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Clinical Trial Results:
Efficacy of citalopram treatment in acute stroke

Summary
EudraCT number	2013-002253-30
Trial protocol	DK
Global end of trial date	19 Dec 2016

Results information
Results version number	v1(current)
This version publication date	29 Nov 2021
First version publication date	29 Nov 2021
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

2011/397

ISRCTN number

US NCT number

NCT01937182

WHO universal trial number (UTN)

Sponsor organisation name

Aarhus University

Sponsor organisation address

Nordre Ringgade 1, Aarhus, Denmark, 8000

Public contact

Department of Neurology, Aarhus University Hospital, +45 89493294, greander@rm.dk

Scientific contact

Department of Neurology, Aarhus University Hospital, +45 89493294, greander@rm.dk

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

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

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

Analysis stage

Final

Date of interim/final analysis

10 May 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Dec 2016

Global end of trial reached?

Yes

Global end of trial date

19 Dec 2016

Was the trial ended prematurely?

Main objective of the trial

To examine wheather citalopram treatment in acute stroke reduces the risk of combined death, re-stroke and myocardial infarction

Protection of trial subjects

Patients, or their proxy respondent, provided written informed consent before enrollment. If patients develop depression dosage is initially doubled, followed by an additional control to evaluate the effect and, if necessary, shifted to open-label antidepressant treatment. After six-months, treatment will either stop or switch to open-label antidepressants at the discretion of the investigator. Exclusion criteria included: - Moderate to severe dementia or other neurodegenerative diseases - Patient on antidepressant medication within one month prior to admission - Contraindications to citalopram - Indication, in the clinician’s view, for antidepressant medication therapy - History of abuse or other circumstances deeming follow-up not possible - Actively bleeding ulcers - Fatal stroke or significant co-morbidity, resulting in an expected short life span - Pregnant or breast-feeding women

Background therapy

Patients included in the trial were treated in accordance with international best medical and surgical guidelines. All patients received standard care for stroke, including reperfusion therapy (ie, intravenous r-tPA (recombinant tissue-type plasminogen activator ) or endovascular treatment), if indicated.

Evidence for comparator

Some small or single-blinded placebo-controlled studies using a selective serotonin reuptake inhibitor (SSRI), and in particular, the FLAME study (Fluoxetine for Motor Recovery After Acute Ischemic Stroke) in 2011 gave rise to optimism. FLAME was a double-blinded randomized study, including 118 patients with moderate to severe stroke and showed increased motor recovery after 3 months of rehabilitation with SSRI treatment. A recent large study of escitalopram on prevention of poststroke depression found no improved functional outcome at 3 months (secondary outcome). Various theories have been suggested for a possible beneficial effect of SSRI treatment including a neurotrophic effect, increased neurogenesis and proliferation, an anti-inflammatory effect, protein expression enhancement, upregulation of 31-adrenergic receptors, or simply prevention or treatment of depression and anxiety, and improved sleep and alertness. In addition, a large observational study (n=5833) in propensity score-matched ischemic stroke patients has indicated a lower long-term risk of recurrent cardiovascular events associated with SSRI treatment. Treatment with SSRI has also been associated with increased bleeding problems; therefore, the safety and a potential antithrombotic effect must be considered when used in the subacute phase after stroke. A potential antithrombotic effect is a plausible effect of SSRI treatment owing to platelet inhibition, for example, by lowering the concentration of platelet serotonin or via the platelet-activating P2Y12-receptor.

Actual start date of recruitment

01 Aug 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Denmark: 642

Worldwide total number of subjects

642

EEA total number of subjects

642

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)

237

From 65 to 84 years

347

85 years and over

Subject disposition

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Recruitment details

Consecutive patients were enrolled in Denmark from 1 highly specialized stroke center (Aarhus) and 2 primary stroke units (Aalborg and Glostrup). Glostrup). The first and the last patient were recruited on September 17, 2013, and June 27, 2016, respectively. The last follow-up was performed on December 19, 2016.

Screening details

Patients who were ≥18 years of age with first-ever ischemic stroke onset (ie, last known to be free of stroke symptoms) within the previous 7 days were eligible for inclusion. A total of 949 patients were screened, 642 of which were included.

Period 1 title

Inclusion (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Blinding implementation details

Treatment allocation is double-blinded and allocated in a 10-block design based on computer-generated algorithm via a dedicated website. Patients whose treatment is stopped within 31 days after inclusion will be replaced.

Are arms mutually exclusive

Yes

Placebo

Arm description

Patients allocated to placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients randomized to placebo received oral treatment with 1 tablet (0,5 when age ≥65 and/or reduced liver function) for six-months with telephone contact after two-weeks and three-months and follow-up visits at one- and six-months. Treatment was initiated as soon as possible and no later than seven days after symptom onset. If patients developed depression dosage was initially doubled, followed by an additional control to evaluate the effect and, if necessary, shifted to open-label antidepressant treatment. After six-months, treatment was either stoped or switched to open-label antidepressants at the discretion of the investigator.

Active

Arm description

Patients allocated to citalopram

Arm type

Active comparator

Investigational medicinal product name

Citalopram

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Initial dose: 20 mg orally once a day Maintenance dose: 20 to 40 mg orally once a day Maximum dose: 40 mg orally per day

Number of subjects in period 1	Placebo	Active
Started	323	319
Completed	284	268
Not completed	39	51
Consent withdrawn by subject	14	29
Physician decision	9	10
Adverse event, non-fatal	4	6
Indication for open label treatment	12	6

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Patients allocated to placebo

Reporting group title

Active

Reporting group description

Patients allocated to citalopram

Reporting group values	Placebo	Active	Total
Number of subjects	323	319	642
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	123	114	237
From 65-84 years	167	180	347
85 years and over	33	25	58
Age continuous
Units: years
arithmetic mean (standard deviation)	68.36 ± 12.8	68.24 ± 12.5	-
Gender categorical
Units: Subjects
Female	101	120	221
Male	222	199	421

End points

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Reporting group title

Placebo

Reporting group description

Patients allocated to placebo

Reporting group title

Active

Reporting group description

Patients allocated to citalopram

Primary: Improvement in functional disability

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End point title

Improvement in functional disability

End point description

Improvement in functional disability from 1 to 6 months, as measured by the modified Rankin Scale (mRS)

End point type

Primary

End point timeframe

6 months

End point values	Placebo	Active
Number of subjects analysed	284 ^[1]	268 ^[2]
Units: modified Rankin Scale
number (not applicable)
mRS	160	136

Notes
[1] - Placebo
[2] - Citalopram

Improvement in functional disability

Comparison groups

Placebo v Active

Number of subjects included in analysis

552

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.05

Method

t-test, 2-sided

Parameter type

Odds ratio (OR)

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.91

Variability estimate

Standard deviation

Primary: Composite vascular end point

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End point title

Composite vascular end point

End point description

A composite vascular end point of TIA/stroke (ischemic and hemorrhagic), MI, or vascular mortality during the first 6 months. Registry-based follow-up was obtained from patients discontinuing study medication before 6 months.

End point type

Primary

End point timeframe

6 months

End point values	Placebo	Active
Number of subjects analysed	323 ^[3]	319 ^[4]
Units: Number of events
TIA/stroke, MI and mortality	26	23

Notes
[3] - Placebo
[4] - Citalopram

The vascular coprimary end point occurred

Comparison groups

Placebo v Active

Number of subjects included in analysis

642

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Fisher exact

Parameter type

Hazard ratio (HR)

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

1.74

Variability estimate

Standard deviation

Adverse events

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Timeframe for reporting adverse events

6 months according to the protocol, or as long as the patients were included.

Adverse event reporting additional description

AE reporting were performed non-systematically for the duration of patient inclusion in the project. Death reporting were done systematically in a intention-to-treat approach with all deaths within 6 months after inclusion reported.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Active

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Active	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	66 / 319 (20.69%)	75 / 323 (23.22%)
number of deaths (all causes)	16	12
number of deaths resulting from adverse events	6	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Carcinoma In Situ
Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps): Carcinoma In Situ
subjects affected / exposed	3 / 319 (0.94%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Vascular disorders
Vascular disorders: New Extremity Ischemia
Additional description: Vascular disorders: New Extremity Ischemia
subjects affected / exposed	1 / 319 (0.31%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders: Peripheral Vascular – Other (Specify)
Additional description: Vascular disorders: Peripheral Vascular – Other (Specify)
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Surgical and medical procedures: Carotid Endarectomy
Additional description: Surgical and medical procedures: Carotid Endarectomy
subjects affected / exposed	2 / 319 (0.63%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures: Other, specify
Additional description: Surgical and medical procedures: Other, specify
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures: Surgery – Other (Specify)
Additional description: Surgical and medical procedures: Surgery – Other (Specify)
subjects affected / exposed	8 / 319 (2.51%)	12 / 323 (3.72%)
occurrences causally related to treatment / all	0 / 8	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders: Respiratory - Other (Specify)
Additional description: Respiratory, thoracic and mediastinal disorders: Respiratory - Other (Specify)
subjects affected / exposed	0 / 319 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders: Respiratory Insufficiency/Failure
Additional description: Respiratory, thoracic and mediastinal disorders: Respiratory Insufficiency/Failure
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Psychiatric disorders: Depression
Additional description: Psychiatric disorders: Depression
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders: Other, specify
Additional description: Psychiatric disorders: Other, specify
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders: Psychiatric - Other (Specify)
Additional description: Psychiatric disorders: Psychiatric - Other (Specify)
subjects affected / exposed	1 / 319 (0.31%)	6 / 323 (1.86%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Investigations: Biochemical - Low Plasma Sodium Concentration
Additional description: Investigations: Biochemical - Low Plasma Sodium Concentration
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations: Paraclinical - Other (Specify)
Additional description: Investigations: Paraclinical - Other (Specify)
subjects affected / exposed	4 / 319 (1.25%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications: Other, specify
Additional description: Injury, poisoning and procedural complications: Other, specify
subjects affected / exposed	3 / 319 (0.94%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac disorders: ACS: Myocardial Infarction – NSTEMI
Additional description: Cardiac disorders: ACS: Myocardial Infarction – NSTEMI
subjects affected / exposed	2 / 319 (0.63%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac disorders: Arrhythmia – Other (Specify)
Additional description: Cardiac disorders: Arrhythmia – Other (Specify)
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Arrhythmia – Severe
Additional description: Cardiac disorders: Arrhythmia – Severe
subjects affected / exposed	2 / 319 (0.63%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Atrial Fibrillation
Additional description: Cardiac disorders: Atrial Fibrillation
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Cardiac Ischemia - Other (Specify)
Additional description: Cardiac disorders: Cardiac Ischemia - Other (Specify)
subjects affected / exposed	1 / 319 (0.31%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Cardiac disorders: Cardiovascular – Other (Specify)
Additional description: Cardiac disorders: Cardiovascular – Other (Specify)
subjects affected / exposed	1 / 319 (0.31%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Chest Pain
Additional description: Cardiac disorders: Chest Pain
subjects affected / exposed	0 / 319 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Electrocardiogram – Other Abnormal Findings (Specify)
Additional description: Cardiac disorders: Electrocardiogram – Other Abnormal Findings (Specify)
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Endovascular Or Surgical Intervention – Planned (Specify Site)
Additional description: Cardiac disorders: Endovascular Or Surgical Intervention – Planned (Specify Site)
subjects affected / exposed	5 / 319 (1.57%)	5 / 323 (1.55%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Endovascular Or Surgical Intervention – Unplanned (Specify Site)
Additional description: Cardiac disorders: Endovascular Or Surgical Intervention – Unplanned (Specify Site)
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Heart Failure – Other (Specify)
Additional description: Cardiac disorders: Heart Failure – Other (Specify)
subjects affected / exposed	2 / 319 (0.63%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Left Ventricular Insufficiency (Specify NYHA-Class)
Additional description: Cardiac disorders: Left Ventricular Insufficiency (Specify NYHA-Class)
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Peripheral Edema
Additional description: Cardiac disorders: Peripheral Edema
subjects affected / exposed	2 / 319 (0.63%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Pulmonary Edema
Additional description: Cardiac disorders: Pulmonary Edema
subjects affected / exposed	1 / 319 (0.31%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Stable Angina
Additional description: Cardiac disorders: Stable Angina
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Syncope – cardiovascular
Additional description: Cardiac disorders: Syncope – cardiovascular
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders: Tachycardia – Sinus
Additional description: Cardiac disorders: Tachycardia – Sinus
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Nervous system disorders: Delirium
Additional description: Nervous system disorders: Delirium
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Disabling Stroke – Haemorrhagic
Additional description: Nervous system disorders: Disabling Stroke – Haemorrhagic
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Disabling Stroke – Ischemic
Additional description: Nervous system disorders: Disabling Stroke – Ischemic
subjects affected / exposed	3 / 319 (0.94%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 0
Nervous system disorders: Dizziness – non-cardiovascular
Additional description: Nervous system disorders: Dizziness – non-cardiovascular
subjects affected / exposed	1 / 319 (0.31%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Headache
Additional description: Nervous system disorders: Headache
subjects affected / exposed	1 / 319 (0.31%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Neurological - Other (Specify)
Additional description: Nervous system disorders: Neurological - Other (Specify)
subjects affected / exposed	1 / 319 (0.31%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Neurovascular - Other (Specify)
Additional description: Nervous system disorders: Neurovascular - Other (Specify)
subjects affected / exposed	1 / 319 (0.31%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Nervous system disorders: Non-Disabling Stroke – Haemorrhagic
Additional description: Nervous system disorders: Non-Disabling Stroke – Haemorrhagic
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Non-Disabling Stroke – Ischemic
Additional description: Nervous system disorders: Non-Disabling Stroke – Ischemic
subjects affected / exposed	3 / 319 (0.94%)	8 / 323 (2.48%)
occurrences causally related to treatment / all	0 / 3	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Other, specify
Additional description: Nervous system disorders: Other, specify
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Seizure
Additional description: Nervous system disorders: Seizure
subjects affected / exposed	1 / 319 (0.31%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Subarachnoid hemorrhage (SAH)
Additional description: Nervous system disorders: Subarachnoid hemorrhage (SAH)
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Nervous system disorders: Syncope – non-cardiovascular
Additional description: Nervous system disorders: Syncope – non-cardiovascular
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders: Transient Ischemic Attack (TIA)
Additional description: Nervous system disorders: Transient Ischemic Attack (TIA)
subjects affected / exposed	5 / 319 (1.57%)	7 / 323 (2.17%)
occurrences causally related to treatment / all	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Blood and lymphatic system disorders: Anaemia
Additional description: Blood and lymphatic system disorders: Anaemia
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal disorders: Diarrhoea
Additional description: Gastrointestinal disorders: Diarrhoea
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders: Gastro-Intestinal - Other (Specify)
Additional description: Gastrointestinal disorders: Gastro-Intestinal - Other (Specify)
subjects affected / exposed	3 / 319 (0.94%)	5 / 323 (1.55%)
occurrences causally related to treatment / all	0 / 5	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal and urinary disorders: Biochemical - Renal Dysfunction
Additional description: Renal and urinary disorders: Biochemical - Renal Dysfunction
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders: Urinary And Genital Organs - Other (Specify)
Additional description: Renal and urinary disorders: Urinary And Genital Organs - Other (Specify)
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Endocrine disorders: Diabetes
Additional description: Endocrine disorders: Diabetes
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders: Endocrine, nutritional and metabolic – Other (Specify)
Additional description: Endocrine disorders: Endocrine, nutritional and metabolic – Other (Specify)
subjects affected / exposed	0 / 319 (0.00%)	2 / 323 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders: Fall causing bone fracture
Additional description: Musculoskeletal and connective tissue disorders: Fall causing bone fracture
subjects affected / exposed	6 / 319 (1.88%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders: Other, specify
Additional description: Musculoskeletal and connective tissue disorders: Other, specify
subjects affected / exposed	0 / 319 (0.00%)	3 / 323 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infections and infestations: Infection – Other (Specify)
Additional description: Infections and infestations: Infection – Other (Specify)
subjects affected / exposed	5 / 319 (1.57%)	7 / 323 (2.17%)
occurrences causally related to treatment / all	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations: Infection – Pulmonary
Additional description: Infections and infestations: Infection – Pulmonary
subjects affected / exposed	12 / 319 (3.76%)	6 / 323 (1.86%)
occurrences causally related to treatment / all	0 / 12	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
Infections and infestations: Infection – Urinary
Additional description: Infections and infestations: Infection – Urinary
subjects affected / exposed	2 / 319 (0.63%)	6 / 323 (1.86%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
Infections and infestations: Other, specify
Additional description: Infections and infestations: Other, specify
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Active	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	167 / 319 (52.35%)	180 / 323 (55.73%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Benign Neoplasms
Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps): Benign Neoplasms
subjects affected / exposed	1 / 319 (0.31%)	2 / 323 (0.62%)
occurrences all number	1	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Carcinoma In Situ
Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps): Carcinoma In Situ
subjects affected / exposed	0 / 319 (0.00%)	2 / 323 (0.62%)
occurrences all number	0	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Neoplasm - Other (Specify)
Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps): Neoplasm - Other (Specify)
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Other, specify
Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps): Other, specify
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Vascular disorders
Vascular disorders: Other, specify
Additional description: Vascular disorders: Other, specify
subjects affected / exposed	1 / 319 (0.31%)	1 / 323 (0.31%)
occurrences all number	1	1
Surgical and medical procedures
Surgical and medical procedures: Carotid Endarectomy
Additional description: Surgical and medical procedures: Carotid Endarectomy
subjects affected / exposed	11 / 319 (3.45%)	15 / 323 (4.64%)
occurrences all number	11	15
Surgical and medical procedures: Other, specify
Additional description: Surgical and medical procedures: Other, specify
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Surgical and medical procedures: Surgery – Other (Specify)
Additional description: Surgical and medical procedures: Surgery – Other (Specify)
subjects affected / exposed	8 / 319 (2.51%)	5 / 323 (1.55%)
occurrences all number	8	6
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders: Other, specify
Additional description: Respiratory, thoracic and mediastinal disorders: Other, specify
subjects affected / exposed	1 / 319 (0.31%)	1 / 323 (0.31%)
occurrences all number	1	1
Respiratory, thoracic and mediastinal disorders: Respiratory - Other (Specify)
Additional description: Respiratory, thoracic and mediastinal disorders: Respiratory - Other (Specify)
subjects affected / exposed	6 / 319 (1.88%)	4 / 323 (1.24%)
occurrences all number	6	4
Respiratory, thoracic and mediastinal disorders: Respiratory Insufficiency/Failure
Additional description: Respiratory, thoracic and mediastinal disorders: Respiratory Insufficiency/Failure
subjects affected / exposed	2 / 319 (0.63%)	0 / 323 (0.00%)
occurrences all number	2	0
Psychiatric disorders
Psychiatric disorders: Depression
Additional description: Psychiatric disorders: Depression
subjects affected / exposed	35 / 319 (10.97%)	47 / 323 (14.55%)
occurrences all number	35	47
Psychiatric disorders: Laugh Lability
Additional description: Psychiatric disorders: Laugh Lability
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Psychiatric disorders: Other, specify
Additional description: Psychiatric disorders: Other, specify
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Psychiatric disorders: Pathological Crying
Additional description: Psychiatric disorders: Pathological Crying
subjects affected / exposed	2 / 319 (0.63%)	17 / 323 (5.26%)
occurrences all number	2	18
Psychiatric disorders: Psychiatric - Other (Specify)
Additional description: Psychiatric disorders: Psychiatric - Other (Specify)
subjects affected / exposed	8 / 319 (2.51%)	14 / 323 (4.33%)
occurrences all number	8	15
Investigations
Investigations: Biochemical - Low Plasma Sodium Concentration
Additional description: Investigations: Biochemical - Low Plasma Sodium Concentration
subjects affected / exposed	2 / 319 (0.63%)	2 / 323 (0.62%)
occurrences all number	2	2
Investigations: Paraclinical - Other (Specify)
Additional description: Investigations: Paraclinical - Other (Specify)
subjects affected / exposed	9 / 319 (2.82%)	10 / 323 (3.10%)
occurrences all number	10	13
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications: Other, specify
Additional description: Injury, poisoning and procedural complications: Other, specify
subjects affected / exposed	6 / 319 (1.88%)	6 / 323 (1.86%)
occurrences all number	6	6
Cardiac disorders
Cardiac disorders: Arrhythmia – Major
Additional description: Cardiac disorders: Arrhythmia – Major
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Cardiac disorders: Arrhythmia – Minor
Additional description: Cardiac disorders: Arrhythmia – Minor
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Cardiac disorders: Arrhythmia – Other (Specify)
Additional description: Cardiac disorders: Arrhythmia – Other (Specify)
subjects affected / exposed	2 / 319 (0.63%)	1 / 323 (0.31%)
occurrences all number	2	1
Cardiac disorders: Atrial Fibrillation
Additional description: Cardiac disorders: Atrial Fibrillation
subjects affected / exposed	5 / 319 (1.57%)	2 / 323 (0.62%)
occurrences all number	5	2
Cardiac disorders: Cardiovascular – Other (Specify)
Additional description: Cardiac disorders: Cardiovascular – Other (Specify)
subjects affected / exposed	9 / 319 (2.82%)	6 / 323 (1.86%)
occurrences all number	10	8
Cardiac disorders: Chest Pain
Additional description: Cardiac disorders: Chest Pain
subjects affected / exposed	2 / 319 (0.63%)	3 / 323 (0.93%)
occurrences all number	2	3
Cardiac disorders: Dizziness – cardiovascular
Additional description: Cardiac disorders: Dizziness – cardiovascular
subjects affected / exposed	3 / 319 (0.94%)	4 / 323 (1.24%)
occurrences all number	3	4
Cardiac disorders: Electrocardiogram – Other Abnormal Findings (Specify)
Additional description: Cardiac disorders: Electrocardiogram – Other Abnormal Findings (Specify)
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Cardiac disorders: Left Ventricular Insufficiency (Specify NYHA-Class)
Additional description: Cardiac disorders: Left Ventricular Insufficiency (Specify NYHA-Class)
subjects affected / exposed	5 / 319 (1.57%)	1 / 323 (0.31%)
occurrences all number	5	1
Cardiac disorders: Orthoestatism
Additional description: Cardiac disorders: Orthoestatism
subjects affected / exposed	10 / 319 (3.13%)	10 / 323 (3.10%)
occurrences all number	10	10
Cardiac disorders: Peripheral Edema
Additional description: Cardiac disorders: Peripheral Edema
subjects affected / exposed	2 / 319 (0.63%)	2 / 323 (0.62%)
occurrences all number	2	2
Cardiac disorders: Stable Angina
Additional description: Cardiac disorders: Stable Angina
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Cardiac disorders: Tachycardia – Sinus
Additional description: Cardiac disorders: Tachycardia – Sinus
subjects affected / exposed	1 / 319 (0.31%)	1 / 323 (0.31%)
occurrences all number	1	1
Cardiac disorders: Syncope – cardiovascular
Additional description: Cardiac disorders: Syncope – cardiovascular
subjects affected / exposed	4 / 319 (1.25%)	4 / 323 (1.24%)
occurrences all number	4	4
Nervous system disorders
Nervous system disorders: Dizziness – non-cardiovascular
Additional description: Nervous system disorders: Dizziness – non-cardiovascular
subjects affected / exposed	1 / 319 (0.31%)	2 / 323 (0.62%)
occurrences all number	1	2
Nervous system disorders: Neurological - Other (Specify)
Additional description: Nervous system disorders: Neurological - Other (Specify)
subjects affected / exposed	15 / 319 (4.70%)	13 / 323 (4.02%)
occurrences all number	17	13
Nervous system disorders: Headache
Additional description: Nervous system disorders: Headache
subjects affected / exposed	9 / 319 (2.82%)	13 / 323 (4.02%)
occurrences all number	9	13
Nervous system disorders: Other, specify
Additional description: Nervous system disorders: Other, specify
subjects affected / exposed	0 / 319 (0.00%)	1 / 323 (0.31%)
occurrences all number	0	1
Nervous system disorders: Seizure
Additional description: Nervous system disorders: Seizure
subjects affected / exposed	2 / 319 (0.63%)	1 / 323 (0.31%)
occurrences all number	2	1
Blood and lymphatic system disorders
Blood and lymphatic system disorders: Anaemia
Additional description: Blood and lymphatic system disorders: Anaemia
subjects affected / exposed	1 / 319 (0.31%)	3 / 323 (0.93%)
occurrences all number	1	3
Ear and labyrinth disorders
Ear and labyrinth disorders: Other, specify
Additional description: Ear and labyrinth disorders: Other, specify
subjects affected / exposed	0 / 319 (0.00%)	3 / 323 (0.93%)
occurrences all number	0	3
Eye disorders
Eye disorders: Other, specify
Additional description: Eye disorders: Other, specify
subjects affected / exposed	1 / 319 (0.31%)	4 / 323 (1.24%)
occurrences all number	1	6
Gastrointestinal disorders
Gastrointestinal disorders: Diarrhoea
Additional description: Gastrointestinal disorders: Diarrhoea
subjects affected / exposed	11 / 319 (3.45%)	9 / 323 (2.79%)
occurrences all number	11	10
Gastrointestinal disorders: Gastro-Intestinal - Other (Specify)
Additional description: Gastrointestinal disorders: Gastro-Intestinal - Other (Specify)
subjects affected / exposed	44 / 319 (13.79%)	38 / 323 (11.76%)
occurrences all number	48	54
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders: Mild To Moderate Bruising Or Ecchymosis
Additional description: Skin and subcutaneous tissue disorders: Mild To Moderate Bruising Or Ecchymosis
subjects affected / exposed	2 / 319 (0.63%)	1 / 323 (0.31%)
occurrences all number	2	1
Skin and subcutaneous tissue disorders: Skin – Other (Specify)
Additional description: Skin and subcutaneous tissue disorders: Skin – Other (Specify)
subjects affected / exposed	6 / 319 (1.88%)	8 / 323 (2.48%)
occurrences all number	7	8
Skin and subcutaneous tissue disorders: Sweating
Additional description: Skin and subcutaneous tissue disorders: Sweating
subjects affected / exposed	6 / 319 (1.88%)	3 / 323 (0.93%)
occurrences all number	6	3
Renal and urinary disorders
Renal and urinary disorders: Urinary And Genital Organs - Other (Specify)
Additional description: Renal and urinary disorders: Urinary And Genital Organs - Other (Specify)
subjects affected / exposed	16 / 319 (5.02%)	7 / 323 (2.17%)
occurrences all number	16	7
Endocrine disorders
Endocrine disorders: Diabetes
Additional description: Endocrine disorders: Diabetes
subjects affected / exposed	0 / 319 (0.00%)	3 / 323 (0.93%)
occurrences all number	0	3
Endocrine disorders: Endocrine, nutritional and metabolic – Other (Specify)
Additional description: Endocrine disorders: Endocrine, nutritional and metabolic – Other (Specify)
subjects affected / exposed	4 / 319 (1.25%)	2 / 323 (0.62%)
occurrences all number	4	2
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders: Fall causing bone fracture
Additional description: Musculoskeletal and connective tissue disorders: Fall causing bone fracture
subjects affected / exposed	1 / 319 (0.31%)	0 / 323 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders: Other, specify
Additional description: Musculoskeletal and connective tissue disorders: Other, specify
subjects affected / exposed	8 / 319 (2.51%)	7 / 323 (2.17%)
occurrences all number	8	7
Infections and infestations
Infections and infestations: Infection – Gastrointestinal
Additional description: Infections and infestations: Infection – Gastrointestinal
subjects affected / exposed	2 / 319 (0.63%)	1 / 323 (0.31%)
occurrences all number	2	1
Infections and infestations: Infection – Other (Specify)
Additional description: Infections and infestations: Infection – Other (Specify)
subjects affected / exposed	6 / 319 (1.88%)	10 / 323 (3.10%)
occurrences all number	6	10
Infections and infestations: Infection – Pulmonary
Additional description: Infections and infestations: Infection – Pulmonary
subjects affected / exposed	4 / 319 (1.25%)	3 / 323 (0.93%)
occurrences all number	4	3
Infections and infestations: Infection – Urinary
Additional description: Infections and infestations: Infection – Urinary
subjects affected / exposed	17 / 319 (5.33%)	16 / 323 (4.95%)
occurrences all number	18	16

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/30355209

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Efficacy of citalopram treatment in acute stroke

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Clinical Trial Results: Efficacy of citalopram treatment in acute stroke

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Primary: Improvement in functional disability

Primary: Improvement in functional disability

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Substantial protocol amendments (globally)

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Clinical Trial Results:
Efficacy of citalopram treatment in acute stroke