| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Episodes Associated with Bipolar I Disorder |
|
| E.1.1.1 | Medical condition in easily understood language |
| Depression in Bipolar Disorder |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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 SEP 4199 200 mg/day and 400 mg/day compared with placebo for major depressive episode associated with bipolar I disorder (diagnosed by DSM 5 criteria) as measured by Montgomery-Asberg Depression Rating Scale (MADRS) total score. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the effect of SEP 4199 200 mg/day and 400 mg/day compared with placebo on severity of illness as measured by the Clinical Global Impression Bipolar Version, Severity of Illness (CGI-BP-S) score (depression). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is 18 to 65 years of age, inclusive, at the time of informed consent with bipolar I disorder, current episode depressed with or without rapid cycling disease course (≥ 4 episodes of mood disturbance but < 8 episodes in the previous 12 months) with or without psychotic features (diagnosed by DSM 5 criteria, and confirmed by the SCID 5 CT). The current episode of major depression associated with bipolar I disorder must be confirmed by the Investigator and noted in the source records.
2. Subject provides written informed consent and is willing and able to comply with the protocol in the opinion of the investigator.
3. Subject must possess an educational level and degree of understanding of English or the local language that enables them to communicate suitably
4. Subject must have a lifetime history of at least one bipolar manic or mixed manic episode. It is strongly recommended that a reliable informant (eg, family member or caregiver) be available to confirm this history.
5. Subject’s current major depressive episode is ≥ 4 weeks and less than 12 months in duration at Screening.
6. Subject has a MADRS total score ≥ 22 at both Screening and Baseline.
7. Subject has a YMRS total score ≤ 12 at Screening.
8. Female subjects of childbearing potential must have a negative serum ß-HCG test at Screening.
9. Females subject of childbearing potentialwho participate in this study must be one of the following:
•are unable to become pregnant (eg, postmenopausal, surgically sterile, etc.)
• Practicing abstinence or part of an abstinent , OR
• are using and willing to continue to useng a highly effective form of birth control for at least 28 days prior to administration of the first dose of study drug, during the treatment period, and 2 months after completion or premature discontinuation from the study drug.
10. Male subjects with partners of child bearing potential must be practicing abstinence, part of an abstinent life style or using protocol-specified methods of birth control.
11. Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening.
12. Subjects with type 2 diabetes are eligible for study inclusion only if all of the following conditions are met within 30 days prior to Screening:
·Subject’s random screening glucose is < 200 mg/dL (11.1 mmol/L).
·Subject’s Hemoglobin A1c (HbA1c) ≤ 7.0%.
·If a subject is currently being treated with oral anti-diabetic medication(s), the dose must have been stable for at least 30 days prior to screening. Such medication may be adjusted or discontinued during the study, as clinically indicated.
·Subject has not required hospitalization for diabetes or related complications in the past 12 months.
·Note: Subjects with type 2 diabetes that is newly diagnosed during screening are ineligible for the study.
13. Subject who requires concomitant medication treatment with the following agents may be included if they have been on stable doses for the specified times: 1) oral hypoglycemics must be stabilized for at least 30 days prior to baseline; 2) thyroid hormone replacement must be stable for at least 90 days prior to baseline; 3) anti hypertensive agents must be stable for at least 30 days prior to baseline. The subject’s medical condition should be deemed clinically stable following consultation with the Medical Monitor as needed.
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|
| E.4 | Principal exclusion criteria |
1. Subject has a lifel ong history or presence of symptoms consistent with a major psychiatric disorder other than bipolar I disorder as defined by DSM 5. Exclusionary disorders include but are not limited to moderate to severe alcohol use disorder (within past 12 months), substance use disorder (other than nicotine or caffeine) within past 12 months, bipolar II disorder, schizoaffective disorder, obsessive compulsive disorder, posttraumatic stress disorder.
2. Subject demonstrates a decrease (improvement) of ≥ 25% in MADRS total score from Screening to Baseline, or subject’s MADRS total score is < 22 at Baseline.
3. Subject has received treatment with antidepressants within 3 days of randomization, fluoxetine at any time within 28 days, an MAO inhibitor within 21 days or clozapine within 120 days. All other psychotropic medications with the exceptions of lorazepam, temazepam, and zolpidem require 3 days minimum washout. Depot neuroleptics must be discontinued at least one treatment cycle prior to randomization.
4. Subject has suspected/confirmed Borderline Personality Disorder.
5. Subject currently has a clinically significant neurological, metabolic (including type 1 diabetes), hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorder such as unstable angina, congestive heart failure (uncontrolled), or central nervous system (CNS) infection that would pose a risk to the subject if they were to participate in the study or that might confound the results of the study. Subjects with a known history of HIV seropositivity will be excluded.
6. Subject has evidence of any chronic organic disease of the CNS such as tumors, inflammation, active (or history of) seizure disorder, vascular disorder, Parkinson’s disease, Alzheimer’s disease or other forms of dementia, myasthenia gravis, or other degenerative processes. In addition, subjects must not have a history of intellectual disability or persistent neurological symptoms attributable to serious head injury. Past history of febrile seizure, is not exclusionary.
7. Subject has a history of malignancy < 5 years prior to signing the informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Subjects with pituitary tumors of any duration are excluded.
8. Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation . Subject has a history of stomach or intestinal surgery or any other condition that could interfere with absorption, distribution, metabolism, or excretion of medications.
9. Subject has knowledge of any kind of cardiovascular disorder/condition known to increase the possibility of QT prolongation or history of additional risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of Long QT Syndrome or Brugada Syndrome) or cardiac conduction disorders, or requires treatment with an antiarrhythmic medication.
10. Subject has family history of QTc prolongation or of unexplainable sudden death at < 50 years of age.
11.Abnormal 12 lead ECG at Screening
12. Subject has a history of neuroleptic malignant syndrome
13.Subject exhibits evidence of severe tardive dyskinesia, severe dystonia, or any other severe movement disorder.
14. Subject has been diagnosed with type 1 diabetes, or insulin-dependent diabetics.
15. Subject who has any abnormal laboratory parameter at screening that indicates a clinically significant medical condition as determined by the investigator. Subjects with random (nonfasting) blood glucose at screening ≥ 200 mg/dL (11.1 mmol/L) must be retested in a fasted state. Subjects with fasting blood glucose at screening ≥ 126 mg/dL (7.0 mmol/L) will be excluded from the study. Subjects with fasting blood glucose from 100 125 mg/dL (5.6 6.9 mmol/L) may enter the study based on the approval of the Medical Monitor. Subjects with HbA1c > 7.0% will be excluded.
16. Subject has a prolactin concentration > 100 ng/mL at screening or have a history of pituitary adenoma.
17. Subject has a body mass index (BMI) ≥ 40 or < 18 kg/m2 at Screening.
18. Subject has a history of non-response to an adequate (6 week) trial of three or more antidepressants (with or without mood stabilizers) during the current episode.
19. Subject is considered by the Investigator to be at imminent risk of suicide or injury to self, others, or answers “yes” to “Suicidal Ideation” item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) on the C SSRS assessment at the Screening visit (in the past month [30 days]) or Baseline.
20. Subject tests positive for drugs of abuse at screening or baseline.
21. Subject has a history of hypersensitivity to more than two distinct chemical classes of drug |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in MADRS total score at Week 6. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Change from baseline in global severity assessed by the CGI-BP-S score (depression) at Week 6. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Japan |
| Poland |
| Russian Federation |
| Serbia |
| Slovakia |
| Ukraine |
| 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
|
| The day of the last visit by the last subject in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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