E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Major depressive episodes associated with bipolar I or bipolar II disorder (bipolar depression) |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004936 |
E.1.2 | Term | Bipolar depression |
E.1.2 | System Organ Class | 100000004873 |
|
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 compare efficacy of 2 doses of ITI-007 adjunctive to treatment with lithium or valproate, administered orally once daily, to that of placebo adjunctive to treatment with lithium or valproate as measured by mean change from baseline to Day 43 in total score of the rater administered Montgomery-Åsberg Depression Rating Scale (MADRS) in patients with bipolar depression. |
|
E.2.2 | Secondary objectives of the trial |
Key secondary efficacy objective is to compare efficacy of 2 doses of ITI 007 adjunctive to treatment with lithium or valproate, administered orally once daily to that of placebo adjunctive to lithium or valproate as measured by mean change from baseline to Day 43 in Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S)-Depression score in patients with bipolar depression. Other objectives (not all listed): • compare efficacy of 2 doses of ITI 007 adjunctive to treatment with lithium or valproate, orally once daily to that of placebo adjunctive to lithium or valproate in relation to MADRS • Time course of improvement, measured by mean change from baseline in the CGI BP-S Depression score at each assessment time point, including at Day 43; • Mean change from baseline in Sheehan Disability Scale (SDS) total score (US patients only); • Mean change from baseline in Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF); |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. capable of understanding written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements. 2. between ages of 18 and 75 years, inclusive, at start of screening (both male and female patients). 3. Meets Diagnostic and Statistical Manual of Mental Disorder, 5th Edition (DSM-5) criteria for Bipolar I or Bipolar II Disorder as confirmed by the Investigator or Sponsor-approved expert site-based rater by a Structured Clinical Interview for DSM-5 Disorders – Clinical Trials Version (SCID-5-CT) (US sites only) or by the Mini International Neuropsychiatric Interview (MINI; non US sites only) and meeting all of the following 6 criteria: a. start of current MDE is at least 2 weeks but no more than 6 months prior to screening visit; b. Appropriate severity of illness, at least moderately ill, as measured by a rater administered MADRS total score ≥20 and corresponding to a CGI-BP-S Depression and Overall scores each ≥4 at the Screening and Baseline visits; c. Sufficient history and/or independent report verifying that current MDE is causing clinically significant distress or impairment in social, occupational, or other important areas of functioning; d. A lifetime history of at least 1 bipolar manic episode or mixed episode (for Bipolar I) or hypomanic episode (for Bipolar II); e. A rater-administered YMRS total score of ≤12 at screening and baseline visits. Presence of psychotic symptoms may result in an increased YMRS without evidence of mania/hypomania; therefore, a patient with a YMRS >12 AND psychotic symptoms may be included pending adjudication review for diagnostic certainty of depressive episode. f. A minimum of 28 days of treatment with either lithium (and 0.4 to 1.5 mEq/L blood level at screening) valproate (minimum 25 µg/mL blood level at screening) and inadequate therapeutic response of depressive symptoms (confirmed by the treating health care provider or other reliable source). A re-test of lithium or valproate levels is not permitted; any patient who does not meet either of the two requirements must be screen failed. 4. body mass index (BMI) of 18 to 35 kg/m2, inclusive. 5. highly effective methods of birth control for at least 2 weeks prior to randomization through to the end-of-study follow up visit or must be of nonchildbearing potential. 6. In the opinion of Investigator, patient is willing and able to comply with study requirements, study visits, and to return to the clinic for follow-up evaluations as specified by protocol.
|
|
E.4 | Principal exclusion criteria |
1.patient experiences a decrease in rater-administered MADRS total score of ≥25% between screening and baseline visits. 2. In the opinion of the Investigator, patient has a significant risk for suicidal behavior during the course of his or her participation in the study or a. At screening, scores “yes” on Items 4 or 5 in the Suicidal Ideation section of the C-SSRS with reference to a 6-month period prior to screening; or b. At screening, has had 1 or more suicidal attempts with reference to a 2-year period prior to screening; or c. At the baseline visit, scores “yes” on Items 4 or 5 in the Suicidal Ideation section of the C-SSRS with reference to screening; or d. At screening or baseline visit, scores ≥4 on Item 10 (suicidal thoughts) on the rater-administered MADRS; or e. Considered to be an imminent danger to himself, herself, or others. 3. The patient is pregnant or breast-feeding; female patients of childbearing potential must have negative serum and urine pregnancy tests at screening. On Day 1, female patients of childbearing potential must have a negative urine pregnancy test prior to study treatment administration. 4. Patient has a history within 12 months of screening, based on previous psychiatric evaluation or a confirmed diagnosis upon screening based on the DSM-5 as assessed by the SCID-5-CT, (US sites only) or by the Mini International Neuropsychiatric Interview (MINI; non US sites only), of a psychiatric diagnosis other than bipolar disorder, including: a. Schizophrenia or other psychotic disorder; b. Anxiety disorders such as panic disorder, general anxiety disorder, or post traumatic stress disorder as a primary diagnosis (however, anxiety symptoms may be allowed, if secondary to bipolar disorder, provided these symptoms do not require current treatment); c. Eating disorder; d. Primary diagnosis of obsessive compulsive disorder; e. Moderate or severe substance use disorder (including for cannabis, excluding for nicotine); f. Any other psychiatric condition (other than bipolar disorder) that has been the main focus of treatment within 12 months of screening; 5. Patients who have experienced hallucinations, delusions, or any other psychotic symptomatology in the current depressive episode may be allowed as long as these symptoms are not attributable to a primary DSM-5 diagnosis other than bipolar disorder as described in Exclusion Criterion 4. presence of these symptoms should be reviewed with the Medical Monitor and adjudication team on a case by case basis prior to inclusion. 6. patient has been hospitalized for mania associated with Bipolar I disorder within 30 days of screening. Note: This criterion is included to ensure that any manic phase has completely resolved before enrollment in the study 12. The patient has a positive test for drugs of abuse or alcohol test at the screening or baseline visits, or presents evidence of either withdrawal from or acute intoxication with cocaine, opiates, amphetamines (including methamphetamine), alcohol, barbiturates, or hallucinogens or similar compounds. 14. abnormal laboratory values or clinical findings at screening that are judged clinically significant and confirmed upon re-test (1 re-test prior to baseline visit is allowed and results must be available prior to the baseline visit and must have returned to within normal range), including, but not limited to: (most important listed): a. Aspartate aminotransferase (AST) >2.0 × upper limit of normal (ULN); b. Alanine aminotransferase (ALT) >2.0 × ULN; c. Alkaline phosphatase >2.0 × ULN; d. Gamma-glutamyl transpeptidase >2.0 × ULN; e. Total bilirubin >1.5 × ULN; 15. clinically significant cardiovascular, endocrine (including poorly controlled diabetes defined as glycated hemoglobin A1c [HbA1c] >53 mmol/mol [7.0%] at screening with no re-test allowed for HbA1c), hepatic, renal, pulmonary, gastrointestinal, neurological, malignancy (including any malignancy and/or chemotherapy within the 2 years prior to screening; malignancy more than 2 years prior to screening must have been local and without metastasis and/or recurrence, and if treated with chemotherapy, without nervous system complications; some malignancies, such as basal cell carcinoma, may not preclude participation and will be individually reviewed), pheochromocytoma, metabolic, psychiatric or other condition that might be detrimental to the patient if he or she participates in the study (in the opinion of the Investigator). 16. history of human immunodeficiency virus (HIV) infection or has HIV antibodies in blood at screening. 17.history of hepatitis B or hepatitis C infection AND at screening has evidence of active disease defined as elevated ALT, AST, or bilirubin levels as specified in Exclusion Criterion |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The change from baseline to Day 43 in the rater administered MADRS total score. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline to Day 43 in the MADRS total score. |
|
E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint is the mean change from baseline to Day 43 in the CGI BP-S-Depression score Other secondary: • MADRS: Mean change from baseline in the MADRS total score at each assessment time point; Time to first sustained response, defined as the number of days from first dose of study medication to the earliest date that the patient experiences a sustained ≥50% reduction from baseline in the MADRS total score. A sustained ≥50% reduction from baseline is defined as achievement of ≥50% reduction in MADRS total score at ≥ 2 consecutive visits that continues through the last assessment; The proportion of treatment responders, where response is defined as a ≥50% decrease in the MADRS total score from baseline at Days 8, 15, 22, 29, 36, and 43. Patients who discontinue treatment early will be imputed as non-responders in the responder analysis. The proportion of remitters, where remission is defined as a MADRS total score ≤12 at Days 8, 15, 22, 29, 36, and 43. Patients who discontinue treatment early will be imputed as non-remitters in the remitter analysis. Change from baseline in MADRS Item 4 “reduced sleep” score for patients with baseline MADRS Item 4 score ≥4 (patients with mild sleep disturbance) at Days 8, 15, 22, 29, 36, and 43. Change from baseline in MADRS individual item scores at Days 8, 15, 22, 29, 36, and 43. •Change from baseline in the CGI-BP-S score at Days 8, 15, 22, 29, 36, and 43; • Change from baseline in the SDS score for each item and total score at Days 22 and 43; Change from baseline in the Q-LES-Q-SF percent score at Days 22 and 43. •Change from baseline in the WHO-5 percent score at Days 22 and 43. •Change from baseline in the NEO-FFI percent score at Days 22 and 43. • Secondary Safety Endpoints: AEs; YMRS total score; C-SSRS scores; AIMS scores; BARS scores; SAS score; Physical examination and neurological findings; Vital signs (blood pressure, heart rate), weight, and waist circumference; ECGs; Clinical laboratory evaluations. • Pharmacokinetic Endpoints: Plasma levels of ITI-007 (IC200056 parent) at selected time points during treatment. Metabolite (IC200131, IC200161, IC200565, IC2001308, and IC2001309) concentrations may also be determined. • Exploratory Endpoints: Protein biomarkers such as p11 protein in blood samples; Genetic biomarkers.
|
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | 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) | 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 | 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 | 16 |
E.8.5 | The trial involves multiple Member States | No |
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 |
Russian Federation |
Serbia |
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
|
|
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 | 4 |
E.8.9.1 | In the Member State concerned days | 24 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 24 |