| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Depressive Episodes associated with Bipolar 1 Disorder |
|
| E.1.1.1 | Medical condition in easily understood language |
Low mood (excessive sadness) in patients who also have had periods of mania (raised mood)
|
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10004939 |
| E.1.2 | Term | Bipolar I disorder |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| 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 TAK-375SL tablet 0.1 mg and 0.4 mg once daily at bedtime (QHS) compared with placebo as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) after 6 weeks of treatment in subjects with acute depressive episodes associated with Bipolar 1 Disorder. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of TAK-375SL tablet 0.1 and 0.4 mg QHS on quality of life compared with placebo after 6 weeks of treatment.
2. To evaluate the efficacy of TAK-375SL tablet 0.1 mg and 0.4 mg QHS compared with placebo based on other parameters of efficacy after 6 weeks of treatment.
3. To evaluate the efficacy of TAK-375SL tablet 0.1 mg and 0.4 mg QHS compared with placebo as assessed by the Quick Inventory of Depressive Symptomatology Self-Rated16 (QIDS-SR16) after 6 weeks of treatment.
4. To evaluate the effect of TAK-375SL tablet 0.1 mg and 0.4 mg QHS on subject functioning compared with placebo after 6 weeks of treatment.
5. To evaluate the safety and tolerability of TAK-375SL tablet compared with placebo during the course of treatment.
Other additional objectives are listed in the protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
2. The subject or, when applicable, the subject’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 subject suffers from Bipolar 1 Disorder, Most Recent Episode Depressed as the primary diagnosis according to DSM-IV-TR criteria (classification code 296.5x) and confirmed by the Structured Clinical Interview for DSM Disorders (SCID).
4. The subject is a man or woman aged between 18 and 75 years, inclusive.
5. The reported duration of the current Major Depressive Episode (MDE) is at least four weeks and less than 6 months.
6. The subject has a Young Mania Rating Scale (YMRS) total score of ≤10 both at the Screening and Baseline Visits.
7. The subject has a MADRS total score of ≥24 at the Screening and Baseline Visits.
8. The subject has a Clinical Global Impression Scale – Severity (CGI-S) score of ≥4 at the Screening and Baseline Visits.
9. The subject has Hamilton Rating Scale for Anxiety (HAM- A) total score of ≤21 at Screening and Baseline Visits.
10. The subject is on lithium and/or one other mood stabilizer (lamotrigine or valproic acid) and/or one atypical antipsychotic (risperidone or olanzapine or aripiprazole or ziprasidone). Patients may be on one, two or three medications but no more than one from each group.
11. The subject is on the same dose of the protocol allowed medications (identified in inclusion # 10) for bipolar 1 disorder for at least two weeks prior to Screening (and at least 6 weeks prior to Screening for lamotrigine only). Further dose adjustments will not be allowed from Screening until end of study, except for downward dose adjustments for adverse events.
12. If the subject is on lithium and/or valproic acid, the trough serum levels must be less than 1.2 mEq/L for lithium and the trough serum must be less than 125 mcg/ml for valproic acid. Downward dose adjustment is allowed to lower trough serum levels for lithium and/or valproic acid below the maximum allowed. This must be confirmed at least two weeks prior to Baseline.
13. The subject screened must have <25% improvement in MADRS total scores from Screening to Baseline visit with a minimum of two weeks between Screening and Baseline visits.
14. A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose.
15. A male subject who is nonsterilized and sexually active with female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. The subject has received any investigational compound <30 days or 5 half-lives prior to Screening, whichever is longer.
2. The subject has ever used ramelteon, or received TAK-375 or TAK-375SL in a previous clinical study.
3. The subject is an immediate family member, study site employee, in a dependent relationship with a study site employee involved in the conduct of this study or may consent under duress.
4. The subject has one or more of the following:
a) Any current psychiatric disorder which is the primary focus of treatment other than Bipolar 1 Disorder.
b) Current or history of schizophrenia or any other psychotic disorder.
c) Current diagnosis or history of alcohol or other substance abuse (excluding nicotine or caffeine) that has not been in full and sustained remission for at least 3 months prior to Screening.
d) Current diagnosis or history of alcohol or other substance dependence (excluding nicotine or caffeine) that has not been in full and sustained remission for at least 3 months prior to Screening.
e) Presence or history of a clinically significant neurological disorder (including epilepsy).
f) Neurodegenerative disorder (Alzheimer disease, Parkinson disease, MS, Huntington disease, etc).
g) Any Axis II disorder that might compromise the study.
h) History of Rapid Cycling Bipolar Disorder.
5. The subject experienced the first episode of mood disorder after the age of 55 years.
6. The current depressive symptoms of the subject are considered by the investigator to have been resistant to 2 adequate treatment trials with any of the mood stabilizers (specifically started to treat the current depressive episode) and/or medications approved for acute bipolar depression for at least 6 weeks duration each.
7. The subject is on any psychotropic medications other than the protocol allowed medications for at least 2 weeks prior to Baseline.
8. The subject has received ECT, vagal nerve stimulation or repetitive transcranial magnetic stimulation within 6 months prior to Screening.
9. The subject has started receiving formal cognitive or behavioral therapy, systematic psychotherapy within 30 days prior to Screening or plans to initiate such therapy during the study.
10. 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.
11. The subject has taken or is anticipated that the subject will take at least 1 of the disallowed concomitant medications listed in Table 7.a Excluded Medications and Treatments.
12. The subject has a clinically significant unstable illness, eg. hepatic impairment or renal insufficiency, or a cardiovascular, pulmonary, gastrointestinal, endocrine, neurological, rheumatologic, immunologic,
hematological, infectious, dermatological disorder or metabolic disturbance.
13. The subject has a history or current diagnosis of fibromyalgia, chronic fatigue syndrome, chronic pain syndrome or sleep apnea (central and/or obstructive).
14. The subject has a previous history of cancer that had been in remission for less than 5 years prior to the first dose of study medication (not including subjects with basal cell or stage I squamous cell carcinoma of the skin).
15. The subject has 1 or more laboratory value outside the normal range, based on the blood or urine samples taken at Screening, that are considered to be clinically significant; or the subject has any of the following values at Screening:
a) A serum creatinine value >1.5 xULN.
b) A serum total bilirubin value >1.5 xULN.
c) A serum ALT or AST value >2 xULN.
16. The subject has HbA1C ≥7% at Screening and no prior diagnosis of diabetes and/or treatment for diabetes. Subjects with known diabetes are not excluded.
17. The subject has a TSH value outside the normal range at Screening that is deemed clinically significant.
18. The subject is positive for HBsAg, HCV Ab or has a history of HIV infection.
19. If male, the subject intends to donate sperm during the course of this study or for 12 weeks thereafter. If female, the subject is pregnant, 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.
20. The subject has clinically significant abnormal vital signs.
21. The subject has a clinically significant abnormal ECG.
22. The subject has a disease or takes medication that could interfere with the assessments of safety, tolerability or efficacy.
23. The subject is unlikely to comply with the clinical study protocol or is unsuitable for any reason.
See Protocol for full details of exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the change from Baseline in the MADRS total score after 6 weeks of treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1 of Week 0 and end of Week 6 |
|
| E.5.2 | Secondary end point(s) |
1. Change from Baseline in Quality of Life, Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) total score at Week 6.
2. MADRS response at Week 6, with response defined as a ≥50% decrease in the MADRS total score from Baseline.
3. Change from Baseline in YMRS total score at Week 6.
4. Clinical Global Impression Scale Improvement (CGI-I) score at Week 6.
5. Change in Clinical Global Impression Scale-Severity (CGI-S) from Baseline to Week 6.
6. MADRS remission at Week 6, with remission defined as a MADRS total score ≤10.
7. Change from Baseline in the Quick Inventory of Depressive Symptomatology - Self-Rated16 (QIDS-SR16) total score at Week 6.
8. Change from Baseline in Sheehan Disability Scale (SDS) total score at Week 6.
9. Safety and tolerability of TAK-375SL will also be evaluated using the following general assessments: adverse events, laboratory values, vital signs, weight, electrocardiograms (ECGs) and physical examination findings.
Other additional endpoints are listed in the protocol. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Q-LES-Q-SF, SDS, MADRS, YMRS, CGI-S and QIDS-SR16 - Day 1 of Week 0 and end of Week 6
CGI-I, physical examination and ECGs - End of Week 6
Adverse event assessments - Day 1 and Day 2 of Week 0, end of Weeks 1, 2, 4, 6, 7 and 10
Vital signs - Day 1 of Week 0, end of Weeks 1, 2, 4, 6 and 7
Clinical laboratory tests and body weight - Day 1 of Week 0, end of Weeks 4 and 6
Please refer to Appendix A in the protocol for the full schedule of assessments.
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|
| 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 | Yes |
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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) | No |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| 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 |
| Czech Republic |
| Germany |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Last follow-up phone call of the last subject. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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