A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of iloperidone for 4 weeks in the treatment of patients with acute manic episodes associated with Bipolar I Disorder

INTERVENTION: Product Name: Iloperidone Product Code: VYV‐683 Pharmaceutical Form: Capsule INN or Proposed INN: ILOPERIDONE CAS Number: 133454‐47‐4 Current Sponsor code: VYV‐683 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Iloperidone Product Code: VYV‐683 Pharmaceutical Form: Capsule INN or Proposed INN: ILOPERIDONE CAS Number: 133454‐47‐4 Current Sponsor code: VYV‐683 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 3‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Iloperidone Product Code: VYV‐683 Pharmaceutical Form: Capsule INN or Proposed INN: ILOPERIDONE CAS Number: 133454‐47‐4 Current Sponsor code: VYV‐683 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 6‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Iloperidone Product Code: VYV‐683 Pharmaceutical Form: Capsule INN or Proposed INN: ILOPERIDONE CAS Number: 133454‐47‐4 Current Sponsor code: VYV‐683 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 9‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Iloperidone Product Code: VYV‐683 Pharmaceutical Form: Capsule INN or Proposed INN: ILOPERIDONE CAS Number: 133454‐47‐4 Current Sponsor code: VYV‐683 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 12‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Iloperidone Product Code: VYV‐683 Pharmaceutical Form: Tabl CONDITION: Acute manic episodes associated with Bipolar I Disorder ; MedDRA version: 20.0 Level: PT Classification code 10004939 Term: Bipolar I disorder System Organ Class: 10037175 ‐ Psychiatric disorders Therapeutic area: Psychiatry and Psychology [F] ‐ Mental Disorders [F03] PRIMARY OUTCOME: Main Objective: Study Primary Objective:; ; • To evaluate the efficacy of iloperidone monotherapy compared to placebo in the treatment of adult patients with bipolar I disorder experiencing an acute manic or mixed episode as measured by reduction in the Young Mania Rating Scale (YMRS) total score at Week 4; ; Primary Objective for the Optional Long‐Term Open‐Label Phase:; ; • To explore the long‐term safety and tolerability of dosing with iloperidone over an additional 52 weeks of treatment; ; Primary end point(s): The primary efficacy outcome measure is the change from baseline in the Young Mania Rating Scale (YMRS) Secondary Objective: •Evaluate efficacy of iloperidone monotherapy vs placebo in the treatment of adult patients diagnosed with bipolar I disorder experiencing an acute manic or mixed episode as measured by:; 1) improvements in the CGI‐S ; 2) reduction in the YMRS total score at each trial visit; 3) improvement in clinical symptoms in the CGI‐C; 4) improvement in clinical symptoms in the MADRS; ; •Assess the rate of YMRS responders. A YMRS responder is defined as at least a 50% decrease from baseline in YMRS total score; ; •Assess safety & tolerability of iloperidone vs placebo in the treatment of adult patients in an acute manic or mixed episode of bipolar I disorder as measured by changes in vital signs and weight, laboratory analytes, ECGs, and the incidence and severity of TEAEs and extrapyramidal symptoms using the BARS, SAS, and the AIMS; ; Exploratory objective: conduct a whole genome association scan to identify potential markers of response and safety for a bipolar indication Timepoint(s) of evaluation of this end point: YMRS total score at Week 4. SECONDARY OUTCOME: Secondary end point(s): Mean baseline‐to‐endpoint change in total score using following parameters:; ; Efficacy parameters: ; ; • Young Mania Rating Scale (YMRS) ; • Overall and mania severity of illness for Clinical Global Impression of Severity (CGI‐S); • Clinical Global Impression of Change (CGI‐C); • Montgomery‐Asberg Depression Rating Scale (MADRS); ; Safety parameters: ; ; • Adverse Events (AEs) and proportion of patients withdrawing due to AEs ; • EPS scale scores as measured by Simpson‐Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BARS) ; • Metabolic risk factors, clinical chemistry, hematology, vital signs, and weight; • Columbia Suicide‐Severity Rating Scale (C‐SSRS); • CYP2D6 genotyping ; • 12‐lead electrocardiograms (ECG); Timepoint(s) of evaluation of this end point: Efficacy parameters: ; ; • YMRS is completed at visits 1 to 8, 11, 14, 15 and 16; • CGI‐C is completed at visits 3 to 8, 11, 14, 15 and 16; • CGI‐S is completed at visits 2 to 8, 11, 14, 15 and 16; • MADRS is completed at visits 2, 3, 5, 6, 7, 8, 11, 14, 15 and 16; ; Safety parameters:; ; • SAS, BARS and AIMS are completed at visits 1 to 8, 11, 14, 15 and 16; • C‐SSRS is completed in all visits; • CYP2D6 genotyping is performed at screening (visit 1); ; Safety will be monitored throughout the entire study and as described in study protocol.; ; INCLUSION CRITERIA: Each patient must meet the following criteria for inclusion in the study: 1. Patients must provide written informed consent (IC) before any assessment is performed. Additionally, if a patient is not mentally stable to provide consent their legal guardian must also sign the inform consent form in accordance with the regulatory requirements for their respective country. 2. Males or non‐fecund females (i.e., surgically sterilized, if procedure was done 6 months before screening or patient is postmenopausal, without menses for 12 months before screening), or females of childbearing potential using adequate contraception from 1 month prior to randomization through 1 month after the last dose of study medication. Note: Examples of acceptable methods of contraception for females include the use of 2 independent barrier methods, hormonal contraception plus 1 barrier method, or surgically sterilized partner. 3. Patients must be 18 through 65 year