Efficacy Study of Vortioxetine on Cognitive Dysfunction in Adult Patients With Major Depressive Disorder (FOCUS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
H. Lundbeck A/S
ClinicalTrials.gov Identifier:
NCT01422213
First received: August 22, 2011
Last updated: July 8, 2014
Last verified: July 2014
  Purpose

Major Depressive Disorder (MDD) is a severe and common psychiatric disorder. Although MDD primarily involves mood disturbances, patients also usually present alterations in cognitive function (attention, memory, executive functioning and psychomotor speed). Even though antidepressants are suggested in the literature to potentially improve cognitive dysfunction in patients with MDD to some degree, there is a lack of adequate and well-controlled studies to investigate this effect. This study will evaluate the efficacy, safety and tolerability of a new antidepressant Vortioxetine versus placebo on cognitive dysfunction in adult patients with MDD.


Condition Intervention Phase
Major Depressive Disorder
Drug: Placebo
Drug: Vortioxetine (Lu AA21004)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Randomised, Double-blind, Parallel-group, Placebo-controlled, Fixed Dose Study on the Efficacy of [Vortioxetine] Lu AA21004 on Cognitive Dysfunction in Adult Patients With Major Depressive Disorder (MDD)

Resource links provided by NLM:


Further study details as provided by H. Lundbeck A/S:

Primary Outcome Measures:
  • Change From Baseline to Week 8 in DSST (Number of Correct Symbols) and RAVLT (Acquisition and Delayed Recall) Using the Composite Z-score Defined as the Weighted Sum of the Individual Patient Z-scores [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]

    DSST assesses psychomotor speed of performance requiring visual perception, spatial decision-making, and motor skills. It consists of 133 digits and requires the patient to substitute each digit with a simple symbol in a 90-s period. Each correct symbol is counted, and the total score ranges from 0 (< normal functioning) to 133 (> normal functioning).

    RAVLT assesses verbal learning and memory, including immediate memory, efficiency of learning, retroactive and proactive interference effects, and encoding versus retrieval. It consists of a number of tasks, including immediate recall and delayed recall. The number of words correctly recalled on each task is recorded.

    The scores are standardized by subtracting the overall mean change from baseline from the individual change from baseline and dividing by the standard deviation estimate of the change from baseline. The 2 tests, DSST and RAVLT are each assigned a weight of 0.5, the 2 subtests of RAVLT are each assigned a weight of 0.25.



Secondary Outcome Measures:
  • Change From Baseline to Week 8 in DSST (Number of Correct Symbols) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
    Digit Symbol Substitution Test (DSST) is a cognitive test designed to assess psychomotor speed of performance requiring visual perception, spatial decision-making, and motor skills. It consists of 133 digits and requires the patient to substitute each digit with a simple symbol in a 90-second period. Each correct symbol is counted, and the total score ranges from 0 (less than normal functioning) to 133 (greater than normal functioning)." as a description of DSST.

  • Change From Baseline to Week 8 in RAVLT (Acquisition) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
    Rey Auditory Verbal Learning Task (RAVLT) is a cognitive test designed to assess verbal learning and memory, including immediate memory, efficiency of learning, retroactive and proactive interference effects, and encoding versus retrieval. It consists of a number of tasks, including immediate recall and delayed recall. The number of words correctly recalled on each task is recorded.

  • Change From Baseline to Week 8 in RAVLT (Delayed Recall) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
    Rey Auditory Verbal Learning Task (RAVLT) is a cognitive test designed to assess verbal learning and memory, including immediate memory, efficiency of learning, retroactive and proactive interference effects, and encoding versus retrieval. It consists of a number of tasks, including immediate recall and delayed recall. The number of words correctly recalled on each task is recorded.

  • Change From Baseline to Week 8 in the TMT A (Speed of Processing) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
    Trail Making Test (TMT) is a cognitive test designed to assess scanning, visuomotor tracking, executive function, and cognitive flexibility. It consists of two parts, A and B: the patient must draw lines to connect consecutively numbered circles (part A) and then connect consecutively numbered and lettered circles alternating between the two sequences (part B). The time taken to complete the two parts is recorded. Part A assesses cognitive processing speed. The lower the score the faster the processing speed.

  • Change From Baseline to Week 8 in the TMT B (Executive Function) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
    TMT is a cognitive test designed to assess scanning, visuomotor tracking, executive function, and cognitive flexibility. It consists of two parts, A and B: the patient must draw lines to connect consecutively numbered circles (part A) and then connect consecutively numbered and lettered circles alternating between the two sequences (part B). The time taken to complete the two parts is recorded. Part B examines executive functioning and ability to shift cognitive set. The lower the score the faster the ability to shift cognitive set.

  • Change From Baseline to Week 8 in Congruent STROOP Time to Complete (Executive Function) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
    Stroop Colour Naming Test (STROOP) is a cognitive test designed to assess the ability to inhibit a prepotent response to reading words while performing a task that requires attention control. It comprises two sheets with 50 words on each, and each word is the name of a colour. On the first sheet, the Congruent STROOP Sheet, the word and ink colour match; on the Incongruent STROOP Sheet, the word and ink colour do not match. For each sheet, the patient has 4 minutes to name the ink colour of each word. When the patient finishes the sheet, or once 4 minutes is up, the clinician notes the time taken and counts the number of correct and incorrect responses. The scale ranges from 0-100, the higher score the greater the cognitive flexibility.

  • Change From Baseline to Week 8 in Incongruent STROOP Time to Complete (Executive Function) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change From Baseline to Week 8 in the SRT (Speed of Processing) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]

    Simple Reaction Time (SRT) is designed to assess psychomotor speed, and Choice Reaction Time (CRT) is designed to assess visual attention. Two computerised tests, part of the CogState battery were used to measure SRT and CRT in milliseconds:

    • The "detection task" measures SRT: the patient presses a "yes" button, whenever an onscreen playing card is turned over.
    • The "identification task" measures CRT: the patient presses a "yes" button whenever an onscreen playing card is turned over and is red, or a "no" button if the card is not red.

  • Change From Baseline to Week 8 in the CRT (Attention) [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change From Baseline to Week 8 in MADRS Total Score [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
    The Montgomery Åsberg Depression Rating Scale (MADRS) is a depression rating scale consisting of 10 items, each rated 0 (no symptom) to 6 (severe symptom). The 10 items represent the core symptoms of depressive illness. The rating should be based on a clinical interview with the patient, moving from broadly phrased questions about symptoms to more detailed ones, which allow a precise rating of severity, covering the last 7 days. Total score from 0 to 60. The higher the score, the more severe.

  • Change From Baseline to Week 8 in CGI-S Score [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
    The Clinical Global Impression - Severity of Illness (CGI-S) is a 7-point scale rated from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). The investigator should use his/her total clinical experience with this patient population to judge how mentally ill the patient is at the time of rating.

  • Clinical Status Using CGI-I Score at Week 8 [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
    The Clinical Global Impression - Global Improvement (CGI-I) is a 7-point scale rated from 1 (very much improved) to 7 (very much worse). The investigator rated the patient's overall improvement relative to baseline, whether or not, in the opinion of the investigator, this was entirely due to the drug treatment.

  • Proportion of Responders at Week 8 (Response Defined as a >=50% Decrease in the MADRS Total Score From Baseline [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Proportion of Remitters at Week 8 (Remission is Defined as a MADRS Total Score <=10) [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  • Change From Baseline to Week 1 Using the MADRS Total Score and the Composite Z-score [ Time Frame: Baseline and Week 1 ] [ Designated as safety issue: No ]

    Effect on cognitive dysfunction after correcting for the effect on depressive symptoms.

    The estimation of the effect on cognitive dysfunction after correcting for the effect on depressive symptoms was based on the composite z-score and the MADRS total score. The effect was estimated in an ANCOVA model using the composite z-score at week 1 as dependent variable and the change from baseline to week 1 in the MADRS total score, the baseline MADRS total score, the baseline composite z-score, the treatment group and site as independent variables.

    In the week 1 analysis the vortioxetine 10 and 20 mg groups were pooled because patients randomized to vortioxetine 20 mg received vortioxetine 10 mg in the first week of the study.


  • Change From Baseline to Week 8 Using the MADRS Total Score and the Composite Z-score [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]

    Effect on cognitive dysfunction after correcting for the effect on depressive symptoms.

    The estimation of the effect on cognitive dysfunction after correcting for the effect on depressive symptoms was based on the composite z-score and the MADRS total score. The effect was estimated in an ANCOVA model using the composite z-score at week 1 as dependent variable and the change from baseline to week 1 in the MADRS total score, the baseline MADRS total score, the baseline composite z-score, the treatment group and site as independent variables.


  • Risk of Suicidality Using C-SSRS Scores [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: Yes ]

    The Columbia-Suicide Severity Rating Scale (C-SSRS) was developed by researchers at Columbia University as a tool to systematically assess suicidal ideation and behaviour in patients during participation in a clinical study. The C-SSRS is composed of questions that address suicidal behaviour and questions that address suicidal ideation, with subquestions that assess severity. The tool was administered via an interview with the patient.

    For 2 patients in each treament group (6 in total) the CSSRS assessments are missing during study.



Enrollment: 598
Study Start Date: December 2011
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo Drug: Placebo
capsules; daily; orally
Experimental: Vortioxetine 10 mg Drug: Vortioxetine (Lu AA21004)
encapsulated tablets; daily; orally
Other Name: Brintellix
Experimental: Vortioxetine 20 mg Drug: Vortioxetine (Lu AA21004)
encapsulated tablets; daily; orally
Other Name: Brintellix

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The patient is an inpatient in a psychiatric hospital or an outpatient at a psychiatric setting at the time of the study entry.
  • The patient is diagnosed with recurrent MDD according to DSM-IV-TR™ criteria (classification code 296.3x). The current Major Depressive Episode (MDE) should be confirmed using the Mini International Neuropsychiatric Interview (MINI).
  • The patient has received prescribed treatment for a previous episode of depression.
  • The patient has a MADRS total score ≥26.
  • The reported duration of the current MDE is at least 3 months.

Exclusion Criteria:

  • The patient has a score ≥70 on the DSST (number of correct symbols), or ≥42 on the RAVLT (learning) or ≥14 on the RAVLT (memory) at the Baseline Visit.
  • The patient has any current Axis I disorder (DSM-IV-TR™ criteria) other than MDD, confirmed using the MINI.
  • The patient has a current diagnosis or history of manic or hypomanic episode, schizophrenia or any other psychotic disorder, including major depression with psychotic features.
  • The patient suffers from personality disorders, mental retardation, pervasive development disorder, attention-deficit/hyperactivity disorder, organic mental disorders, or mental disorders due to a general medical condition (DSM-IV-TR™ criteria).
  • The patient has physical, cognitive, or language impairment of such severity as to adversely affect the validity of the data derived from the neuropsychological tests.
  • The patient is diagnosed with reading disability (dyslexia).
  • The patient is at significant risk of suicide or has a score ≥5 on Item 10 (suicidal thoughts) of the MADRS, or has attempted suicide <6 months prior to the Screening Visit.
  • The patient has received electroconvulsive therapy <6 months prior to the Screening Visit.
  • The current depressive symptoms are considered by the investigator to have been resistant to 2 adequate antidepressant treatments of at least 6 weeks duration each at the recommended dose.
  • The patient has a history of moderate or severe head trauma (for example, loss of consciousness for more than 1 hour) or other neurological disorders or systemic medical diseases that are, in the opinion of the investigator, likely to affect central nervous system functioning.
  • The patient has a history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of the skin, that has not been in remission for >5 years prior to the first drug dose.
  • The patient has a clinically significant unstable illness, for example:

    • cardiovascular disease
    • seizure disorder or encephalopathy
    • congestive heart failure
    • cardiac hypertrophy
    • arrhythmia
    • bradycardia (pulse <50 bpm)
    • respiratory disease
    • hepatic impairment or renal insufficiency
    • metabolic disorder
    • endocrinological disorder
    • gastrointestinal disorder
    • haematological disorder
    • infectious disorder
    • any clinically significant immunological condition
    • dermatological disorder
    • venereal disease
  • The patient has, at the Screening Visit, an abnormal ECG that is, in the investigator's opinion, clinically significant.
  • The patient is, in the investigator's opinion, unlikely to comply with the protocol or is unsuitable for any reason.
  • The patient has previously been exposed to Vortioxetine.

Other protocol-defined inclusion and exclusion criteria may apply.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01422213

Sponsors and Collaborators
H. Lundbeck A/S
Investigators
Study Director: Email contact via H. Lundbeck A/S LundbeckClinicalTrials@lundbeck.com
  More Information

No publications provided

Responsible Party: H. Lundbeck A/S
ClinicalTrials.gov Identifier: NCT01422213     History of Changes
Other Study ID Numbers: 14122A, 2011-001572-19
Study First Received: August 22, 2011
Results First Received: May 14, 2014
Last Updated: July 8, 2014
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Canada: Health Canada
Finland: Finnish Medicines Agency
France: Agence Nationale de Sécurité du Médicament et des produits de santé
Germany: Federal Institute for Drugs and Medical Devices
Latvia: State Agency of Medicines
Mexico: Ministry of Health
Serbia: Medicines and Medical Devices Agency
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
Ukraine: Ministry of Health
United States: Food and Drug Administration

Keywords provided by H. Lundbeck A/S:
MDD
Cognitive dysfunction

Additional relevant MeSH terms:
Depressive Disorder
Depression
Depressive Disorder, Major
Disease
Cognition Disorders
Mood Disorders
Mental Disorders
Behavioral Symptoms
Pathologic Processes
Delirium, Dementia, Amnestic, Cognitive Disorders
Vortioxetine
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Serotonin Agents
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptor Agonists
Serotonin 5-HT1 Receptor Antagonists
Serotonin Antagonists
Serotonin 5-HT3 Receptor Antagonists

ClinicalTrials.gov processed this record on September 29, 2014