| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cognitive Function in Major Depressive Disorder (MDD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Intellectual function in depression |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of treatment with flexible doses of Lu AA21004 (10 or 20 mg QD) versus placebo on cognitive dysfunction in patients with MDD. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of flexible dose of Lu AA21004 (10 or 20 mg QD) versus placebo on:
– Depressive symptoms;
– Global clinical status;
– Proportion of cognitive dysfunction improvement that is not due to an improvement in depressive symptoms;
– The safety and tolerability of Lu AA21004 (10 or 20 mg QD). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject has recurrent MDD as the primary diagnosis 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 V6.0.0).
2. The subject has received prescribed treatment for a previous episode of depression.
3. The subject has a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26 at both screening and
baseline.
4. Subject reports subjective cognitive dysfunction (such as difficulty concentrating, slow thinking, and difficulty in
learning new things or remembering things).
5. The reported duration of the current MDE is at least 3 months.
6. The subject is a man or woman between 18 and 65 years old, inclusive. |
|
| E.4 | Principal exclusion criteria |
1. The subject has a score ≥70 on the Digit Symbol Substitution Test (DSST) (numbers correct) at the Baseline Visit.
2.The subject has 1 or more of the following:
– Any current psychiatric disorder other than MDD as defined in the DSM-IV-TR (as assessed by the MINI, Version 6.0.0).
– 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.
– 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.
(Subject must also have negative urine drug screen prior to Baseline.)
– Presence or history of a clinically significant neurological disorder (including epilepsy).
– Neurodegenerative disorder (Alzheimer’s Disease, Parkinson’s Disease, multiple sclerosis, Huntington’s Disease, etc).
– Any DSM-IV Axis II disorder that might compromise the study.
3. The subject 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.
4. The subject has physical, cognitive, or language impairment of such severity as to adversely affect the validity of the data derived from the neuropsychological tests.
5. The subject 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.
6. The subject, in the opinion of the investigator, poses a risk of harm to others.
7. The subject 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.
8. The subject has received electroconvulsive therapy, vagal nerve stimulation, or repetitive transcranial magnetic stimulation within 6 months prior to Screening.
9. 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.
10. The subject has a history of lack of response to previous adequate treatment with duloxetine.
11. The subject 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.
12. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for this study is the change from Baseline to Week 8 in the DSST score (speed processing, executive functioning). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1 of Week 1 and end of Week 8 |
|
| E.5.2 | Secondary end point(s) |
1. Cognitive dysfunction
– Change from Baseline to Week 8 in the Trail Making Test (TMT) A (speed of processing).
– Change from Baseline to Week 8 in the Trail Making Test (TMT) B (executive functioning).
– Change from Baseline to Week 8 in the Stroop Test (executive functioning).
– Change from Baseline to Week 8 in the Groton Maze Learning Test (executive function, visual learning and memory).
– Change from Baseline to Week 8 in the Detection Task (motor speed).
– Change from Baseline to Week 8 in the Identification Task (attention).
– Change from Baseline to Week 8 in the One-Back Task (attention, working memory).
– Proportion of cognitive dysfunction improvement using change from Baseline to Week 8 in the MADRS total score and the DSST score.
2. Depressive symptoms
– Change from Baseline to Week 8 in the MADRS total score.
– Response rates (defined as a ≥50% decrease in MADRS total score from Baseline) at Week 8.
– Remission rates (defined as a MADRS total score 10) at Week 8.
3. Global Clinical Status
– Change from Baseline to Week 8 in the Clinical Global Impressions-Severity (CGI-S) score.
– Clinical Global Impressions-Improvement (CGI-I) score at Week 8.
4. Safety
– Adverse events (AEs).
– Clinical safety laboratory tests, vital signs and weight, electrocardiograms (ECGs), and physical
examination.
– Columbia Suicide Severity Rating Scale (C-SSRS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Neuropsychological tests (DSST, TMT A, TMT B, Stroop Test, Groton Maze Learning Test, Detection Task, Identification Task and One-Back Task) - Day 1 of Week 1 and end of Week 8
MADRS, CGI-S, vital signs and weight - Day 1 of Week 1 and end of Weeks 1, 4 and 8
CGI-I - End of Weeks 1, 4 and 8
Adverse events assessment - Day 1 of Week 1, end of Weeks 1, 4, 6, 8, 9 and 12
C-SSRS - Day 1 of Week 1, end of Weeks 1, 4, 6 and 8
Blood and urine sampling for clinical safety laboratory tests, ECGs and physical examination - End of Week 8
See Appendix A in the protocol
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Finland |
| Germany |
| Poland |
| Russian Federation |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 13 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 13 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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