard deviation)	13.7 ± 2.7	14.8 ± 1.6	9.2 ± 1.3
Gender categorical
Units: Subjects
Female	247	216	31
Male	149	101	48

End points

Top of page

Reporting group title

Agomelatine 10 mg - Total population

Reporting group description

Reporting group title

Agomelatine 25 mg - Total population

Reporting group description

Reporting group title

Placebo - Total population

Reporting group description

Reporting group title

Fluoxetine - Total population

Reporting group description

Reporting group title

Agomelatine 10 mg - Adolescents

Reporting group description

Reporting group title

Agomelatine 25 mg - Adolescents

Reporting group description

Reporting group title

Placebo - Adolescents

Reporting group description

Reporting group title

Fluoxetine - Adolescents

Reporting group description

Reporting group title

Agomelatine 10 mg - Children

Reporting group description

Reporting group title

Agomelatine 25 mg - Children

Reporting group description

Reporting group title

Placebo - Children

Reporting group description

Reporting group title

Fluoxetine - Children

Reporting group description

Reporting group title

Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period

Reporting group description

Reporting group title

Placebo / Agomelatine 10-25 mg - W012-W104 period

Reporting group description

Reporting group title

Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period

Reporting group description

Reporting group title

All - W012-W104 period

Reporting group description

Reporting group title

Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104

Reporting group description

Reporting group title

Placebo / Agomelatine 10-25 mg - Ado - W012-W104

Reporting group description

Reporting group title

Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012-W104

Reporting group description

Reporting group title

All - Adolescents - W012-W104

Reporting group description

Reporting group title

Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period

Reporting group description

Reporting group title

Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104

Reporting group description

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Adolescents of the Full Analysis Set (FAS_ADO)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Children of the Full Analysis Set (FAS_CHILD)

Subject analysis set type

Full analysis

Subject analysis set description

Primary: CDRS-R raw total score: change from baseline to W12 (Total population of the FAS)

Top of page

End point title

CDRS-R raw total score: change from baseline to W12 (Total population of the FAS)

End point description

The superiority of each agomelatine dose as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. The CDRS-R was used to assess the diagnosis and severity of the current depressed episode in children and adolescents. This is a 17-item clinician rated instrument integrating multiple-source information. Each of them can be rated within the ranges of 1-5 or 1-7. The total score ranges from 17 (normal) to 113 (severe depression). The rater has to: - complete the rating scale during 2 separate interviews: 1 with the patient and 1 with the parent(s)/legally authorized representative(s). - fill in the rating comments for each item, from both sources. - evaluate the symptoms rating from both sources and provide/define the “best description of the child”. - enter in the e-CRF the final rated values of each item corresponding to the “best description of the child” an

End point type

Primary

End point timeframe

The Children’s Depression Rating Scale-Revised (CDRS-R) (Poznanski & Mokros, 1996) was assessed by the investigator at each visit from the selection visit to W12.

End point values	Agomelatine 10 mg - Total population	Agomelatine 25 mg - Total population	Placebo - Total population	Fluoxetine - Total population
Number of subjects analysed	102	94	101	99
Units: No unit
arithmetic mean (standard deviation)	-20.9 ± 14.0	-22.5 ± 15.2	-19.7 ± 14.4	-21.7 ± 14.1

Placebo minus agomelatine 10 mg

Statistical analysis description

The superiority of agomelatine 10 mg as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. A three-way analysis of covariance (ANCOVA) model was used. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.

Comparison groups

Agomelatine 10 mg - Total population v Placebo - Total population

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.079 ^[1]

Method

ANCOVA

Parameter type

Estimate of the adjusted difference

Point estimate

3.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

6.73

Variability estimate

Standard error of the mean

Dispersion value

1.81

Notes
[1] - Dunnett-adjusted p-value

Placebo minus agomelatine 25 mg

Statistical analysis description

The superiority of agomelatine 25 mg as compared to placebo on antidepressant efficacy after a 12-week treatment period was assessed, from the CDRS-R raw total score expressed in terms of change from baseline to W12. A three-way analysis of covariance (ANCOVA) model was used. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.

Comparison groups

Agomelatine 25 mg - Total population v Placebo - Total population

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.04 ^[2]

Method

ANCOVA

Parameter type

Estimate of the adjusted difference

Point estimate

4.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.63

upper limit

7.82

Variability estimate

Standard error of the mean

Dispersion value

1.83

Notes
[2] - Dunnett-adjusted p-value

Placebo minus fluoxetine

Statistical analysis description

An assay sensitivity was studied with a three-way analysis of covariance (ANCOVA) model using the comparison of fluoxetine to placebo. Analysis included the fixed, categorical effects of treatment, age subgroup and country, and the continuous, fixed covariate of baseline. Missing data were imputed with the Last Observation Carried Forward (LOCF) approach.

Comparison groups

Placebo - Total population v Fluoxetine - Total population

Number of subjects included in analysis

200

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.039

Method

ANCOVA

Parameter type

Estimate of the difference

Point estimate

3.74

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

7.3

Variability estimate

Standard error of the mean

Dispersion value

1.81

Primary: CDRS-R raw total score: change from baseline to W12 (Adolescents of the FAS)

Top of page

End point title

CDRS-R raw total score: change from baseline to W12 (Adolescents of the FAS)

End point description

End point type

Primary

End point timeframe

The Children’s Depression Rating Scale-Revised (CDRS-R) (Poznanski & Mokros, 1996) was assessed by the investigator at each visit from the selection visit to W12.

End point values	Agomelatine 10 mg - Adolescents	Agomelatine 25 mg - Adolescents	Placebo - Adolescents	Fluoxetine - Adolescents
Number of subjects analysed	81	75	81	80
Units: No unit
arithmetic mean (standard error)	-21.1 ± 14.1	-23.8 ± 15.4	-19.8 ± 13.4	-22.0 ± 14.2

Placebo minus agomelatine 10 mg

Statistical analysis description

Comparison groups

Placebo - Adolescents v Agomelatine 10 mg - Adolescents

Number of subjects included in analysis

162

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.132 ^[3]

Method

ANCOVA

Parameter type

Estimate of the adjusted difference

Point estimate

3.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.96

upper limit

7.32

Variability estimate

Standard error of the mean

Dispersion value

2.11

Notes
[3] - Dunnett-adjusted p-value

Placebo minus agomelatine 25 mg

Statistical analysis description

Comparison groups

Placebo - Adolescents v Agomelatine 25 mg - Adolescents

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.028 ^[4]

Method

ANCOVA

Parameter type

Estimate of the adjusted difference

Point estimate

5.22

Confidence interval

level

95%

sides

2-sided

lower limit

1.03

upper limit

9.4

Variability estimate

Standard error of the mean

Dispersion value

2.13

Notes
[4] - Dunnett-adjusted p-value

Placebo minus fluoxetine

Statistical analysis description

Comparison groups

Placebo - Adolescents v Fluoxetine - Adolescents

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.079

Method

ANCOVA

Parameter type

Estimate of the difference

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.43

upper limit

7.84

Variability estimate

Standard error of the mean

Dispersion value

2.1

Primary: CDRS-R raw total score: change from baseline to W12 (Children of the FAS)

Top of page

End point title

CDRS-R raw total score: change from baseline to W12 (Children of the FAS) ^[5]

End point description

The CDRS-R was used to assess the diagnosis and severity of the current depressed episode in children and adolescents. This is a 17-item clinician rated instrument integrating multiple-source information. Each of them can be rated within the ranges of 1-5 or 1-7. The total score ranges from 17 (normal) to 113 (severe depression). The rater has to: - complete the rating scale during 2 separate interviews: 1 with the patient and 1 with the parent(s)/legally authorized representative(s). - fill in the rating comments for each item, from both sources. - evaluate the symptoms rating from both sources and provide/define the “best description of the child”. - enter in the e-CRF the final rated values of each item corresponding to the “best description of the child” and the corresponding Raw summary score.

End point type

Primary

End point timeframe

The Children’s Depression Rating Scale-Revised (CDRS-R) (Poznanski & Mokros, 1996) was assessed by the investigator at each visit from the selection visit to W12.

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: No statistical inferences for children

End point values	Agomelatine 10 mg - Children	Agomelatine 25 mg - Children	Placebo - Children	Fluoxetine - Children
Number of subjects analysed	21	19	20	19
Units: No unit
arithmetic mean (standard deviation)	-20.0 ± 13.9	-17.1 ± 13.3	-19.0 ± 18.3	-20.7 ± 14.4

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

All adverse events which occurred or worsen or became serious according to the investigator, or upgraded by the Sponsor, between the first IMP intake date (included) and the last IMP intake date + 1 day (included).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Agomelatine 10 mg - Total population

Reporting group description

Reporting group title

Agomelatine 25 mg - Total population

Reporting group description

Reporting group title

Placebo - Total population

Reporting group description

Reporting group title

Fluoxetine - Total population

Reporting group description

Reporting group title

Agomelatine 10 mg - Adolescents

Reporting group description

Reporting group title

Agomelatine 25 mg - Adolescents

Reporting group description

Reporting group title

Placebo - Adolescents

Reporting group description

Reporting group title

Fluoxetine - Adolescents

Reporting group description

Reporting group title

Agomelatine 10 mg - Children

Reporting group description

Reporting group title

Agomelatine 25 mg - Children

Reporting group description

Reporting group title

Placebo - Children

Reporting group description

Reporting group title

Fluoxetine - Children

Reporting group description

Reporting group title

Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period

Reporting group description

Reporting group title

Placebo / Agomelatine 10-25 mg - W012-W104 period

Reporting group description

Reporting group title

Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period

Reporting group description

Reporting group title

All - W012-W104 period

Reporting group description

Reporting group title

Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104

Reporting group description

Reporting group title

Placebo / Agomelatine 10-25 mg - Ado - W012-W104

Reporting group description

Reporting group title

Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012- W104

Reporting group description

Reporting group title

All - Adolescents - W012-W104

Reporting group description

Reporting group title

Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period

Reporting group description

Reporting group title

Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104

Reporting group description

Agomelatine 10 mg - Total population

Agomelatine 25 mg - Total population

Placebo - Total population

Fluoxetine - Total population

Agomelatine 10 mg - Adolescents

Agomelatine 25 mg - Adolescents

Placebo - Adolescents

Fluoxetine - Adolescents

Agomelatine 10 mg - Children

Agomelatine 25 mg - Children

Placebo - Children

Fluoxetine - Children

Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period

Placebo / Agomelatine 10-25 mg - W012-W104 period

Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period

All - W012-W104 period

Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104

Placebo / Agomelatine 10-25 mg - Ado - W012-W104

Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012- W104

All - Adolescents - W012-W104

Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period

Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104

Total subjects affected by serious adverse events

subjects affected / exposed

6 / 102 (5.88%)

3 / 94 (3.19%)

0 / 103 (0.00%)

7 / 100 (7.00%)

5 / 81 (6.17%)

2 / 75 (2.67%)

0 / 82 (0.00%)

7 / 81 (8.64%)

1 / 21 (4.76%)

1 / 19 (5.26%)

0 / 21 (0.00%)

0 / 19 (0.00%)

8 / 170 (4.71%)

12 / 85 (14.12%)

9 / 84 (10.71%)

29 / 339 (8.55%)

7 / 134 (5.22%)

11 / 69 (15.94%)

8 / 68 (11.76%)

26 / 271 (9.59%)

11 / 170 (6.47%)

8 / 134 (5.97%)

number of deaths (all causes)

number of deaths resulting from adverse events

Investigations

Alanine aminotransferase increased

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

1 / 100 (1.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

1 / 81 (1.23%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

2 / 85 (2.35%)

0 / 84 (0.00%)

2 / 339 (0.59%)

0 / 134 (0.00%)

2 / 69 (2.90%)

0 / 68 (0.00%)

2 / 271 (0.74%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Neutrophil count decreased

subjects affected / exposed

0 / 102 (0.00%)

1 / 94 (1.06%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

1 / 19 (5.26%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

1 / 170 (0.59%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

1 / 100 (1.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

1 / 81 (1.23%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

1 / 84 (1.19%)

2 / 339 (0.59%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Platelet count decreased

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

1 / 84 (1.19%)

2 / 339 (0.59%)

1 / 134 (0.75%)

0 / 69 (0.00%)

1 / 68 (1.47%)

2 / 271 (0.74%)

1 / 170 (0.59%)

1 / 134 (0.75%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 1

0 / 0

0 / 1

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Alcohol poisoning

subjects affected / exposed

1 / 102 (0.98%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

1 / 81 (1.23%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intentional overdose

subjects affected / exposed

0 / 102 (0.00%)

1 / 94 (1.06%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

1 / 75 (1.33%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

1 / 84 (1.19%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

1 / 68 (1.47%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fall

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

1 / 100 (1.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

1 / 81 (1.23%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Concussion

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

1 / 100 (1.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

1 / 81 (1.23%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ankle fracture

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

0 / 84 (0.00%)

1 / 339 (0.29%)

1 / 134 (0.75%)

0 / 69 (0.00%)

0 / 68 (0.00%)

1 / 271 (0.37%)

1 / 170 (0.59%)

1 / 134 (0.75%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Humerus fracture

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Liver contusion

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Meniscus injury

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary contusion

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rib fracture

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Road traffic accident

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Haemorrhagic vasculitis

subjects affected / exposed

1 / 102 (0.98%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

1 / 21 (4.76%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

1 / 170 (0.59%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Somnolence

subjects affected / exposed

0 / 102 (0.00%)

1 / 94 (1.06%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

1 / 75 (1.33%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

1 / 102 (0.98%)

0 / 94 (0.00%)

0 / 103 (0.00%)

2 / 100 (2.00%)

1 / 81 (1.23%)

0 / 75 (0.00%)

0 / 82 (0.00%)

2 / 81 (2.47%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

1 / 84 (1.19%)

2 / 339 (0.59%)

1 / 134 (0.75%)

0 / 69 (0.00%)

1 / 68 (1.47%)

2 / 271 (0.74%)

2 / 170 (1.18%)

2 / 134 (1.49%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 1

0 / 0

0 / 1

0 / 2

deaths causally related to treatment / all

0 / 0

Cerebral cyst

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

1 / 170 (0.59%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Thrombocytopenia

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

0 / 84 (0.00%)

1 / 339 (0.29%)

1 / 134 (0.75%)

0 / 69 (0.00%)

0 / 68 (0.00%)

1 / 271 (0.37%)

1 / 170 (0.59%)

1 / 134 (0.75%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Pancreatitis

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

0 / 84 (0.00%)

1 / 339 (0.29%)

1 / 134 (0.75%)

0 / 69 (0.00%)

0 / 68 (0.00%)

1 / 271 (0.37%)

1 / 170 (0.59%)

1 / 134 (0.75%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Abdominal pain

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastritis

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Anorexia nervosa

subjects affected / exposed

1 / 102 (0.98%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

1 / 81 (1.23%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Suicide attempt

subjects affected / exposed

0 / 102 (0.00%)

1 / 94 (1.06%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

1 / 75 (1.33%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

1 / 84 (1.19%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

1 / 68 (1.47%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Suicidal ideation

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

1 / 100 (1.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

1 / 81 (1.23%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

1 / 84 (1.19%)

2 / 339 (0.59%)

0 / 134 (0.00%)

1 / 69 (1.45%)

1 / 68 (1.47%)

2 / 271 (0.74%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Intentional self-injury

subjects affected / exposed

1 / 102 (0.98%)

1 / 94 (1.06%)

0 / 103 (0.00%)

1 / 100 (1.00%)

1 / 81 (1.23%)

1 / 75 (1.33%)

0 / 82 (0.00%)

1 / 81 (1.23%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Depression

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

3 / 85 (3.53%)

1 / 84 (1.19%)

4 / 339 (1.18%)

0 / 134 (0.00%)

3 / 69 (4.35%)

1 / 68 (1.47%)

4 / 271 (1.48%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 1

0 / 4

0 / 0

0 / 3

0 / 1

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Adjustment disorder

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

anger

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

drug abuse

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Emotional disorder of childhood

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Irritability

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mood swings

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

self-injurious ideation

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Suicidal behaviour

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Endocrine disorders

Goitre

subjects affected / exposed

0 / 102 (0.00%)

1 / 94 (1.06%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

1 / 75 (1.33%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypothyroidism

subjects affected / exposed

0 / 102 (0.00%)

1 / 94 (1.06%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

1 / 75 (1.33%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Appendicitis

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

1 / 100 (1.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

1 / 81 (1.23%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Measles

subjects affected / exposed

1 / 102 (0.98%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

1 / 81 (1.23%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infectious mononucleosis

subjects affected / exposed

1 / 102 (0.98%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

1 / 21 (4.76%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

0 / 84 (0.00%)

0 / 339 (0.00%)

0 / 134 (0.00%)

0 / 69 (0.00%)

0 / 68 (0.00%)

0 / 271 (0.00%)

1 / 170 (0.59%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

1 / 84 (1.19%)

2 / 339 (0.59%)

1 / 134 (0.75%)

0 / 69 (0.00%)

1 / 68 (1.47%)

2 / 271 (0.74%)

1 / 170 (0.59%)

1 / 134 (0.75%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 1

0 / 0

0 / 1

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 0

Respiratory tract infection

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

0 / 84 (0.00%)

1 / 339 (0.29%)

1 / 134 (0.75%)

0 / 69 (0.00%)

0 / 68 (0.00%)

1 / 271 (0.37%)

1 / 170 (0.59%)

1 / 134 (0.75%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Tonsillitis bacterial

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

1 / 84 (1.19%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

1 / 68 (1.47%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tracheitis

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

0 / 85 (0.00%)

1 / 84 (1.19%)

1 / 339 (0.29%)

0 / 134 (0.00%)

0 / 69 (0.00%)

1 / 68 (1.47%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Latent tetany

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

1 / 170 (0.59%)

0 / 85 (0.00%)

0 / 84 (0.00%)

1 / 339 (0.29%)

1 / 134 (0.75%)

0 / 69 (0.00%)

0 / 68 (0.00%)

1 / 271 (0.37%)

1 / 170 (0.59%)

1 / 134 (0.75%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Dehydration

subjects affected / exposed

0 / 102 (0.00%)

0 / 94 (0.00%)

0 / 103 (0.00%)

0 / 100 (0.00%)

0 / 81 (0.00%)

0 / 75 (0.00%)

0 / 82 (0.00%)

0 / 81 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 21 (0.00%)

0 / 19 (0.00%)

0 / 170 (0.00%)

1 / 85 (1.18%)

0 / 84 (0.00%)

1 / 339 (0.29%)

0 / 134 (0.00%)

1 / 69 (1.45%)

0 / 68 (0.00%)

1 / 271 (0.37%)

0 / 170 (0.00%)

0 / 134 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Agomelatine 10 mg - Total population	Agomelatine 25 mg - Total population	Placebo - Total population	Fluoxetine - Total population	Agomelatine 10 mg - Adolescents	Agomelatine 25 mg - Adolescents	Placebo - Adolescents	Fluoxetine - Adolescents	Agomelatine 10 mg - Children	Agomelatine 25 mg - Children	Placebo - Children	Fluoxetine - Children	Agomelatine 10 or 25 mg / 10-25 mg - W012-W104 period	Placebo / Agomelatine 10-25 mg - W012-W104 period	Fluoxetine 10-20 mg / Agomelatine 10-25 mg - W012-W104 period	All - W012-W104 period	Agomelatine 10 or 25 mg / 10-25 mg - Ado - W012-W104	Placebo / Agomelatine 10-25 mg - Ado - W012-W104	Fluoxetine 10-20 mg / Agomelatine 10-25 mg - Ado - W012- W104	All - Adolescents - W012-W104	Agomelatine 10 or 25 mg / 10-25 mg - W000-W104 period	Agomelatine 10 or 25 mg / 10-25 mg - Ado - W000-W104
Total subjects affected by non serious adverse events
subjects affected / exposed	61 / 102 (59.80%)	59 / 94 (62.77%)	63 / 103 (61.17%)	55 / 100 (55.00%)	50 / 81 (61.73%)	47 / 75 (62.67%)	49 / 82 (59.76%)	45 / 81 (55.56%)	11 / 21 (52.38%)	12 / 19 (63.16%)	14 / 21 (66.67%)	10 / 19 (52.63%)	102 / 170 (60.00%)	51 / 85 (60.00%)	49 / 84 (58.33%)	202 / 339 (59.59%)	77 / 134 (57.46%)	43 / 69 (62.32%)	39 / 68 (57.35%)	159 / 271 (58.67%)	136 / 170 (80.00%)	106 / 134 (79.10%)
General disorders and administration site conditions
Drug interaction
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 170 (0.00%)	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 339 (0.00%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	0 / 170 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Fatigue
subjects affected / exposed	5 / 102 (4.90%)	6 / 94 (6.38%)	7 / 103 (6.80%)	2 / 100 (2.00%)	4 / 81 (4.94%)	6 / 75 (8.00%)	4 / 82 (4.88%)	2 / 81 (2.47%)	1 / 21 (4.76%)	0 / 19 (0.00%)	3 / 21 (14.29%)	0 / 19 (0.00%)	6 / 170 (3.53%)	4 / 85 (4.71%)	2 / 84 (2.38%)	12 / 339 (3.54%)	5 / 134 (3.73%)	4 / 69 (5.80%)	1 / 68 (1.47%)	10 / 271 (3.69%)	14 / 170 (8.24%)	12 / 134 (8.96%)
occurrences all number	5	6	9	2	4	6	6	2	1	0	3	0	6	4	4	14	5	4	1	10	14	12
Thirst
subjects affected / exposed	16 / 102 (15.69%)	13 / 94 (13.83%)	10 / 103 (9.71%)	15 / 100 (15.00%)	15 / 81 (18.52%)	11 / 75 (14.67%)	9 / 82 (10.98%)	13 / 81 (16.05%)	1 / 21 (4.76%)	2 / 19 (10.53%)	1 / 21 (4.76%)	2 / 19 (10.53%)	7 / 170 (4.12%)	3 / 85 (3.53%)	2 / 84 (2.38%)	12 / 339 (3.54%)	5 / 134 (3.73%)	3 / 69 (4.35%)	2 / 68 (2.94%)	10 / 271 (3.69%)	26 / 170 (15.29%)	21 / 134 (15.67%)
occurrences all number	16	15	10	15	15	13	9	13	1	2	1	2	8	3	2	13	6	3	2	11	31	26
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	1 / 81 (1.23%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 170 (0.00%)	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 339 (0.00%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	0 / 170 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	1	0	1	0	0	0	1	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 102 (0.00%)	0 / 94 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 170 (0.59%)	0 / 85 (0.00%)	1 / 84 (1.19%)	2 / 339 (0.59%)	1 / 134 (0.75%)	0 / 69 (0.00%)	0 / 68 (0.00%)	1 / 271 (0.37%)	1 / 170 (0.59%)	1 / 134 (0.75%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1	1	0	1	2	1	0	0	0	1	1
Epistaxis
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 170 (0.59%)	0 / 85 (0.00%)	1 / 84 (1.19%)	2 / 339 (0.59%)	0 / 134 (0.00%)	0 / 69 (0.00%)	1 / 68 (1.47%)	1 / 271 (0.37%)	1 / 170 (0.59%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	2	0	1	3	0	0	1	1	3	0
Psychiatric disorders
Aggression
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	1 / 103 (0.97%)	5 / 100 (5.00%)	0 / 81 (0.00%)	1 / 75 (1.33%)	0 / 82 (0.00%)	3 / 81 (3.70%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 21 (4.76%)	2 / 19 (10.53%)	0 / 170 (0.00%)	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 339 (0.00%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	1 / 170 (0.59%)	1 / 134 (0.75%)
occurrences all number	0	1	1	5	0	1	0	3	0	0	1	2	0	0	0	0	0	0	0	0	1	1
Anxiety
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	2 / 103 (1.94%)	3 / 100 (3.00%)	0 / 81 (0.00%)	1 / 75 (1.33%)	2 / 82 (2.44%)	1 / 81 (1.23%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	2 / 19 (10.53%)	3 / 170 (1.76%)	1 / 85 (1.18%)	2 / 84 (2.38%)	6 / 339 (1.77%)	2 / 134 (1.49%)	1 / 69 (1.45%)	1 / 68 (1.47%)	4 / 271 (1.48%)	4 / 170 (2.35%)	3 / 134 (2.24%)
occurrences all number	0	1	2	3	0	1	2	1	0	0	0	2	3	1	2	6	2	1	1	4	4	3
Impulsive behaviour
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	2 / 100 (2.00%)	0 / 81 (0.00%)	1 / 75 (1.33%)	0 / 82 (0.00%)	1 / 81 (1.23%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 170 (0.00%)	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 339 (0.00%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	1 / 170 (0.59%)	1 / 134 (0.75%)
occurrences all number	0	1	0	2	0	1	0	1	0	0	0	1	0	0	0	0	0	0	0	0	1	1
Learning disability
subjects affected / exposed	0 / 102 (0.00%)	0 / 94 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 170 (0.00%)	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 339 (0.00%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	0 / 170 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	2 / 100 (2.00%)	0 / 81 (0.00%)	1 / 75 (1.33%)	0 / 82 (0.00%)	1 / 81 (1.23%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	4 / 170 (2.35%)	1 / 85 (1.18%)	0 / 84 (0.00%)	5 / 339 (1.47%)	4 / 134 (2.99%)	1 / 69 (1.45%)	0 / 68 (0.00%)	5 / 271 (1.85%)	4 / 170 (2.35%)	4 / 134 (2.99%)
occurrences all number	0	1	0	2	0	1	0	1	0	0	0	1	4	1	0	5	4	1	0	5	4	4
Blood glucose increased
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 170 (0.00%)	1 / 85 (1.18%)	0 / 84 (0.00%)	1 / 339 (0.29%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	1 / 170 (0.59%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0	1	0	1	0	0	0	0	1	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	1 / 102 (0.98%)	2 / 94 (2.13%)	2 / 103 (1.94%)	2 / 100 (2.00%)	0 / 81 (0.00%)	2 / 75 (2.67%)	2 / 82 (2.44%)	1 / 81 (1.23%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	3 / 170 (1.76%)	0 / 85 (0.00%)	0 / 84 (0.00%)	3 / 339 (0.88%)	3 / 134 (2.24%)	0 / 69 (0.00%)	0 / 68 (0.00%)	3 / 271 (1.11%)	6 / 170 (3.53%)	5 / 134 (3.73%)
occurrences all number	1	2	2	2	0	2	2	1	1	0	0	1	3	0	0	3	3	0	0	3	6	5
Electrocardiogram PR shortened
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 170 (0.59%)	0 / 85 (0.00%)	0 / 84 (0.00%)	1 / 339 (0.29%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	1 / 170 (0.59%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	1	0	0	1	0	0	0	0	1	0
Haemoglobin decreased
subjects affected / exposed	1 / 102 (0.98%)	1 / 94 (1.06%)	0 / 103 (0.00%)	0 / 100 (0.00%)	1 / 81 (1.23%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 170 (0.59%)	1 / 85 (1.18%)	2 / 84 (2.38%)	4 / 339 (1.18%)	1 / 134 (0.75%)	1 / 69 (1.45%)	2 / 68 (2.94%)	4 / 271 (1.48%)	2 / 170 (1.18%)	1 / 134 (0.75%)
occurrences all number	1	1	0	0	1	0	0	0	0	1	0	0	1	1	2	4	1	1	2	4	3	2
Weight increased
subjects affected / exposed	6 / 102 (5.88%)	5 / 94 (5.32%)	0 / 103 (0.00%)	2 / 100 (2.00%)	4 / 81 (4.94%)	4 / 75 (5.33%)	0 / 82 (0.00%)	1 / 81 (1.23%)	2 / 21 (9.52%)	1 / 19 (5.26%)	0 / 21 (0.00%)	1 / 19 (5.26%)	8 / 170 (4.71%)	4 / 85 (4.71%)	1 / 84 (1.19%)	13 / 339 (3.83%)	7 / 134 (5.22%)	3 / 69 (4.35%)	0 / 68 (0.00%)	10 / 271 (3.69%)	15 / 170 (8.82%)	12 / 134 (8.96%)
occurrences all number	6	5	0	2	4	4	0	1	2	1	0	1	8	4	1	13	7	3	0	10	16	13
Blood prolactin increased
subjects affected / exposed	4 / 102 (3.92%)	1 / 94 (1.06%)	1 / 103 (0.97%)	0 / 100 (0.00%)	3 / 81 (3.70%)	1 / 75 (1.33%)	1 / 82 (1.22%)	0 / 81 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	8 / 170 (4.71%)	1 / 85 (1.18%)	3 / 84 (3.57%)	12 / 339 (3.54%)	4 / 134 (2.99%)	1 / 69 (1.45%)	2 / 68 (2.94%)	7 / 271 (2.58%)	11 / 170 (6.47%)	6 / 134 (4.48%)
occurrences all number	4	1	1	0	3	1	1	0	1	0	0	0	8	1	3	12	4	1	2	7	12	7
Blood bilirubin increased
subjects affected / exposed	3 / 102 (2.94%)	2 / 94 (2.13%)	1 / 103 (0.97%)	0 / 100 (0.00%)	3 / 81 (3.70%)	2 / 75 (2.67%)	1 / 82 (1.22%)	0 / 81 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	2 / 170 (1.18%)	1 / 85 (1.18%)	0 / 84 (0.00%)	3 / 339 (0.88%)	2 / 134 (1.49%)	1 / 69 (1.45%)	0 / 68 (0.00%)	3 / 271 (1.11%)	7 / 170 (4.12%)	7 / 134 (5.22%)
occurrences all number	3	2	1	0	3	2	1	0	0	0	0	0	2	1	0	3	2	1	0	3	7	7
Injury, poisoning and procedural complications
Limb injury
subjects affected / exposed	0 / 102 (0.00%)	0 / 94 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 170 (0.00%)	1 / 85 (1.18%)	0 / 84 (0.00%)	1 / 339 (0.29%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	0 / 170 (0.00%)	0 / 134 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1	0	1	0	1	0	0	0	0	0	0
Cardiac disorders
Bundle branch block right
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 170 (0.59%)	0 / 85 (0.00%)	0 / 84 (0.00%)	1 / 339 (0.29%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	1 / 170 (0.59%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	1	0	0	1	0	0	0	0	1	0
Nervous system disorders
Disturbance in attention
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	2 / 103 (1.94%)	1 / 100 (1.00%)	0 / 81 (0.00%)	1 / 75 (1.33%)	1 / 82 (1.22%)	0 / 81 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 21 (4.76%)	1 / 19 (5.26%)	1 / 170 (0.59%)	1 / 85 (1.18%)	0 / 84 (0.00%)	2 / 339 (0.59%)	1 / 134 (0.75%)	1 / 69 (1.45%)	0 / 68 (0.00%)	2 / 271 (0.74%)	1 / 170 (0.59%)	1 / 134 (0.75%)
occurrences all number	0	1	2	1	0	1	1	0	0	0	1	1	1	1	0	2	1	1	0	2	1	1
Dizziness postural
subjects affected / exposed	2 / 102 (1.96%)	5 / 94 (5.32%)	1 / 103 (0.97%)	2 / 100 (2.00%)	2 / 81 (2.47%)	5 / 75 (6.67%)	1 / 82 (1.22%)	2 / 81 (2.47%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	3 / 170 (1.76%)	0 / 85 (0.00%)	2 / 84 (2.38%)	5 / 339 (1.47%)	5 / 134 (3.73%)	0 / 69 (0.00%)	2 / 68 (2.94%)	5 / 271 (1.85%)	9 / 170 (5.29%)	9 / 134 (6.72%)
occurrences all number	2	5	1	2	2	5	1	2	0	0	0	0	3	0	2	5	5	0	2	5	9	9
Headache
subjects affected / exposed	16 / 102 (15.69%)	11 / 94 (11.70%)	14 / 103 (13.59%)	11 / 100 (11.00%)	13 / 81 (16.05%)	7 / 75 (9.33%)	12 / 82 (14.63%)	9 / 81 (11.11%)	3 / 21 (14.29%)	4 / 19 (21.05%)	2 / 21 (9.52%)	2 / 19 (10.53%)	21 / 170 (12.35%)	10 / 85 (11.76%)	9 / 84 (10.71%)	40 / 339 (11.80%)	19 / 134 (14.18%)	9 / 69 (13.04%)	9 / 68 (13.24%)	37 / 271 (13.65%)	40 / 170 (23.53%)	32 / 134 (23.88%)
occurrences all number	21	15	14	11	17	9	12	9	4	6	2	2	32	11	11	54	30	10	11	51	65	54
Dizziness
subjects affected / exposed	4 / 102 (3.92%)	3 / 94 (3.19%)	4 / 103 (3.88%)	3 / 100 (3.00%)	4 / 81 (4.94%)	3 / 75 (4.00%)	3 / 82 (3.66%)	3 / 81 (3.70%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	5 / 170 (2.94%)	2 / 85 (2.35%)	4 / 84 (4.76%)	11 / 339 (3.24%)	5 / 134 (3.73%)	2 / 69 (2.90%)	3 / 68 (4.41%)	10 / 271 (3.69%)	10 / 170 (5.88%)	10 / 134 (7.46%)
occurrences all number	5	3	4	3	5	3	3	3	0	0	1	0	6	2	4	12	6	2	3	11	13	13
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	8 / 102 (7.84%)	7 / 94 (7.45%)	7 / 103 (6.80%)	4 / 100 (4.00%)	5 / 81 (6.17%)	5 / 75 (6.67%)	6 / 82 (7.32%)	3 / 81 (3.70%)	3 / 21 (14.29%)	2 / 19 (10.53%)	1 / 21 (4.76%)	1 / 19 (5.26%)	5 / 170 (2.94%)	5 / 85 (5.88%)	1 / 84 (1.19%)	11 / 339 (3.24%)	4 / 134 (2.99%)	3 / 69 (4.35%)	1 / 68 (1.47%)	8 / 271 (2.95%)	17 / 170 (10.00%)	11 / 134 (8.21%)
occurrences all number	9	8	10	4	6	5	8	3	3	3	2	1	5	7	1	13	4	3	1	8	21	14
Diarrhoea
subjects affected / exposed	6 / 102 (5.88%)	4 / 94 (4.26%)	6 / 103 (5.83%)	8 / 100 (8.00%)	5 / 81 (6.17%)	3 / 75 (4.00%)	5 / 82 (6.10%)	8 / 81 (9.88%)	1 / 21 (4.76%)	1 / 19 (5.26%)	1 / 21 (4.76%)	0 / 19 (0.00%)	2 / 170 (1.18%)	4 / 85 (4.71%)	2 / 84 (2.38%)	8 / 339 (2.36%)	2 / 134 (1.49%)	4 / 69 (5.80%)	1 / 68 (1.47%)	7 / 271 (2.58%)	11 / 170 (6.47%)	9 / 134 (6.72%)
occurrences all number	6	5	7	9	5	4	6	9	1	1	1	0	2	5	4	11	2	5	2	9	13	11
Dry mouth
subjects affected / exposed	21 / 102 (20.59%)	13 / 94 (13.83%)	11 / 103 (10.68%)	13 / 100 (13.00%)	18 / 81 (22.22%)	10 / 75 (13.33%)	10 / 82 (12.20%)	11 / 81 (13.58%)	3 / 21 (14.29%)	3 / 19 (15.79%)	1 / 21 (4.76%)	2 / 19 (10.53%)	7 / 170 (4.12%)	0 / 85 (0.00%)	2 / 84 (2.38%)	9 / 339 (2.65%)	5 / 134 (3.73%)	0 / 69 (0.00%)	2 / 68 (2.94%)	7 / 271 (2.58%)	31 / 170 (18.24%)	24 / 134 (17.91%)
occurrences all number	21	14	12	13	18	11	11	11	3	3	1	2	7	0	2	9	5	0	2	7	37	29
Nausea
subjects affected / exposed	10 / 102 (9.80%)	12 / 94 (12.77%)	14 / 103 (13.59%)	9 / 100 (9.00%)	9 / 81 (11.11%)	10 / 75 (13.33%)	12 / 82 (14.63%)	8 / 81 (9.88%)	1 / 21 (4.76%)	2 / 19 (10.53%)	2 / 21 (9.52%)	1 / 19 (5.26%)	5 / 170 (2.94%)	9 / 85 (10.59%)	4 / 84 (4.76%)	18 / 339 (5.31%)	3 / 134 (2.24%)	8 / 69 (11.59%)	4 / 68 (5.88%)	15 / 271 (5.54%)	24 / 170 (14.12%)	19 / 134 (14.18%)
occurrences all number	11	14	17	9	10	12	15	8	1	2	2	1	5	12	5	22	3	9	5	17	28	23
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	3 / 102 (2.94%)	4 / 94 (4.26%)	2 / 103 (1.94%)	2 / 100 (2.00%)	2 / 81 (2.47%)	4 / 75 (5.33%)	2 / 82 (2.44%)	2 / 81 (2.47%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	4 / 170 (2.35%)	2 / 85 (2.35%)	0 / 84 (0.00%)	6 / 339 (1.77%)	2 / 134 (1.49%)	1 / 69 (1.45%)	0 / 68 (0.00%)	3 / 271 (1.11%)	9 / 170 (5.29%)	6 / 134 (4.48%)
occurrences all number	4	4	2	2	3	4	2	2	1	0	0	0	4	2	0	6	2	1	0	3	10	7
Dermatitis allergic
subjects affected / exposed	0 / 102 (0.00%)	2 / 94 (2.13%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 81 (0.00%)	1 / 75 (1.33%)	0 / 82 (0.00%)	1 / 81 (1.23%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 170 (0.00%)	0 / 85 (0.00%)	0 / 84 (0.00%)	0 / 339 (0.00%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	1 / 170 (0.59%)	1 / 134 (0.75%)
occurrences all number	0	2	0	1	0	1	0	1	0	1	0	0	0	0	0	0	0	0	0	0	1	1
Endocrine disorders
Hyperprolactinaemia
subjects affected / exposed	2 / 102 (1.96%)	0 / 94 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	1 / 81 (1.23%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	2 / 170 (1.18%)	1 / 85 (1.18%)	3 / 84 (3.57%)	6 / 339 (1.77%)	1 / 134 (0.75%)	1 / 69 (1.45%)	2 / 68 (2.94%)	4 / 271 (1.48%)	2 / 170 (1.18%)	1 / 134 (0.75%)
occurrences all number	2	0	0	1	1	0	0	0	1	0	0	1	2	2	3	7	1	2	2	5	2	1
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	2 / 102 (1.96%)	3 / 94 (3.19%)	6 / 103 (5.83%)	1 / 100 (1.00%)	1 / 81 (1.23%)	3 / 75 (4.00%)	5 / 82 (6.10%)	1 / 81 (1.23%)	1 / 21 (4.76%)	0 / 19 (0.00%)	1 / 21 (4.76%)	0 / 19 (0.00%)	0 / 170 (0.00%)	1 / 85 (1.18%)	0 / 84 (0.00%)	1 / 339 (0.29%)	0 / 134 (0.00%)	0 / 69 (0.00%)	0 / 68 (0.00%)	0 / 271 (0.00%)	5 / 170 (2.94%)	4 / 134 (2.99%)
occurrences all number	2	3	6	1	1	3	5	1	1	0	1	0	0	2	0	2	0	0	0	0	5	4
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 102 (0.00%)	0 / 94 (0.00%)	1 / 103 (0.97%)	2 / 100 (2.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	1 / 82 (1.22%)	1 / 81 (1.23%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	3 / 170 (1.76%)	0 / 85 (0.00%)	0 / 84 (0.00%)	3 / 339 (0.88%)	2 / 134 (1.49%)	0 / 69 (0.00%)	0 / 68 (0.00%)	2 / 271 (0.74%)	3 / 170 (1.76%)	2 / 134 (1.49%)
occurrences all number	0	0	1	2	0	0	1	1	0	0	0	1	3	0	0	3	2	0	0	2	3	2
Gastroenteritis
subjects affected / exposed	2 / 102 (1.96%)	0 / 94 (0.00%)	0 / 103 (0.00%)	1 / 100 (1.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	1 / 81 (1.23%)	2 / 21 (9.52%)	0 / 19 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 170 (0.00%)	0 / 85 (0.00%)	1 / 84 (1.19%)	1 / 339 (0.29%)	0 / 134 (0.00%)	0 / 69 (0.00%)	1 / 68 (1.47%)	1 / 271 (0.37%)	1 / 170 (0.59%)	0 / 134 (0.00%)
occurrences all number	2	0	0	1	0	0	0	1	2	0	0	0	0	0	1	1	0	0	1	1	1	0
Gastrointestinal infection
subjects affected / exposed	1 / 102 (0.98%)	0 / 94 (0.00%)	1 / 103 (0.97%)	2 / 100 (2.00%)	1 / 81 (1.23%)	0 / 75 (0.00%)	0 / 82 (0.00%)	1 / 81 (1.23%)	0 / 21 (0.00%)	0 / 19 (0.00%)	1 / 21 (4.76%)	1 / 19 (5.26%)	1 / 170 (0.59%)	0 / 85 (0.00%)	0 / 84 (0.00%)	1 / 339 (0.29%)	1 / 134 (0.75%)	0 / 69 (0.00%)	0 / 68 (0.00%)	1 / 271 (0.37%)	2 / 170 (1.18%)	2 / 134 (1.49%)
occurrences all number	1	0	1	2	1	0	0	1	0	0	1	1	2	0	0	2	2	0	0	2	3	3
Gastrointestinal viral infection
subjects affected / exposed	1 / 102 (0.98%)	1 / 94 (1.06%)	4 / 103 (3.88%)	0 / 100 (0.00%)	1 / 81 (1.23%)	0 / 75 (0.00%)	1 / 82 (1.22%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	3 / 21 (14.29%)	0 / 19 (0.00%)	1 / 170 (0.59%)	0 / 85 (0.00%)	0 / 84 (0.00%)	1 / 339 (0.29%)	1 / 134 (0.75%)	0 / 69 (0.00%)	0 / 68 (0.00%)	1 / 271 (0.37%)	2 / 170 (1.18%)	1 / 134 (0.75%)
occurrences all number	1	1	4	0	1	0	1	0	0	1	3	0	1	0	0	1	1	0	0	1	2	1
Nasopharyngitis
subjects affected / exposed	3 / 102 (2.94%)	5 / 94 (5.32%)	3 / 103 (2.91%)	1 / 100 (1.00%)	1 / 81 (1.23%)	4 / 75 (5.33%)	3 / 82 (3.66%)	1 / 81 (1.23%)	2 / 21 (9.52%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	11 / 170 (6.47%)	9 / 85 (10.59%)	4 / 84 (4.76%)	24 / 339 (7.08%)	8 / 134 (5.97%)	7 / 69 (10.14%)	2 / 68 (2.94%)	17 / 271 (6.27%)	19 / 170 (11.18%)	13 / 134 (9.70%)
occurrences all number	3	5	3	1	1	4	3	1	2	1	0	0	15	11	4	30	12	8	2	22	23	17
Pharyngitis bacterial
subjects affected / exposed	0 / 102 (0.00%)	0 / 94 (0.00%)	0 / 103 (0.00%)	2 / 100 (2.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	1 / 81 (1.23%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 170 (0.59%)	1 / 85 (1.18%)	0 / 84 (0.00%)	2 / 339 (0.59%)	1 / 134 (0.75%)	1 / 69 (1.45%)	0 / 68 (0.00%)	2 / 271 (0.74%)	1 / 170 (0.59%)	1 / 134 (0.75%)
occurrences all number	0	0	0	2	0	0	0	1	0	0	0	1	1	1	0	2	1	1	0	2	1	1
Respiratory tract infection viral
subjects affected / exposed	1 / 102 (0.98%)	1 / 94 (1.06%)	3 / 103 (2.91%)	2 / 100 (2.00%)	1 / 81 (1.23%)	0 / 75 (0.00%)	2 / 82 (2.44%)	1 / 81 (1.23%)	0 / 21 (0.00%)	1 / 19 (5.26%)	1 / 21 (4.76%)	1 / 19 (5.26%)	6 / 170 (3.53%)	2 / 85 (2.35%)	1 / 84 (1.19%)	9 / 339 (2.65%)	2 / 134 (1.49%)	1 / 69 (1.45%)	1 / 68 (1.47%)	4 / 271 (1.48%)	7 / 170 (4.12%)	3 / 134 (2.24%)
occurrences all number	2	1	3	2	2	0	2	1	0	1	1	1	7	2	1	10	2	1	1	4	9	4
Upper respiratory tract infection
subjects affected / exposed	1 / 102 (0.98%)	0 / 94 (0.00%)	1 / 103 (0.97%)	1 / 100 (1.00%)	1 / 81 (1.23%)	0 / 75 (0.00%)	1 / 82 (1.22%)	0 / 81 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	4 / 170 (2.35%)	2 / 85 (2.35%)	3 / 84 (3.57%)	9 / 339 (2.65%)	2 / 134 (1.49%)	2 / 69 (2.90%)	2 / 68 (2.94%)	6 / 271 (2.21%)	5 / 170 (2.94%)	3 / 134 (2.24%)
occurrences all number	1	0	1	1	1	0	1	0	0	0	0	1	6	3	4	13	3	3	2	8	7	4
Viral upper respiratory tract infection
subjects affected / exposed	1 / 102 (0.98%)	1 / 94 (1.06%)	2 / 103 (1.94%)	0 / 100 (0.00%)	1 / 81 (1.23%)	0 / 75 (0.00%)	2 / 82 (2.44%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	6 / 170 (3.53%)	2 / 85 (2.35%)	0 / 84 (0.00%)	8 / 339 (2.36%)	3 / 134 (2.24%)	2 / 69 (2.90%)	0 / 68 (0.00%)	5 / 271 (1.85%)	8 / 170 (4.71%)	4 / 134 (2.99%)
occurrences all number	1	2	2	0	1	0	2	0	0	2	0	0	7	2	0	9	3	2	0	5	10	4
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 102 (2.94%)	5 / 94 (5.32%)	7 / 103 (6.80%)	5 / 100 (5.00%)	1 / 81 (1.23%)	4 / 75 (5.33%)	4 / 82 (4.88%)	4 / 81 (4.94%)	2 / 21 (9.52%)	1 / 19 (5.26%)	3 / 21 (14.29%)	1 / 19 (5.26%)	8 / 170 (4.71%)	2 / 85 (2.35%)	3 / 84 (3.57%)	13 / 339 (3.83%)	8 / 134 (5.97%)	1 / 69 (1.45%)	3 / 68 (4.41%)	12 / 271 (4.43%)	15 / 170 (8.82%)	12 / 134 (8.96%)
occurrences all number	3	5	7	5	1	4	4	4	2	1	3	1	8	2	3	13	8	1	3	12	16	13
Food intolerance
subjects affected / exposed	0 / 102 (0.00%)	1 / 94 (1.06%)	0 / 103 (0.00%)	0 / 100 (0.00%)	0 / 81 (0.00%)	0 / 75 (0.00%)	0 / 82 (0.00%)	0 / 81 (0.00%)	0 / 21 (0.00%)	1 / 19 (5.26%)	0 / 21 (0.00%)	0 / 19 (0.00%)	0 / 170 (0.00%)	1 / 85 (1.18%)	0 / 84 (0.00%)	1 / 339 (0.29%)	0 / 134 (0.00%)	1 / 69 (1.45%)	0 / 68 (0.00%)	1 / 271 (0.37%)	1 / 170 (0.59%)	0 / 134 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0	1	0	1	0	1	0	1	1	0
Increased appetite
subjects affected / exposed	7 / 102 (6.86%)	6 / 94 (6.38%)	0 / 103 (0.00%)	3 / 100 (3.00%)	5 / 81 (6.17%)	6 / 75 (8.00%)	0 / 82 (0.00%)	3 / 81 (3.70%)	2 / 21 (9.52%)	0 / 19 (0.00%)	0 / 21 (0.00%)	0 / 19 (0.00%)	5 / 170 (2.94%)	0 / 85 (0.00%)	0 / 84 (0.00%)	5 / 339 (1.47%)	4 / 134 (2.99%)	0 / 69 (0.00%)	0 / 68 (0.00%)	4 / 271 (1.48%)	13 / 170 (7.65%)	11 / 134 (8.21%)
occurrences all number	7	6	0	3	5	6	0	3	2	0	0	0	5	0	0	5	4	0	0	4	15	12

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Were there any global substantial amendments to the protocol? Yes

19 Sep 2016

It mainly concerned: - Supplementary non-inclusion criteria for liver function: *Free bilirubin > 2 ULN (criterion n°63), to exclude patients with Gilbert-syndrome who could present unpredictable timing and level of free bilirubin levels. *ALP and GGT > 1 ULN (criterion n°65), to exclude patients in normal growth but with potential hepatic enzyme alterations. *In the inclusion criteria (n°56): the selection criteria on scales scores which had to be still fulfilled were specified in the text. - Measures concerning liver function tests: *Liver function tests (AST, ALT, total bilirubin, free bilirubin, conjugated bilirubin, ALP, GGT) were added during double-blind period (W004) and during open label extension period (W014, W048 and W068). *Close monitoring through blood samplings re-tests in case of abnormalities observed on ALT/AST, bilirubin, ALP or GGT was defined as a monitoring every two weeks. *In case of ALT/AST > 2ULN under study treatment, a monitoring was organized every two weeks until values return to normal/baseline values. *Additional investigations which were to be performed in case of AST and/or ALT > 3 ULN were described in detail. - PAERS scale was added as individual safety assessment in addition to AEs. - Data of the PAERS scale (clinician part) were to be reported in the e-CRF and adverse events from the PAERS were to be reported in the AE form of the e-CRF. - Period of time i.e. “in the morning” was defined to perform biological sampling required in the seven days after the selection visit. - ECG recording was to be done under the supervision of the qualified specialist.

13 Dec 2019

It mainly concerned: - Integration of agreed modifications on the Paediatric Investigation Plan by EMA: decreased sample size (at least 390 patients instead of 484) and adapted statistical analysis including the modifications of subgroup analyses of primary endpoint and the update of statistical patient sets (at least 312 adolescents, with no requirement on children population). - Update of the total number of centres (63 instead of 67) and the list of participating countries (deletion of Germany and addition of Serbia). - Modifications of centres’ downloads of participants’ data from the e-CRF for archiving.

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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Primary: CDRS-R raw total score: change from baseline to W12 (Total population of the FAS)

Primary: CDRS-R raw total score: change from baseline to W12 (Total population of the FAS)

Primary: CDRS-R raw total score: change from baseline to W12 (Adolescents of the FAS)

Primary: CDRS-R raw total score: change from baseline to W12 (Adolescents of the FAS)

Primary: CDRS-R raw total score: change from baseline to W12 (Children of the FAS)

Primary: CDRS-R raw total score: change from baseline to W12 (Children of the FAS)

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