Clinical trial NCT03543410: A Clinical Study to Test the Effectiveness of an Investigational Drug to Treat People That Have Major Depressive Episodes When They Have Bipolar 1 Depression
Official title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of SEP-4199 for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I Depression)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Depressive Episode
Bipolar 1 Depression
Keywords: Depression, Depressive episode, Bipolar, Bipolar 1, Bipolar 1 depression
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2018-06-01
Enrollment: 344
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: A clinical study to test the effectiveness of an investigational drug to treat people that have major depressive episodes when they have Bipolar 1 Depression

Detailed description: This is a randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study designed to evaluate the efficacy, safety, and tolerability of treatment with SEP-4199 monotherapy given as 200 mg/day or 400 mg/day compared with placebo for the treatment of major depressive episodes associated with bipolar I disorder (bipolar I depression).

Eligibility criteria: Inclusion Criteria:

* 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.
* Subject provides written informed consent and is willing and able to comply with the protocol in the opinion of the investigator.
* Subject or legally acceptable representative must possess an educational level and degree of understanding of English or the local language that enables them to communicate suitably with the Investigator and the study coordinator.
* Subject must have a lifetime history of at least one bipolar manic or mixed manic episode. It is strongly recommended that a reliable informant (e.g., family member or caregiver) be available to confirm this history.
* Subject's current major depressive episode is ≥ 4 weeks and less than 12 months in duration at Screening.
* Subject has a MADRS total score ≥ 22 at both Screening and Baseline.
* Subject has a YMRS total score ≤ 12 at Screening.
* Female subjects of childbearing potential must have a negative serum ß-hCG test at Screening.
* Females who participate in this study must be . one of the following:

  * unable to become pregnant (e.g., postmenopausal, surgically sterile, etc.) -OR-
  * Practicing abstinence or part of an abstinent lifestyle
  * using and willing to continue using 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.
* 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. See Section 10.4 for further information on acceptable methods of birth control.
* Subject is in good physical health on the basis of medical history, physical examination, and laboratory screening.
* 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.
* 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.

Exclusion Criteria:

* Subject has a lifelong 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.
* 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.
* 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,eszopiclone, zopiclone, zolpidem and zolpidem CR require 3 days minimum washout. Depot neuroleptics must be discontinued at least one treatment cycle prior to randomization.
* Subject has suspected/confirmed Borderline Personality Disorder
* 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.

Note: Active medical conditions that are minor or well-controlled are not exclusionary if they do not affect risk to the subject or the study results. In cases in which the impact of the condition upon risk to the subject or study results is unclear, the Medical Monitor should be consulted. Any subject with a known cardiovascular disease or condition (even if under control) must be discussed with the Medical Monitor before being randomized in the study.

* 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.
* 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.
* Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically significant impaired hepatic function through clinical and laboratory evaluation (use screening values for 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.
* 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 (e.g., heart failure, hypokalemia, family history of Long QT Syndrome or Brugada Syndrome) or cardiac conduction disorders, or requires treatment with an antiarrhythmic medication.
* Subject has family history of QTc prolongation or of unexplainable sudden death at \< 50 years of age.
* Abnormal 12 lead ECG at Screening, including:

  * QTcF \> 450 ms (male subjects) or \> 470 ms (female subjects)
  * QRS \> 110 ms
  * PR \> 200 ms
  * Second- or third-degree atrioventricular block
  * Any rhythm other than sinus rhythm, which is interpreted by the Investigator to be clinically significant
* Subject has a history of neuroleptic malignant syndrome (NMS).
* Subject exhibits evidence of severe tardive dyskinesia, severe dystonia, or any other severe movement disorder. Severity is to be determined by the investigator.
* Subject has been diagnosed with type 1 diabetes, or insulin-dependent diabetics.
* Subject who has any abnormal laboratory parameter at screening that indicates a clinically significant medical condition as determined by the investigator. 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. Subjects who are found to have been non-fasting at Screening may be allowed if their blood glucose is \< 200 mg/dL. Subjects with random (nonfasting) blood glucose at screening ≥ 200 mg/dL (11.1 mmol/L) must be retested in a fasted state. Subjects with HbA1c \> 7.0% will be excluded.
* Subject has a prolactin concentration \> 100 ng/mL at screening or have a history of pituitary adenoma.
* Subject has a body mass index (BMI) ≥ 40 or \< 18 kg/m2.
* 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.
* 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.
* Subject tests positive for drugs of abuse at screening or baseline. In the event a subject tests positive for cannabinoids (tetrahydrocannabinol), the investigator will evaluate the subject's ability to abstain from cannabis during the study. This information will be discussed with the Medical Monitor for study enrollment consideration.
* Subject has a history of hypersensitivity to more than two distinct chemical classes of drug (e.g., sulfas and penicillins).
* Subjects have received depot neuroleptics unless the last injection was at least one treatment cycle before randomization.
* Subject requires treatment with a drug that consistently prolongs the QTc interval
* Subject has received ECT within 90 days prior to randomization or is expected to require ECT during the study course.
* Subject is currently participating, or has participated in a study with an investigational or marketed compound or device within 6 months prior to signing the informed consent, or has participated in 3 or more studies within 18 months prior to signing the informed consent.

Primary outcomes:
measure: Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at Week 6
timeFrame: 6 Weeks
Secondary outcomes:
measure: Change From Baseline in Global Severity Assessed by the Clinical Global Impressions - Severity: Bipolar Version (CGI-BP-S) Score (Depression) at Week 6
timeFrame: 6 Weeks
Other outcomes:
Locations:
city: Cerritos
country: United States
facility: CNS Research Science, Inc.
state: California
city: Garden Grove
country: United States
facility: Collaborative Neuroscience Network, LLC
state: California
city: San Diego
country: United States
facility: Artemis Insitute for Clinical Research
state: California
city: Jacksonville
country: United States
facility: Clinical Neuroscience Solutions, Inc.
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions, Inc.
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Everett
country: United States
facility: Eastside Therapeutic Resource dba Core Clinical Research
state: Washington
city: Burgas
country: Bulgaria
facility: Mental Health Centre -Prof. Dr. Ivan Temkov - Burgas EOOD
city: Kardzhali
country: Bulgaria
facility: State Psychiatric Hospital-Kardzhali
city: Kazanlak
country: Bulgaria
facility: MHAT-Dr. Hristo Stambolski EOOD, Department of Psychiatry
city: Ruse
country: Bulgaria
facility: Mental Health Center - Ruse EOOD
city: Shumen
country: Bulgaria
facility: Neli Nikolova Todorova, MD ,State Psychatric Hospital - s. Tsarev brod
city: Sofia
country: Bulgaria
facility: Mental Health Center - Sofia EOOD
city: Fukuoka
country: Japan
facility: Fukuoka University Hospital
city: Fukuoka
country: Japan
facility: Hatakeyama Clinic, Department of Psychiatry
city: Fukuoka
country: Japan
facility: Hiro Mental Clinic, Department of Psychiatry
city: Fukuoka
country: Japan
facility: Kokura Mental Clinic
city: Fukuoka
country: Japan
facility: Kuramitsu Hospital, Department of Psychiatry
city: Fukuoka
country: Japan
facility: Shinseikai Kaku Mental Clinic, Department of Psychiatry
city: Fukuoka
country: Japan
facility: Someikai Kanagami Clinic, Department of Psychiatry
city: Fukushima
country: Japan
facility: Jisenkai Nanko Psychiatric Institute, Department of Psychiatry
city: Hyogo
country: Japan
facility: Takahashi Psychiatric Clinic
city: Kanagawa
country: Japan
facility: Azamino Mental clinic, Department of Psychiatry
city: Kanagawa
country: Japan
facility: Medical Corporation Seishinkai Kishiro Mental Clinic, Department of Psychiatry
city: Kanagawa
country: Japan
facility: Musashikosugi J. Kokorono Clinic
city: Kanagawa
country: Japan
facility: Yokohama Onoecho Clinic, Department of Psychiatry
city: Kanagawa
country: Japan
facility: Yutaka Clinic
city: Kyoto
country: Japan
facility: SagaArashiyama / Tanaka Clinic, Department of Psychiatry
city: Minato-Ku, Tokyo
country: Japan
facility: Minami-aoyama Anique Street Clinic, Department of Psychiatry
city: Okayama
country: Japan
facility: Clinic Sophia
city: Osaka
country: Japan
facility: Nagaokai Neyagawa Sanitorium
city: Osaka
country: Japan
facility: Asakayama Hospital
city: Osaka
country: Japan
facility: Koshokai Ainhanazono Hospital
city: Osaka
country: Japan
facility: Osaka Institute of Clinical Psychiatry Shin-abuyama Hospital
city: Tokyo
country: Japan
facility: Etoh Mental Clinic Meguro, Department of Psychiatry
city: Tokyo
country: Japan
facility: Himorogi Psychiatric Institute, Department of Psychiatry
city: Tokyo
country: Japan
facility: JCHO Yokyo Shinjuku Medical Center
city: Tokyo
country: Japan
facility: Jisenkai Hozumi Himorogi Clinic, Department of Psychiatry
city: Tokyo
country: Japan
facility: Maynds Tower Mental Clinic, Department of Psychiatry
city: Tokyo
country: Japan
facility: Nishi-shinjuku Concieria Clnic
city: Tokyo
country: Japan
facility: Ohwa Mental clinic, Department of Psychiatry
city: Tokyo
country: Japan
facility: Sangenjaya Nakamura Mental Clinic, Department of Psychiatry
city: Tokyo
country: Japan
facility: Sangenjaya Neurology-Psychosomatic Clinic, Department of Psychiatry
city: Tokyo
country: Japan
facility: Senzoku Psychosomatic Clinic, Department of Psychiatry
city: Tokyo
country: Japan
facility: Shinjuku Research Park Clinic
city: Tokyo
country: Japan
facility: Tamaki Clinic, Department of Psychiatry
city: Tokyo
country: Japan
facility: Uguisudani Mental Clinic, Department of Psychiatry
city: Tokyo
country: Japan
facility: Yoyogi Mental Clinic
city: Bydgoszcz
country: Poland
facility: Przychodnia Srodmiescie Sp. z.o.o.
city: Leszno
country: Poland
facility: Niepubliczny Zaklad Opieki Psychiatrycznej MENTIS
city: Lublin
country: Poland
facility: Specjalistyczna Praktyka Lekarska Marek Domanski
city: Poznan
country: Poland
facility: Filip Rybakowski Specjalistyczna Praktka Lekarska
city: Pruszcz Gdanski
country: Poland
facility: Poradnia Zdrowia Psychicznego "Syntonia"
city: Torun
country: Poland
facility: Gabinet Lekarski Torunskie Centrum PsychiatriI NEUROMED
city: Torun
country: Poland
facility: Osrodek Badan Klinicznych Clinsante Spolka Cywilna
city: Lipetsk
country: Russian Federation
facility: Lipetsk regional psychoneurological hospital
city: Moscow
country: Russian Federation
facility: State Budgetary Institution of Healthare of the City of Moscow "Psychiatric clinical Hospital #4 n.a. P.B. Gannushkin of the Department of Healthcare of the City o Moscow" Branch "Psychiatric hospital n.a. V.A. Gilyarovsky"
city: Nizhniy Novgorod
country: Russian Federation
facility: State Budgetary Institution of Healthcare of Nizhniy Novgorod region "Clinical Psychiatric Hospital #1 of Nizhniy Novgorod"
city: Omsk
country: Russian Federation
facility: Budgetary Institution of Healthcare of Omsk region "Clinical Psychiatric Hospital named after N.N. Solodnikov"
city: Rostov-on-don
country: Russian Federation
facility: Limited Liability Company "Treatment and Rehabilitational Scientific Center Phoenix"
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg State Institution of Healthcare "Psychiatric Hospital of Sain Nikolai hudotvorets "
city: Saint Petersburg
country: Russian Federation
facility: Federal State Budgetary Institution "National Medical Research Centre of psychiatry and nuerology named after V.M. Bekhterev" of the Ministry of Healthcare of the Russian Federation, department #12
city: Saint Petersburg
country: Russian Federation
facility: Stain Petersburg State Budgetary Institution of Healthcare "Psychoneurological Dispensary #1"
city: Saratov
country: Russian Federation
facility: State Institution of Healtcare "Regional Clinical Psychiatric Hospital of Saint Sofia"
city: Tomsk
country: Russian Federation
facility: Limited Liability Company "Clinic StoLet"
city: Belgrade
country: Serbia
facility: Bel Medic General Hospital
city: Belgrade
country: Serbia
facility: Clinical Center "Dr. Dragisa Misovic-Dedinje"
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Belgrade
country: Serbia
facility: General Hospital Euromedik
city: Belgrade
country: Serbia
facility: Institute of Mental Health
city: Kovin
country: Serbia
facility: Special Hospital for Psychiatric Diseases "Kovin"
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac
city: Bratislava
country: Slovakia
facility: Vavrusova Consulting s.r.o. Psychiatricka ambulancia
city: Kosice
country: Slovakia
facility: Investa spol. s.r.o., Kosice Psychiatricka ambulancia
city: Rimavska Sobota
country: Slovakia
facility: Psycholine s.r.0. Psychiatricka ambulancia
city: Svidnik
country: Slovakia
facility: Centrum zdravia R.B.K. Psychiatricka ambulancia
city: Vranov nad Toplou
country: Slovakia
facility: Crystal Comfort s.r.o. Psychiatricka ambulancia
city: Ivano-Frankivsk
country: Ukraine
facility: Regional Psychoneurological Hospital #3, Department of Neurosis and Borderline States # 8
city: Kharkiv
country: Ukraine
facility: State Institution Institue of Neurology, Psychiatry and Narcology of NAMS of Ukraine, Unit of Emergency sychiatry and Narcology
city: Kharkiv
country: Ukraine
facility: State Institution Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine, Unit of Borderline Psychiatry
city: Kherson
country: Ukraine
facility: CI Kherson Regional Psychiatric Hospital of Kherson Regional Council, Male Dep of Psychiatry #3, Female Dep of Psychiatry #10
city: Kyiv
country: Ukraine
facility: Communal Institution (CI) of Kyiv Regional Council regional Psychiatric and Narcological Medical Assocation, Dep #10 (male), Dep #2 (female)
city: Odesa
country: Ukraine
facility: Communal Institution Odesa regional Medical Center of Mental Health, Dep #6 (Male), Dep #12 (Female)
city: Odesa
country: Ukraine
facility: Communal Institution Odesa Regional Psychiatric Hospital #2, Department #14 (female), Department #16 (male)
city: Smila
country: Ukraine
facility: Communal Institution Cherkasy regional Psychiatric Hospital of Cherkasy Regional Council, Female Department #11, Male Department #12
city: Uzhgorod
country: Ukraine
facility: Transcarpathian Regional Narcological Dispensary, Department of Psychiatry
city: Vinnytsia
country: Ukraine
facility: communal Institution Acad. O.I. Yushchenko Vinnytsia Regional Psychoneurological hosital, Male Deparmtent #14, Female Department #15, Vinnytsia M.I. Pyrogov National Medical University, Chair of Psychiatry, Narcology and Psychotherapy with the Course of P
Study officials:
affiliation: Sumitomo Pharma America, Inc.
name: CNS Medical Director
role: STUDY_CHAIR
References:
citation: Hopkins SC, Wilkinson S, Corriveau TJ, Nishikawa H, Nakamichi K, Loebel A, Koblan KS. Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5-HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders. Clin Pharmacol Ther. 2021 Sep;110(3):808-815. doi: 10.1002/cpt.2282. Epub 2021 Jun 12.