The Efficacy of Citalopram Treatment in Acute Stroke (TALOS)

We wish to conduct a prospective, randomized, double blind, placebo controlled multi center study of the combined neuroprotective and antithrombotic effects of SSRI treatment after stroke.

Hypotheses:

SSRI treatment commenced in the acute phase of stroke (day 0-7) protects against new thromboembolic events and leads to better rehabilitation. 600 stroke patients will be randomized in a 1:1 ratio.

The treatment and follow up period is 6 months. During these 6 months there will be 2 clinical follow up visits, one telephone control and one visit to evaluate compliance regarding medication.

Study Overview

• Status: Completed
• Conditions: Stroke, Ischemic
• Intervention / Treatment: Drug: Citalopram; Drug: Placebo

Detailed Description

Design TALOS is an investigator-initiated, national multicenter randomized- and placebo-controlled, double blind trial testing citalopram in acute ischemic stroke.

Randomization Eligible patients will be randomized 1:1 to treatment with either citalopram or placebo. Treatment allocation is double-blinded based on computer-generated algorithm via a dedicated website. Patients whose treatment is stopped within 31 days after inclusion will be replaced.

Intervention and follow-up Patients randomized to citalopram will receive oral treatment with 20 mg tablets (10 mg if age ≥65 and/or reduced liver function) for 6 months with telephone contact after 2 weeks and 3 months and follow-up visits at 1 and 6 months. If patients develop depression dosage is initially doubled, followed by an additional control to evaluate effect and, if necessary, shifted to open-label antidepressant treatment. After 6 months, treatment will either stop or switch to open-label antidepressants at the discretion of the investigator.

Substudy 120 of patients will begin treatment within 12 hours after treatment with recombinant tissue plasminogen activator. These patients will receive a standard acute magnetic resonance imaging (MRI) with additional perfusion and angio sequences. The 24-hour control scan will be done using MRI instead of conventional CT.

Data monitoring When 300 patients have been included in the trial, an interim analysis will be performed. The unblinded results of this analysis will be reviewed by an independent data monitoring committee.

• Study Type: Interventional
• Enrollment (Actual): 642
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9100
    • Aalborg University Hospital, Department of Neurology
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital, Department of Neurology
  • Glostrup, Denmark, 2600
    • Glostrup University Hospital, Department of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• First ever ischemic stroke
• Age 18 years or above

Exclusion Criteria:

• Hemorrhagic stroke
• Dementia or other neurodegenerative disease
• Antidepressant medical treatment within 6 months of admission
• Acute need for antidepressant treatment
• Drug abuse or other conditions that may indicate noncompliant behavior
• Liver failure (increased liver enzyme levels up to or more than 2 times upper limit)
• Renal failure (eGFR below 30 ml/min per 1.73m2)
• Hyponatremia (S-potassium below 130 mmol/l)
• Actively bleeding ulcer
• Fatal stroke or other severe co-morbidity that markedly decreases expected life span
• Prolonged corrected QT-interval (QTc above 480 ms)
• Ongoing treatment with drugs known to prolong the QTc interval

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Selective Serotonin Reuptake Inhibitors; Intervention Drug: Citalopram	Drug: Citalopram; Citalopram 10-40 mg per day administered orally; Other Names: Selective Serotonin Reuptake Inhibitors; SSRI; Seropram®; Cipramil®
Placebo Comparator: Placebo; Intervention Drug: Placebo	Drug: Placebo; 1/2-2 tablets per day with no intrinsic drug activity; Other Names: inactive drug; inactive substance; inactive medicine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vascular death, Transient Ischemic Attack (TIA)/stroke and myocardial infarction (combined)	Myocardial Infarction: STEMI (ST segment elevation myocardial infarction) and NSTEMI (non-ST segment elevation myocardial infarction)	6 months
Functional status at 6-months	Functional status at 6-months, measured by the modified Rankin Scale	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vascular death		6 months
Death of any cause		6 months
TIA/stroke		6 months
Bleeding	Using the Global Utilization Of Streptokinase And Tpa For Occluded Arteries definition for bleeding (GUSTO)	6 months
Myocardial infarction	STEMI (ST segment elevation myocardial infarction) and NSTEMI (non-ST segment elevation myocardial infarction)	6 months
Disability/dependence	Using the modified Rankin Scale and the Barthel Index (BI)	6 months
Physical activity	Using the Physical Activity Scale for the Elderly (PASE)	6 months
Cognitive and organic cerebral impairment	Using the Mini-Mental State Examination and the Symbol Digit Modalities Test	6 months
Fatigue	Using the Multidimensional Fatigue Inventory	6 months
Post-stroke depression	Using the Major Depression Inventory test (MDI), Global depression scale (self and clinician and Hamilton Depression Scale - 6 item (HAM-D6)	6 months
Pathological Crying	Using the Pathological Crying Scale	6 months
Lesion size	Using FLAIR positive lesion size on MRI 24 hours after treatment with Alteplase	6 months

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Danish Council for Independent Research; The Danish Regions Medicine Foundation
• Investigators: Study Chair: Grethe Andersen, DSMc, Aarhus University Hospital; Study Director: Kristian L Kraglund, M.D., Aarhus University Hospital; Principal Investigator: Boris Modrau, M.D., Aalborg University Hospital; Principal Investigator: Helle Iversen, DSMc, Glostrup University Hospital

Publications and helpful links

General Publications

• Siepmann T, Penzlin AI, Kepplinger J, Illigens BM, Weidner K, Reichmann H, Barlinn K. Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence. Brain Behav. 2015 Sep 23;5(10):e00373. doi: 10.1002/brb3.373. eCollection 2015 Oct.
• Bonaventura A, Liberale L, Vecchie A, Casula M, Carbone F, Dallegri F, Montecucco F. Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke. Int J Mol Sci. 2016 Nov 25;17(12):1967. doi: 10.3390/ijms17121967.
• Mortensen JK, Johnsen SP, Larsson H, Andersen G. Early Antidepressant Treatment and All-Cause 30-Day Mortality in Patients with Ischemic Stroke. Cerebrovasc Dis. 2015;40(1-2):81-90. doi: 10.1159/000435819. Epub 2015 Jul 11.
• Adelborg K, Sundboll J, Videbech P, Grove EL. The Risk of Thromboembolism in Users of Antidepressants and Antipsychotics. Adv Exp Med Biol. 2017;906:351-361. doi: 10.1007/5584_2016_125.
• Kraglund KL, Mortensen JK, Damsbo AG, Modrau B, Simonsen SA, Iversen HK, Madsen M, Grove EL, Johnsen SP, Andersen G. Neuroregeneration and Vascular Protection by Citalopram in Acute Ischemic Stroke (TALOS). Stroke. 2018 Nov;49(11):2568-2576. doi: 10.1161/STROKEAHA.117.020067.

Helpful Links

• LinkedIn

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2013
• Primary Completion (Actual): December 19, 2016
• Study Completion (Actual): December 19, 2016

Study Registration Dates

• First Submitted: September 3, 2013
• First Submitted That Met QC Criteria: September 3, 2013
• First Posted (Estimate): September 9, 2013

Study Record Updates

• Last Update Posted (Actual): February 24, 2017
• Last Update Submitted That Met QC Criteria: February 23, 2017
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Stroke; Serotonin; Neuroprotection; Platelet; MRI (Magnetic Resonance Imaging); SSRI (Selective Serotonin Reuptake Inhibitors); 5-HT (5-Hydroxytryptamine); CT (computerized tomography); Post Stroke Depression
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Serotonin Receptor Agonists; Antidepressive Agents, Second-Generation; Citalopram; Serotonin; Serotonin Uptake Inhibitors
• Other Study ID Numbers: 2013-002253-30