A Study to Evaluate SAGE-217 in Participants With Moderate to Severe Major Depressive Disorder

Phase 2

Completed

Conditions: Major Depression

Interventions: Drug: SAGE-217
Drug: Placebo

Registration Number: NCT03000530

Lead Sponsor: Biogen

Brief Summary: This is a two-part (open-label followed by double-blind) study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SAGE-217 in 102 participants diagnosed with moderate to severe Major Depressive Disorder.

Detailed Description: Part A of the study is an open-label design with dosing of SAGE-217 for 14 days.

Part B of the study is a randomized, double-blind, parallel-group, placebo-controlled design. Eligible participants were randomized to SAGE-217 or placebo for 14 days.

This study was previously posted by Sage Therapeutics. In November 2023, sponsorship of the trial was transferred to Biogen.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 102

Inclusion Criteria

Participant has a diagnosis of Major Depressive Disorder that has been present for at least a 4-week period as diagnosed by Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)

Exclusion Criteria

Participant has a history of suicide attempt
Participant has a history of treatment-resistant depression, defined as persistent depressive symptoms despite treatment with adequate doses of antidepressants from two different classes for an adequate amount of time
Participant has active psychosis
Participant has a medical history of seizures
Participant has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part A: SAGE-217	SAGE-217	Participants received SAGE-217, 30 milligrams (mg), oral solution, once daily for 14 days, as tolerated.
Part B: Placebo	Placebo	Eligible participants received matching placebo capsules once daily for 14 days.
Part B: SAGE-217	SAGE-217	Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) - Part A	Day 1 up to Day 21	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. A TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. The analysis was performed in participants included in Part A of the study.
Change From Baseline in Basophils to Leukocytes Ratio [Percentage (%)] - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as International System (SI) unit, percentage (%).
Change From Baseline in Eosinophils - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Neutrophils - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Neutrophils to Leukocytes Ratio (%) - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in Platelets - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Erythrocytes - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Eosinophils to Leukocytes Ratio (%) - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in Monocytes - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Percentage of Participants With TEAEs, Graded by Severity - Part A	Day 1 up to Day 21	Severity was assessed according to the following scale: mild (awareness of sign or symptom, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); severe (incapacitating, with inability to perform normal activities). The analysis was performed in participants included in Part A of the study.
Change From Baseline in Basophils - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Hematocrit - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Monocytes to Leukocytes Ratio (%) - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in Hemoglobin - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Lymphocytes - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Lymphocytes to Leukocytes Ratio (%) - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in Reticulocytes - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Leukocytes - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes and leukocytes. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Albumin - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Alkaline Phosphatase - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Alanine Aminotransferase - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Carbon Dioxide - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Creatinine - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Potassium - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Aspartate Aminotransferase - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Bilirubin - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Chloride - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Protein - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Sodium - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Urea Nitrogen - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, chloride, carbon dioxide, creatinine, potassium, protein, sodium, and urea nitrogen. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Activated Partial Thromboplastin Time - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Prothrombin International Normalized Ratio (%) - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination. The data for prothrombin international normalized ratio are presented as SI unit, percentage (%).
Change From Baseline in Prothrombin Time - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in pH - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline in Specific Gravity - Part A	Baseline, Day 8, Day 15/ET, follow-up Day 21, follow-up Day 28	Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part A of the study. ET = Early Termination.
Change From Baseline (CFB) in Supine Systolic Blood Pressure - Part A	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Supine Diastolic Blood Pressure - Part A	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Standing Systolic Blood Pressure - Part A	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Standing Diastolic Blood Pressure - Part A	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Heart Rate - Part A	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Oral Temperature - Part A	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Change From Baseline in QTcF Interval - Part A	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Change From Baseline in PR Interval - Part A	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Change From Baseline (CFB) in Respiratory Rate - Part A	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Day 21, follow-up Day 28	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Oxygen Saturation - Part A	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Day 8 (predose, 1 hour postdose)	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part A of the study. H = Hour(s).
Change From Baseline in QT Interval - Part A	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	Electrocardiogram (ECG) measures included QT interval, QTc based on Fridericia formula (QTcF interval), ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Change From Baseline in ECG Mean Heart Rate - Part A	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Change From Baseline in RR Interval - Part A	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Change From Baseline in QRS Interval - Part A	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part A of the study.
Percentage of Participants With a Response of 'Yes' to Any Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Item - Part A	Day 1 up to Day 28	The C-SSRS scale consisted of a baseline evaluation (at screening) that assessed the lifetime experience of participants with suicidal ideation (SI) and behavior and a postbaseline evaluation that focused on suicidality since the last study visit. The C-SSRS included "yes" or "no"' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). The C-SSRS SI items involved wish to be dead, non-specific active suicidal thoughts, active SI with any methods, active SI with some intent and active SI with specific plan. The analysis was performed in participants included in Part A of the study.
Change From Baseline in Stanford Sleepiness Scale (SSS) Score at Day 15 - Part A	Baseline, Day 15	The SSS was participant-rated scale designed to quickly assess how alert a participant was feeling. Degrees of sleepiness and alertness were rated on a scale of one to seven, where the lowest score of 'one' indicated the participant was 'feeling active, vital, alert, or wide awake' and the highest score of 'seven' indicated the participant was 'no longer fighting sleep, sleep onset soon; having dream-like thoughts'. A negative change from baseline indicated less sleepiness. A positive change from baseline indicated more sleepiness. The analysis was performed in participants included in Part A of the study.
Change From Baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) Total Score at Day 15 - Part B	Baseline, Day 15	The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Lymphocytes - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Lymphocytes to Leukocytes Ratio (%) - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Percentage of Participants With AEs During Post-TEAE Period	Day 21 up to Day 42	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. Post-TEAE period was defined as 7 days after final dose through last follow-up (Day 42). The analysis was performed in participants included in Part B of the study.
Change From Baseline in Basophils - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Basophils to Leukocytes Ratio (%) - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in Calcium - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Chloride - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Glucose - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Monocytes - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Monocytes to Leukocytes Ratio (%) - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in Neutrophils - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Neutrophils to Leukocytes Ratio (%) - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in Reticulocytes to Erythrocytes Ratio (%) - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in the HAM-D Total Score at Day 15 and All Other Time Points - Part A	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28	The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicate a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.
Percentage of Participants With TEAEs - Part B	Day 1 up to Day 21	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was defined as an adverse event with onset after the start of study drug, or any worsening of a pre-existing medical condition/adverse event with onset after the start of study drug and until 7 days after the last dose. The analysis was performed in participants included in Part B of the study.
Percentage of Participants With TEAEs, Graded by Severity - Part B	Day 1 up to Day 21	Severity was assessed according to the following scale: mild (awareness of sign or symptom, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); severe (incapacitating, with inability to perform normal activities). The analysis was performed in participants included in Part B of the study.
Change From Baseline in Eosinophils - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Eosinophils to Leukocytes Ratio (%) - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The blood cell differential (ratio) data are presented as SI unit, percentage (%).
Change From Baseline in Hematocrit - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Hemoglobin - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Prothrombin Time - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in pH - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Specific Gravity - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Urinalysis measures included pH and specific gravity. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline (CFB) in Supine Systolic Blood Pressure - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Supine Diastolic Blood Pressure - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Standing Systolic Blood Pressure - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Standing Diastolic Blood Pressure - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Change From Baseline in Platelets - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Leukocytes - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Albumin - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Alkaline Phosphatase - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Erythrocytes - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Reticulocytes - Part B	Baseline, Day 8, Day 15/ET	Hematology measures included basophils, basophils to leukocytes ratio, eosinophils, eosinophils to leukocytes ratio, hematocrit, hemoglobin, lymphocytes, lymphocytes to leukocytes ratio, monocytes, monocytes to leukocytes ratio, neutrophils, neutrophils to leukocytes ratio, platelets, erythrocytes, reticulocytes, reticulocytes to erythrocytes ratio and leukocytes. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Aspartate Aminotransferase - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Alanine Aminotransferase - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Bilirubin - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Carbon Dioxide - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Creatinine - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Potassium - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Phosphate - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Magnesium - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Protein - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Sodium - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Urea Nitrogen - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Activated Partial Thromboplastin Time - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline in Prothrombin International Normalized Ratio (%) - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Coagulation measures included activated partial thromboplastin time, prothrombin international normalized ratio, and prothrombin time. The analysis was performed in participants included in Part B of the study. ET = Early Termination. The data for prothrombin international normalized ratio are presented as SI unit, percentage (%).
Change From Baseline in Thyrotropin - Part B	Baseline, Day 8, Day 15/ET, follow-up Days 21, 28, 35 and 42	Clinical chemistry measures included albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, calcium, chloride, carbon dioxide, creatinine, glucose, potassium, magnesium, phosphate, protein, sodium, thyrotropin, and urea nitrogen. The analysis was performed in participants included in Part B of the study. ET = Early Termination.
Change From Baseline (CFB) in Heart Rate - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Respiratory Rate - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Oral Temperature - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15/ET, follow-up Days 21, 28, 35 and 42	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Change From Baseline (CFB) in Oxygen Saturation - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2, 12 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2, 12 hours postdose), Day 8 (predose, 1 hour postdose)	Vital signs measures included supine systolic blood pressure, supine diastolic blood pressure, standing systolic blood pressure, standing diastolic blood pressure, heart rate, respiratory rate, oral temperature, and oxygen saturation. The analysis was performed in participants included in Part B of the study. H = Hour(s). ET = Early Termination.
Change From Baseline in QT Interval - Part B	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Change From Baseline in QTcF Interval - Part B	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Change From Baseline in ECG Mean Heart Rate - Part B	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Change From Baseline in RR Interval - Part B	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Change From Baseline in PR Interval - Part B	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Change From Baseline in QRS Duration - Part B	Baseline, Days 1, 2, 7, 14 and follow-up Day 21	ECG measures included QT interval, QTcF interval, ECG mean heart rate, RR interval, PR interval, and QRS duration. The analysis was performed in participants included in Part B of the study.
Percentage of Participants With a Response of "Yes" to Any C-SSRS Suicidal Ideation (SI) Item - Part B	Screening, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 21, 28, 35 and 42	The C-SSRS scale consisted of a baseline evaluation (at screening) that assessed the lifetime experience of participants with suicidal ideation and behavior and a postbaseline evaluation that focused on suicidality since the last study visit. The C-SSRS included "yes" or "no"' responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe). The C-SSRS SI items involved wish to be dead, non-specific active suicidal thoughts, active SI with any methods, active SI with some intent and active SI with specific plan. The analysis was performed in participants included in Part B of the study. SCLR = screening: lifetime recall.
Percentage of Participants With HAM-D Response - Part A	Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28	HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicate a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study. Data is reported for participants who had HAM-D response.
Percentage of Participants With HAM-D Remission - Part A	Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28	HAM-D remission was defined as having a HAM-D total score of ≤7. The HAM-D total score comprised a sum of the 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.
Change From Baseline in the Montgomery and Åsberg Depression Rating Scale (MADRS) Total Score at Day 15 and All Other Time Points - Part A	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28	The MADRS was a ten-item diagnostic questionnaire which psychiatrists used to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicated more severe depression. A negative change from baseline indicated less severe depression. A positive change from baseline indicated more severe depression. The analysis was performed in participants included in Part A of the study.
Change From Baseline in HAM-D Subscale Scores at Day 15 and All Other Time Points - Part A	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28	HAM-D subscales were: Core, symptoms: depressed mood (DM), feelings of guilt (FG), suicide, work and activities (WA), and retardation (RE); Anxiety, symptoms: anxiety (psychic and somatic), somatic symptoms (SS) (gastrointestinal and general), hypochondriasis, and loss of weight; Bech-6, symptoms: DM, FG, WA, RE, anxiety psychic (AP), and SS general; and Maier, symptoms: DM, FG, WA, RE, agitation, and AP. Each item was scored in a range of 0 to 2 or 0 to 4. Higher scores indicated a greater degree of depression. Subscale scores were calculated as sum of individual rating scores related to each subscale, divided by total possible score within subscale, multiplied by 100, and rounded to a whole number. Therefore, subscale scores would be within range of 0-100 and might be larger than total score. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of study.
Change From Baseline (CFB) in HAM-D Individual Item Scores at Day 15 and All Other Time Points - Part A	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21 and 28	The HAM-D comprised individual ratings of the following symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms \[gastrointestinal (GI) and general\], genital symptoms, loss of weight, and insight. The following symptoms were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part A of the study.
Change From Baseline in Hamilton Anxiety Rating Scale (HAM-A) Total Score at All Time Points - Part A	Baseline, Days 2, 3, 8, 15, 21 and 28	The 14-item HAM-A was used to rate the severity of symptoms of anxiety. Each of the 14 items was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A was calculated by assigning scores of 0 (not present) to 4 (very severe), with a total score range of 0 to 56, where 0-13=Normal, 14-17 Mild Anxiety, 18-24 Moderate Anxiety, \>=25 Severe Anxiety, per the Psych Congress Network. The HAM-A total score was calculated as the sum of the 14 individual item scores. A negative change from baseline indicated less anxiety. A positive change from baseline indicated more anxiety. The analysis was performed in participants included in Part A of the study.
Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Response - Part A	Days 2, 3, 8, 15, 21 and 28	The CGI-I item employed a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions. CGI-I response was defined as having a CGI-I global improvement score of 1 (very much improved) or 2 (much improved). The analysis was performed in participants included in Part A of the study. Data is reported for participants who had CGI-I response.
Change From Baseline (CFB) in the SSS Score - Part B	Baseline, Day 1 (0.25, 0.5, 1, 2 hours postdose), Days 2, 3, 4, 5, 6 and 7 (predose, 0.25, 0.5, 1, 2 hours postdose), Days 8, 9, 10, 11, 12, 13 and 14 (predose, 1 hour postdose), Day 15	The SSS was participant-rated scale designed to quickly assess how alert a participant was feeling. Degrees of sleepiness and alertness were rated on a scale of one to seven, where the lowest score of 'one' indicated the participant was 'feeling active, vital, alert, or wide awake' and the highest score of 'seven' indicated the participant was 'no longer fighting sleep, sleep onset soon; having dream-like thoughts'. A negative change from baseline indicated less sleepiness. A positive change from baseline indicated more sleepiness. The analysis was performed in participants included in Part B of the study. H = Hour(s).
Change From Baseline in the 17-item HAM-D Total Score at All Time Points - Part B	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42	The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.
Percentage of Participants With HAM-D Response - Part B	Days 2, 8, 15, 21, 28, 35 and 42	HAM-D response was defined as having a 50% or greater reduction from baseline in HAM-D total score. The HAM-D total score comprised a sum of 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study. Data is reported for participants who had HAM-D response.
Percentage of Participants With HAM-D Remission - Part B	Days 2, 8, 15, 21, 28, 35 and 42	HAM-D remission was defined as having a HAM-D total score of ≤7. The HAM-D total score comprised a sum of the 17 individual item scores. Items scored in a range of 0 to 2 included: insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following items were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. The total score could range from 0 to 52. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.
Change From Baseline in the MADRS Total Score at Day 15 and All Other Time Points - Part B	Baseline, Days 2, 8, 15, 21, 28, 35 and 42	The MADRS was a ten-item diagnostic questionnaire which psychiatrists used to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D, to be more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms of treatment. Each item yielded a score of 0 to 6. The MADRS total score was calculated as the sum of the 10 individual item scores, which ranged from 0 to 60. Higher MADRS scores indicated more severe depression. A negative change from baseline indicated less severe depression. A positive change from baseline indicated more severe depression. The analysis was performed in participants included in Part B of the study.
Change From Baseline in HAM-D Subscale Scores at All Time Points - Part B	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42	HAM-D subscales were: Core, symptoms: depressed mood (DM), feelings of guilt (FG), suicide, work and activities (WA), and retardation (RE); Anxiety, symptoms: anxiety (psychic and somatic), somatic symptoms (SS) (gastrointestinal and general), hypochondriasis, and loss of weight; Bech-6, symptoms: DM, FG, WA, RE, anxiety psychic (AP), and SS general; and Maier, symptoms: DM, FG, WA, RE, agitation, and AP. Each item was scored in a range of 0 to 2 or 0 to 4. Higher scores indicated a greater degree of depression. Subscale scores were calculated as sum of individual rating scores related to each subscale, divided by total possible score within subscale, multiplied by 100, and rounded to a whole number. Therefore, subscale scores would be within range of 0-100 and might be larger than total score. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of study.
Change From Baseline (CFB) in HAM-D Individual Item Scores at All Time Points - Part B	Baseline, Days 2, 3, 4, 5, 6, 7, 8, 15, 21, 28, 35 and 42	The HAM-D comprised individual ratings of the following symptoms scored in a range of 0 to 2: insomnia (early, middle, late), somatic symptoms (GI and general), genital symptoms, loss of weight, and insight. The following symptoms were scored in a range of 0 to 4: agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. Higher scores indicated a greater degree of depression. A negative change from baseline indicated less depression. A positive change from baseline indicated more depression. The analysis was performed in participants included in Part B of the study.
Change From Baseline in HAM-A Total Score at Day 15 and All Other Time Points - Part B	Baseline, Days 2, 8, 15, 21, 28, 35 and 42	The 14-item HAM-A was used to rate the severity of symptoms of anxiety. Each of the 14 items was defined by a series of symptoms, and measured both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A was calculated by assigning scores of 0 (not present) to 4 (very severe), with a total score range of 0 to 56, where 0-13=Normal, 14-17 Mild Anxiety, 18-24 Moderate Anxiety, \>=25 Severe Anxiety, per the Psych Congress Network. The HAM-A total score was calculated as the sum of the 14 individual item scores. A negative change from baseline indicated less anxiety. A positive change from baseline indicated more anxiety. The analysis was performed in participants included in Part B of the study.
Percentage of Participants With CGI-I Response - Part B	Days 2, 8, 15, 21, 28, 35 and 42	The CGI-I item employed a 7-point Likert scale to measure the overall improvement in the participant's condition post-treatment. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The CGI-I was only rated at post-treatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions. CGI-I response was defined as having a score of 1 (very much improved) or 2 (much improved). The analysis was performed in participants included in Part B of the study. Data is reported for participants who had CGI-I response.