Clinical trial NCT01564862: Efficacy of Lu AA21004 on Cognitive Dysfunction in Major Depressive Disorder
Official title: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Active-Referenced, Flexible Dose Study on the Efficacy of Lu AA21004 on Cognitive Dysfunction in Adult Subjects With Major Depressive Disorder (MDD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Depressive Disorder, Major
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-03-28
Enrollment: 602
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the effects of Lu AA21004, once daily (QD), on cognitive dysfunction in patients with major depressive disorder.

Detailed description: Lu AA21004 is under codevelopment by Takeda Global Research \& Development Center, Inc. and H. Lundbeck A/S for the treatment of MDD.

This study will consist of a screening period within 10 days of the Baseline Visit followed by an 8-week double-blind treatment period and a one-week taper down period.

Eligibility criteria: Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. The participant has recurrent MDD as the primary diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria (classification code 296.3x). The current MDE should be confirmed using the Mini International Neuropsychiatric Interview (MINI) V6.0.0.
4. The participant has received prescribed treatment for a previous episode of depression.
5. The participant has a MADRS total score ≥26 at both the screening and baseline visits.
6. Participant reports subjective cognitive dysfunction (such as difficulty concentrating, slow thinking, and difficulty in learning new things or remembering things).
7. The reported duration of the current major depressive episode (MDE) is at least 3 months
8. The participant is a man or woman between 18 and 65 years old, inclusive.
9. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent throughout the duration of the study and for 30 days after completion of the study.

Exclusion Criteria:

1. The participant has previously participated in this study.
2. The participant has a history of severe drug allergy or hypersensitivity, or known hypersensitivity to any of the excipients of the investigational medicinal product (IMP).
3. The participant has known hypersensitivity to duloxetine.
4. The participant has hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrose-isomaltase insufficiency.
5. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.
6. The participant has a score ≥70 on the DSST (numbers correct) at the Baseline Visit.
7. The participant is, in the opinion of the investigator, not able to complete the neuropsychological tests validly at the Baseline Visit.
8. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.
9. The participant has 1 or more of the following:

   1. Any current psychiatric disorder other than MDD as defined in the DSM-IV-TR (as assessed by the MINI Version 6.0.0).
   2. Current or history of attention deficit hyperactivity disorder (ADHD), pervasive developmental disorder, manic or hypomanic episode, schizophrenia, or any other psychotic disorder, including major depression with psychotic features, mental retardation, organic mental disorders, or mental disorders due to a general medical condition as defined in the DSM-IV-TR.
   3. Current diagnosis of alcohol or other substance abuse or dependence (excluding nicotine or caffeine) as defined in the DSM-IV-TR that has not been in sustained full remission for at least 2 years prior to Screening. (Participant must also have negative urine drug screen prior to Baseline).
   4. Presence or history of a clinically significant neurological disorder (including epilepsy).
   5. Neurodegenerative disorder (Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, etc).
   6. Any DSM-IV Axis II disorder that might compromise the study.
10. The participant has any other disorder for which the treatment takes priority over treatment of MDD or is likely to interfere with study treatment or impair treatment compliance.
11. The participant has physical, cognitive, or language impairment of such severity as to adversely affect the validity of the data derived from the neuropsychological tests.
12. The participant is diagnosed with reading disability (dyslexia).
13. The participant has a significant risk of suicide according to the investigator's clinical judgment or has a score ≥5 on item 10 (suicidal thoughts) of the MADRS or has made a suicide attempt in the previous 6 months.
14. The participant, in the opinion of the investigator, poses a risk of harm to others.
15. The participant has initiated formal cognitive or behavioral therapy, systemic psychotherapy within less than 6 months of study screening, or has plans to initiate such therapy during the study.
16. The participant has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening.
17. 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.
18. The participant 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.
19. The participant has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of investigational drug. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin.
20. The participant has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance.

    Note: For the purposes of this protocol, the following conditions are considered unstable due to the potential impact on assessment of MDD response and/or cognitive status: pain disorders, chronic fatigue syndrome, fibromyalgia, obstructive sleep apnea, and known cases of HIV, HBV, and HCV
21. The participant has a known history of or currently has increased intraocular pressure or is at risk of acute narrow-angle glaucoma.
22. The participant is required to take excluded medications or it is anticipated that the participant will require treatment with at least 1 of the disallowed concomitant medications during the study evaluation period as specified in the Excluded Medications Section.
23. The participant has received any investigational compound \<30 days before Screening or 5 half-lives prior to Screening.
24. The participant has clinically significant abnormal vital signs as determined by the investigator.
25. The subject has thyroid stimulating hormone (TSH) outside the normal range at the Screening Visit.

    Note: If TSH value is outside the normal range, a free T4 will be obtained. Subjects who have elevated TSH but normal T4 (i.e. subclinical hypothyroidism) will be excluded. For subjects who are on thyroid hormone replacement therapy, a lower TSH with normal T4, are eligible to participate in the study only if there are no clinical symptoms of hypothyroidism .
26. The participant has 1 or more laboratory value outside the normal range, based on the blood or urine samples taken at the Screening Visit, that are considered by the investigator to be clinically significant; or the participant has any of the following values at the Screening Visit:

    1. A serum creatinine value \>1.5 times the upper limits of normal (×ULN).
    2. A total serum total bilirubin value \>1.5×ULN.
    3. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value \>2×ULN.
27. The participant has an abnormal electrocardiogram (ECG) as determined by the central reader and confirmed as clinically significant by the investigator.
28. The participant has a disease or takes medication that, in the opinion of the investigator, could interfere with the assessments of safety, tolerability, or efficacy.
29. The participant, in the opinion of the investigator, is unlikely to comply with the clinical study protocol or is unsuitable for any reason.
30. The participant has been previously exposed to LuAA21004 compound.
31. The participant has a history of lack of response to previous adequate treatment with duloxetine.

Primary outcomes:
measure: Change From Baseline to Week 8 in the Digit Symbol Substitution Test (DSST)
timeFrame: Baseline and Week 8
Secondary outcomes:
measure: Change From Baseline to Week 8 in the Perceived Deficits Questionnaire (PDQ) Attention/Concentration and Planning/Organization Subscore
timeFrame: Baseline and Week 8
measure: Clinical Global Impressions-Improvement (CGI-I) Score at Week 8
timeFrame: Baseline, Week 8
measure: Change From Baseline to Week 8 in the Trail Making Test (TMT-A)
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Trail Making Test B (TMT-B)
timeFrame: Baseline and Week 8
measure: Change in Time From Baseline to Week 8 in the Stroop Test
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Groton Maze Learning Test (GMLT)
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Detection Task (DT)
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Identification Task (IT)
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the One-Back Task
timeFrame: Baseline and Week 8
measure: Proportion of Cognitive Dysfunction Improvement Due to Improvement of Depression
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the MADRS Total Score
timeFrame: Baseline, Week 1, Week 4 and Week 8
measure: Percentage of Participants With MADRS Response at Week 8
timeFrame: Baseline and Week 8
measure: Percentage of Participants in MADRS Remission at Week 8
timeFrame: Week 8
measure: Change From Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) Score
timeFrame: Baseline, Week 1, Week 4 and Week 8
Other outcomes:
Locations:
city: Tucson
country: United States
state: Arizona
city: Little Rock
country: United States
state: Arkansas
city: Bellflower
country: United States
state: California
city: Carson
country: United States
state: California
city: Cerritos
country: United States
state: California
city: Glendale
country: United States
state: California
city: Imperial
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Norwalk
country: United States
state: California
city: Oakland
country: United States
state: California
city: Paramount
country: United States
state: California
city: San Bernardino
country: United States
state: California
city: Santa Ana
country: United States
state: California
city: Wildomar
country: United States
state: California
city: Colorado Springs
country: United States
state: Colorado
city: Denver
country: United States
state: Colorado
city: Norwalk
country: United States
state: Connecticut
city: Lauderhill
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Sanford
country: United States
state: Florida
city: St. Petersburg
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: West Palm Beach
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Hoffman Estates
country: United States
state: Illinois
city: Naperville
country: United States
state: Illinois
city: Oak Brook
country: United States
state: Illinois
city: Skokie
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Prairie Village
country: United States
state: Kansas
city: Shreveport
country: United States
state: Louisiana
city: Baltimore
country: United States
state: Maryland
city: Haverhill
country: United States
state: Massachusetts
city: St. Louis
country: United States
state: Missouri
city: North Platte
country: United States
state: Nebraska
city: Las Vegas
country: United States
state: Nevada
city: Buffalo
country: United States
state: New York
city: New York
country: United States
state: New York
city: Staten Island
country: United States
state: New York
city: Avon lake
country: United States
state: Ohio
city: Beachwood
country: United States
state: Ohio
city: Garfield Heights
country: United States
state: Ohio
city: Toledo
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Portland
country: United States
state: Oregon
city: Allentown
country: United States
state: Pennsylvania
city: Norristown
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Columbia
country: United States
state: South Carolina
city: Franklin
country: United States
state: Tennessee
city: Memphis
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: The Woodlands
country: United States
state: Texas
city: Orem
country: United States
state: Utah
city: Salt Lake City
country: United States
state: Utah
city: Kirkland
country: United States
state: Washington
city: Seattle
country: United States
state: Washington
city: Brown Deer
country: United States
state: Wisconsin
city: Milwaukee
country: United States
state: Wisconsin
city: Kazanlak
country: Bulgaria
city: Novi Iskar
country: Bulgaria
city: Pleven
country: Bulgaria
city: Plovdiv
country: Bulgaria
city: Sofia
country: Bulgaria
city: Tzerova Koria
country: Bulgaria
city: Helsinki
country: Finland
city: Kuopio
country: Finland
city: Turku
country: Finland
city: Berlin
country: Germany
city: Bochum
country: Germany
city: Chemnitz
country: Germany
city: Hannover
country: Germany
city: Munchen
country: Germany
city: Schwerin
country: Germany
city: Westerstede
country: Germany
city: Wiesbaden
country: Germany
city: Bialystok
country: Poland
city: Leszno
country: Poland
city: Lodz
country: Poland
city: Torun
country: Poland
city: Ekaterinburg
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Smolensk
country: Russian Federation
city: Stavropol
country: Russian Federation
city: Kharkiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Luhansk
country: Ukraine
city: Ternopil
country: Ukraine
Study officials:
affiliation: Takeda
name: Senior Medical Director Clinical Science
role: STUDY_DIRECTOR
References:
citation: Jacobson W, Zhong W, Nomikos GG, Christensen MC, Kurre Olsen C, Harvey PD. Effects of vortioxetine on functional capacity across different levels of functional impairment in patients with major depressive disorder: a University of California, San Diego Performance-based Skills Assessment (UPSA) analysis. Curr Med Res Opin. 2020 Jan;36(1):117-124. doi: 10.1080/03007995.2019.1657692. Epub 2019 Aug 29.
citation: Christensen MC, Sluth LB, McIntyre RS. Validation of the University of California San Diego Performance-based Skills Assessment (UPSA) in major depressive disorder: Replication and extension of initial findings. J Affect Disord. 2019 Feb 15;245:508-516. doi: 10.1016/j.jad.2018.11.034. Epub 2018 Nov 5.
citation: Christensen MC, Loft H, McIntyre RS. Vortioxetine improves symptomatic and functional outcomes in major depressive disorder: A novel dual outcome measure in depressive disorders. J Affect Disord. 2018 Feb;227:787-794. doi: 10.1016/j.jad.2017.11.081. Epub 2017 Nov 16.
citation: Keefe RSE, Nomikos G, Zhong W, Christensen MC, Jacobson W. A Subgroup Analysis of the Impact of Vortioxetine on Functional Capacity, as Measured by UPSA, in Patients with Major Depressive Disorder and Subjective Cognitive Dysfunction. Int J Neuropsychopharmacol. 2018 May 1;21(5):442-447. doi: 10.1093/ijnp/pyy020.
citation: Christensen MC, Munro V. Cost per successfully treated patient for vortioxetine versus duloxetine in adults with major depressive disorder: an analysis of the complete symptoms of depression and functional outcome. Curr Med Res Opin. 2018 Apr;34(4):593-600. doi: 10.1080/03007995.2017.1416952. Epub 2018 Jan 16.
citation: Harvey PD, Jacobson W, Zhong W, Nomikos GG, Cronquist Christensen M, Kurre Olsen C, Merikle E. Determination of a clinically important difference and definition of a responder threshold for the UCSD performance-based skills assessment (UPSA) in patients with major depressive disorder. J Affect Disord. 2017 Apr 15;213:105-111. doi: 10.1016/j.jad.2017.02.014. Epub 2017 Feb 14.