A Study of Aripiprazole (Abilify) in Patients With Bipolar Mania

Mean Baseline and Unadjusted Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Total Score Through Phase 2

The Y-MRS consists of 11 items: 1) Elevated Mood, 2) Increased Motor Activity -Energy, 3) Sexual Interest, 4) Sleep, 5) Irritability, 6) Speech (Rate and Amount), 7) Language -Thought Disorder, 8) Content, 9) Disruptive-Aggressive Behavior, 10) Appearance, 11) Insight. Seven items are rated on a 0 to 4 scale, while 4 items (items 5, 6, 8 and 9) are rated on a 0 to 8 scale (twice the weight of the other items.) For all items, 0 is the "best" rating and 4 or 8 is the "worst" rating. Total Score is the sum of the ratings for all 11 items. The possible Total Scores are from 0 (best) to 60 (worst).

Time frame: Baseline (end of ph 1), Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 (Ph2) Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, + Confirmation of Partial Nonresponse Phase)

Mean Baseline and Adjusted Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Total Score Through Phase 3

The Y-MRS consists of 11 items: 1) Elevated Mood, 2) Increased Motor Activity -Energy, 3) Sexual Interest, 4) Sleep, 5) Irritability, 6) Speech (Rate and Amount), 7) Language -Thought Disorder, 8) Content, 9) Disruptive-Aggressive Behavior, 10) Appearance, 11) Insight. 7 items are rated on a 0 to 4 scale, while 4 items (items 5, 6, 8 and 9) are rated on a 0 to 8 scale (twice the weight of the other items.) For all items, 0 is the "best" rating and 4 or 8 is the "worst" rating. Total Score is the sum of the ratings for all 11 items. The possible Total Scores are from 0 (best) to 60 (worst).

Time frame: Baseline (end of Ph 2), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 of Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Mean Baseline and Unadjusted Mean Change From Baseline in Montgomery Åsberg Depression Rating Scale (MADRS) Total Score Through Phase 2 and at Phase 2 Endpoint

The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. MADRS total score, a 10-item, ordinal rating scale (0=no symptoms; 60=most severe symptoms). Change from baseline=postbaseline score - baseline score. A negative change score indicates improvement.

Time frame: Baseline (end of Ph 1), Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 (Ph2) Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Mean Baseline and Adjusted Mean Change From Baseline in Montgomery Åsberg Depression Rating Scale (MADRS) Total Score Through Phase 3

The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. MADRS total score, a 10-item, ordinal rating scale (0=no symptoms; 60=most severe symptoms). Change from baseline=postbaseline score - baseline score. A negative change score indicates improvement.

Time frame: Baseline (end of Ph 2), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Unadjusted Mean Change Baseline and Mean Change From Baseline in the CGI-BP Severity of Illness (Overall) Through Phase 2

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline (end of Ph 1), Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Baseline and Adjusted Mean Change From Baseline in the CGI-BP Severity of Illness (Overall) Through Phase 3

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline (end of Ph 2), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Unadjusted Mean Change Baseline and Mean Change From Baseline in the CGI-BP Severity of Illness (Depression) Through Phase 2

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from baseline (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline (end of Ph 1), Weeks 1, 2, 4,6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Baseline and Adjusted Mean Change From Baseline in CGI-BP Severity of Illness (Depression) Score Through Phase 3

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline (end of Ph 2), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Unadjusted Mean Change From Preceding Phase in the CGI-BP (Mania) Through Phase 2

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall change from preceding phase items on a 7-point scale \[1 to 7\], with 1 being very much improved and 7 being very much worse).

Time frame: Weeks 1, 2, 4,6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Unadjusted Mean Baseline and Mean Change From Baseline in the CGI-BP Severity of Illness (Mania) Through Phase 2

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from baseline (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline (end of Ph 1), Weeks 1, 2, 4,6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Adjusted Mean Change in CGI-BP From Preceding Phase (Mania) Through Phase 3

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Unadjusted Mean Change From Preceding Phase in the CGI-BP (Depression) Through Phase 2

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being very much improved and 7 being very much worse).

Time frame: Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Adjusted Mean Change in CGI-BP From Preceding Phase (Depression) Through Phase 3

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline (in this case, preceding phase) in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale \[1 to 7\], with 1 being very much improved and 7 being very much worse).

Time frame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Unadjusted Mean Change From Preceding Phase in the CGI-BP (Overall) Through Phase 2

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline (in this case, preceding phase) in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale \[1 to 7\], with 1 being very much improved and 7 being very much worse).

Time frame: Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Adjusted Mean Change in CGI-BP From Preceding Phase (Overall) Through Phase 3

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline (in this case, preceding phase) in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale \[1 to 7\], with 1 being very much improved and 7 being very much worse).

Time frame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Number of Participants Maintaining Remission During Phase 3

Remission is defined as Y-MRS Total Score \<=12 and MADRS Total Score \<=12.

Time frame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Proportion of Participants Discontinuing For Any Reason Through Week 52 (During Phase 3)

Time frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuations Due to AEs During Phase 2

Participants with Adverse Events (AEs), Deaths, Serious AEs (SAEs), and AEs leading to study discontinuation. AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.

Time frame: During Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Treatment-Emergent Adverse Events in >=5 Percent of Participants, by Severity, During Phase 2

AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. By Common Terminology Criteria Version 3.0 (CTC v3) Grade (Gr): Gr 1 (mild); Gr 2 (moderate); Gr 3 (severe); Gr 4 (life-threatening); Gr 5 (death).

Time frame: During Phase 2. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Number of Participants With Potentially Clinically Relevant Electrocardiogram (ECG) Abnormalities During Phase 2

Sinus Tachycardia: ≥120bpm+↑≥15bpm+no current diagnosis of supraventricular (SV) or ventricular tachycardia or atrial fibrillation (AF) or flutter or other rhythm abnormality (RA). Sinus Bradycardia:≥50bpm+↓≥15bpm+no current diagnosis of AF or flutter or other RA. AF:not present→present or present at rate \<100bpm pretreatment to present with rate ≥100bpm+increase of ≥15bpm. AV=atrioventricular; PR=PR interval. Other Intraventricular Block: QRS wave ≥0.12 sec+↑≥0.02 sec+no current diagnosis of left or right bundle branch block. Old Infarction not present→present at ≥12 weeks post study entry.

Time frame: Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Number of Participants With Potentially Clinically Relevant Vital Sign Abnormalities During Phase 2

Heart Rate: increase, ≥120 beats per minute (bpm) and ≥15 relative to baseline (RBL); decrease, ≤50 bpm and ≥15 RBL. Systolic BP: increase, ≥180 mmHg and ≥20 RBL; decrease, ≤90 mmHg and ≥20 RBL. Diastolic BP: increase, ≥105 mmHg and ≥15 RBL; decrease, ≤50 mmHg and ≥15 RBL. For patients missing a baseline value, an on-treatment value was considered potentially clinically relevant if the value meets the criterion value.

Time frame: Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Number of Participants With Potentially Clinically Relevant Laboratory Abnormalities During Phase 2

ULN=upper limit of normal; HDL=high density lipoprotein; LDL=low density lipoprotein. Values for ULN are provided by the lab in the database and could be different for each individual patient based on characteristics such as age, gender, or other patient attributes.

Time frame: Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Median Baseline and Change From Baseline in ECG Measurements During Phase 2

Time frame: Baseline (end of Ph 1), Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Median Baseline and Change From Baseline in Heart Rate Vital Sign Measurements During Phase 2

Time frame: Baseline (end of Ph 1), Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Median Baseline and Change From Baseline in Blood Pressure (BP) Vital Sign Measurements During Phase 2

Time frame: Baseline (end of Ph 1), Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Median Baseline and Change From Baseline in Weight Vital Sign Measurements At Phase 2 Endpoint

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Median Baseline and Change From Baseline in Body Mass Index (BMI) Vital Sign Measurements at Phase 2 Endpoint

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Median Baseline Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), and Lactate Dehydrogenase (LD), Phase 2 Safety Sample

Time frame: Baseline

Median Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), and Lactate Dehydrogenase (LD) at the End of Phase 2

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Median Baseline and Change From Baseline in Heart Rate Measurements During Phase 2

Time frame: Baseline (end of Ph 1), Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Median Baseline Blood Urea Nitrogen (BUN), Total Cholesterol-Fasting (TC), Creatine, Glucose, High Density Lipoprotein Cholesterol-Fasting (HDL-C), Low Density Lipoprotein Cholesterol-Fasting (LDL-C), Bilirubin-Total, Triglycerides, and Uric Acid

Time frame: Baseline

Median Change From Baseline in BUN, TC, Creatine, Glucose, HDL-C, LDL-C, Bilirubin-Total, Triglycerides, and Uric Acid at the End of Phase 2

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Median Baseline Eosinophils (Relative) and Neutrophils (Relative)

Time frame: Baseline

Median Change From Baseline in Eosinophils (Relative) and Neutrophils (Relative)

Time frame: Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Median Baseline Hemoglobin

Time frame: Baseline

Median Change From Baseline in Hemoglobin

Time frame: Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Median Baseline Hematocrit

Time frame: Baseline

Median Change From Baseline in Hematocrit

Time frame: Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Median Baseline Homeostasis Model Assessment 2 (HOMA2)-Percent Beta

HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses beta-cell function (HOMA2-%β) relative to expected normal function (indexed to 100% for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-%Beta is a percentage of 'normal function.'

Time frame: Baseline

Median Baseline Homeostasis Model Assessment 2 HOMA2-Insulin Resistance (IR)

HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses insulin resistance (HOMA2-IR) relative to expected normal function (indexed to 1.0 for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-IR is a proportion of 'normal function.'

Time frame: Baseline

Median Change From Baseline in Homeostasis Model Assessment 2(HOMA2)-Percent Beta at Phase 2 Endpoint

HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses beta-cell function (HOMA2-%β) relative to expected normal function (indexed to 100% for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-%Beta is a percentage of 'normal function.'

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint (endpoint of a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Median Change From Baseline in HOMA2 Model Assesses Insulin Resistance (HOMA2-IR) at Phase 2 Endpoint

HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses insulin resistance (HOMA2-IR) relative to expected normal function (indexed to 1.0 for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-IR is a proportion of 'normal function.'

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint (endpoint of a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase)

Median Baseline Platelet Count

Time frame: Baseline

Median Change From Baseline in Platelet Count at Phase 2 Endpoint

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Median Baseline Prolactin

Time frame: Baseline

Median Change From Baseline in Prolactin at Phase 2 Endpoint

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Median Baseline Leukocytes

Time frame: Baseline

Median Change From Baseline in Leukocytes at Phase 2 Endpoint

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Baseline Abnormal Involuntary Movement Scale (AIMS)

The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). The AIMS Total Score has a possible range from 0 to 28. Negative change scores indicate improvement in movement dysfunction.

Time frame: Baseline

Unadjusted Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) at Phase 2 Endpoint

The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). The AIMS Total Score has a possible range from 0 to 28. Negative change scores indicate improvement in movement dysfunction.

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Baseline in Simpson-Angus Scale (SAS) Total Score

The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50.(lower score=less severe). Negative change scores indicate improvement.

Time frame: Baseline

Unadjusted Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score at Phase 2 Endpoint

The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50(lower score=less severe). Negative change scores indicate improvement.

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Baseline in Barnes Akathisia Global Clinical Assessment

The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia.

Time frame: Baseline

Unadjusted Mean Change From Baseline in Barnes Akathisia Global Clinical Assessment at Phase 2 Endpoint

The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia.

Time frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase)

Deaths, Treatment-Emergent Serious Adverse Events (SAEs), Adverse Events (AEs) in >=2% of Participants, and AEs Leading to Discontinuation During Phase 3

Participants with Adverse Events (AEs), Deaths, Serious AEs (SAEs), and AEs leading to study discontinuation. AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.

Time frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Treatment-Emergent AEs in >=5% of Participants During Phase 3, by Age, Gender, Race, and Maximum Intensity

AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. By Common Terminology Criteria Version 3.0 (CTC v3) Grade (Gr): Gr 1 (mild); Gr 2 (moderate); Gr 3 (severe); Gr 4 (life-threatening); Gr 5 (death).

Time frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Participants With Potentially Clinically Relevant Vital Sign Abnormalities During Phase 3

Heart Rate: increase, ≥120 beats per minute (bpm) and ≥15 relative to baseline (RBL); decrease, ≤50 bpm and ≥15 RBL. Systolic BP: increase, ≥180 mmHg and ≥20 RBL; decrease, ≤90 mmHg and ≥20 RBL. Diastolic BP: increase, ≥105 mmHg and ≥15 RBL; decrease, ≤50 mmHg and ≥15 RBL. For patients missing a baseline value, an on-treatment value was considered potentially clinically relevant if the value meets the criterion value.

Time frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Median Baseline, Change From Baseline, and Highest and Lowest Values in Supine Systolic BP During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Median Baseline, Change From Baseline, and Highest and Lowest Values in Supine Diastolic BP During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Median Baseline, Change From Baseline, and Highest and Lowest Values in Supine Heart Rate During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Median Baseline, Change From Baseline, and Highest and Lowest Values in Sitting Systolic BP During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Median Baseline, Change From Baseline, and Highest and Lowest Values in Sitting Diastolic BP During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Median Baseline, Change From Baseline, and Highest and Lowest Values in Sitting Heart Rate During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Median Baseline, Change From Baseline, and Highest and Lowest Values in Standing Systolic BP During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Median Baseline, Change From Baseline, and Highest and Lowest Values in Standing Diastolic BP During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Median Baseline, Change From Baseline, and Highest and Lowest Values in Standing Heart Rate During Phase 3

Time frame: Baseline, During Phase 3 (for highest/lowest values), Week 52

Baseline and Adjusted Mean Change From Baseline in Weight

Time frame: Baseline, Weeks 12, 24, 36, 52, During Phase 3 (for highest value)

Number of Participants Showing Relevant Weight Gain During Phase 3

Relevant weight gain: \>=7% increase from baseline

Time frame: Weeks 12, 24, 36, 52, 52 (LOCF), and throughout Phase 3 (for 'at any time' assessment)

Number of Participants Showing Relevant Weight Loss During Phase 3

Relevant weight loss: \>=7% decrease from baseline

Time frame: Weeks 12, 24, 36, 52, 52 (LOCF), and throughout Phase 3 (for 'at any time' assessment)

Median Baseline and Change From Baseline in Body Mass Index (BMI) During Phase 3

Time frame: Baseline, Week 12, Week 24, Week 36, Week 52, Week 52 (LOCF), During Phase 3 (for lowest/highest values)

Number of Participants With Potentially Clinically Relevant Laboratory Abnormalities During Phase 3

ULN=upper limit of normal; Hb=hemoglobin

Time frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Median Baseline, Change From Baseline, and Highest Value of Change in Alkaline Phosphatase (ALP), Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in ALT, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in AST, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in BUN, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Total Cholesterol (Fasting), Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Creatine Kinase, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Creatinine, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Eosinophils (Relative), Phase 3 Safety Sample

The change values reported are the median of (post baseline percentage (of white blood cell count) minus baseline percentage (of white blood cell count).

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Glucose (Fasting), Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Lowest Value of Change in Hemoglobin, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for lowest value)

Median Baseline, Change From Baseline, and Lowest Value of Change in Hematocrit, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for lowest value)

Median Baseline, Change From Baseline, and Lowest Value of Change in HDL Cholesterol (Fasting), Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for lowest value

Median Baseline, Change From Baseline, and Highest Value of Change in HOMA2-Percent Beta, Phase 3 Safety Sample

HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses beta-cell function (HOMA2-%β) relative to expected normal function (indexed to 100% for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-%Beta is a percentage of 'normal function.'

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value

Median Baseline, Change From Baseline, and Highest Value of Change in HOMA2-IR, Phase 3 Safety Sample

HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses insulin resistance (HOMA2-IR) relative to expected normal function (indexed to 1.0 for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-IR is a proportion of 'normal function.'

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value

Median Baseline, Change From Baseline, and Highest Value of Change in Lactate Dehydrogenase, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Change Value in LDL Cholesterol (Fasting), Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Neutrophils (Relative), Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest and Lowest Value of Change in Platelet Count, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest/lowest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Prolactin, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Total Bilirubin, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Triglycerides (Fasting), Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in Uric Acid, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest and Lowest Value of Change in Leukocytes, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest/lowest value)

Number of Participants With Potentially Clinically Relevant Electrocardiogram (ECG) Abnormalities During Phase 3

Sinus Tachycardia: ≥120bpm+↑≥15bpm+no current diagnosis of supraventricular (SV) or ventricular tachycardia or atrial fibrillation (AF) or flutter or other rhythm abnormality (RA). Sinus Bradycardia:≥50bpm+↓≥15bpm+no current diagnosis of AF or flutter or other RA. AF:not present→present or present at rate \<100bpm pretreatment to present with rate ≥100bpm+increase of ≥15bpm. AV=atrioventricular; PR=PR interval. Other Intraventricular Block: QRS wave ≥0.12 sec+↑≥0.02 sec+no current diagnosis of left or right bundle branch block. Old Infarction not present→present at ≥12 weeks post study entry.

Time frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Median Baseline, Change From Baseline, and Highest Value of Change in QT Interval Corrected for Heart Rate (QTc) Bazett, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in QTc (0.33), Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in PR, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in RR, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Median Baseline, Change From Baseline, and Highest Value of Change in QRS, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Adjusted Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score During Phase 3

The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50(lower scores=less severe). Negative change scores indicate improvement.

Time frame: Baseline, Weeks 4,8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change)

Median Baseline, Change From Baseline, and Highest Value of Change in Heart Rate, Phase 3 Safety Sample

Time frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value)

Adjusted Mean Change From Baseline in AIMS Total Score During Phase 3

The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). The AIMS Total Score has a possible range from 0 to 28. Negative change scores indicate improvement in movement dysfunction.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change)

Adjusted Mean Change From Baseline in AIMS Item 8 During Phase 3

The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). AIMS Item 8 Score range from 0 to 4. A negative score signifies improvement.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change)

Adjusted Mean Change From Baseline in AIMS Item 9 During Phase 3

The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). AIMS Item 9 Score range from 0 to 4. A negative score signifies improvement.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change)

Adjusted Mean Change From Baseline in AIMS Item 10 During Phase 3

The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). AIMS Item 10 Score range from 0 to 4. A negative score signifies improvement.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change)

Adjusted Mean Change From Baseline in Barnes Akathisia Global Clinical Assessment During Phase 3

The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change)

Number of Participants Taking Concomitant Medications for Potential Treatment of Extrapyramidal Syndrome (EPS) During Phase 3

Time frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Mean Baseline and Mean Change From Baseline in CGI-BP (Mania)

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline, Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72 of LTE Phase. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Mean Change From Baseline in CGI-BP (Mania) Severity of Illness at Extension Phase Endpoint

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline, Extension Phase Endpoint. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Mean Change From Baseline in CGI-BP Severity of Illness (Depression) at Extension Phase Endpoint

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline, Extension Phase Endpoint. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Mean Baseline and Mean Change From Baseline in CGI-BP Severity of Illness (Depression) Through Extension Phase

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline, Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Mean Baseline and Mean Change From Baseline in CGI-BP Severity of Illness (Overall) Through Extension Phase

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline, Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Mean Change From Baseline in CGI-BP Severity of Illness (Overall) at Extension Phase Endpoint

Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale \[1 to 7\], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

Time frame: Baseline, Extension Phase Endpoint. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Deaths, Adverse Events (AES), Serious Adverse Events (SAEs), and Discontinuations

Participants with Adverse Events (AEs), Deaths, Serious AEs (SAEs), and AEs leading to study discontinuation. AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.

Time frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Participants With Potentially Clinically Relevant Metabolic Laboratory Abnormalities During Extension Phase

Metabolic abnormalities considered by the investigator as clinically relevant. (Need normal values for each.)

Time frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Participants With Potentially Clinically Relevant Vital Sign Abnormalities

Vital sign abnormalities considered by the investigator as clinically relevant.

Time frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Adverse Events (AEs), by Maximum Intensity

AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. By Common Terminology Criteria Version 3.0 (CTC v3) Grade (Gr): Gr 1 (mild); Gr 2 (moderate); Gr 3 (severe); Gr 4 (life-threatening); Gr 5 (death).

Time frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Participants With Potentially Clinically Relevant Laboratory Abnormalities

Chemistry, hematology, and urinalysis abnormalities considered by the investigator as clinically relevant. Hematocrit: ≤37%(M)/≤32%(F)+3 percentage pts↓from baseline.

Time frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])

Extension Phase: Participants With Potentially Clinically Relevant ECG Abnormalities

ECG abnormalities considered by the investigator as clinically relevant.Left Bundle Branch Block: Not present at Baseline--\> present post-baseline.

Time frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks])