Evaluate SAGE-547 in Participants With Essential Tremor

Phase 2

Completed

Conditions: Essential Tremor

Interventions: Drug: SAGE-547
Drug: Placebo

Registration Number: NCT02277106

Lead Sponsor: Sage Therapeutics

Brief Summary: Stage 1 is a double-blind, proof-of-concept study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of SAGE-547 Injection in male and female participants with essential tremor in the upper limb.

Stage 2 is an open-label arm designed to evaluate the safety, tolerability, PK, and effectiveness of SAGE-547 Injection at a higher dose than in Stage 1. Participants who completed Stage 1 were invited to participate in Stage 2.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

Inclusion Criteria

Males and females, 35-75 years old with a diagnosis of essential tremor with symptoms clearly present in at least 1 upper limb; participant has had tremor present for at least 2 years prior to Screening
Off medication, or on a stable dose of medication for their tremor for at least 28 days prior to Screening

Exclusion Criteria

Recent history or active clinically significant manifestations of metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, eyes, ears, nose, or throat, psychiatric, or neurological (other than essential tremor) disorders
Medical history of seizures

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Stage 1 (Double-blind): SAGE 547, Then Placebo	SAGE-547	Participants received a 12-hour intravenous (IV) infusion of SAGE 547, at ascending doses of 29, 58, and 86 micrograms per kilogram of body weight per hour (μg/kg/h), 4 hours each, on Day 1 of Stage 1 \[Treatment Period 1 (TP 1)\]. After a washout period of approximately 7 days, participants received a 12-hour IV infusion of SAGE-547 matching-placebo, on Day 10 of Stage 1 \[Treatment Period 2 (TP 2)\].
Stage 1 (Double-blind): SAGE 547, Then Placebo	Placebo	Participants received a 12-hour intravenous (IV) infusion of SAGE 547, at ascending doses of 29, 58, and 86 micrograms per kilogram of body weight per hour (μg/kg/h), 4 hours each, on Day 1 of Stage 1 \[Treatment Period 1 (TP 1)\]. After a washout period of approximately 7 days, participants received a 12-hour IV infusion of SAGE-547 matching-placebo, on Day 10 of Stage 1 \[Treatment Period 2 (TP 2)\].
Stage 1 (Double-blind): Placebo, Then SAGE-547	SAGE-547	Participants received a 12-hour IV infusion of SAGE-547 matching-placebo on Day 1 of Stage 1 (TP 1). After a washout period of approximately 7 days, participants received a 12-hour IV infusion of SAGE 547 at ascending doses of 29, 58, and 86 μg/kg/h, 4 hours each, on Day 10 of Stage 1 (TP 2).
Stage 1 (Double-blind): Placebo, Then SAGE-547	Placebo	Participants received a 12-hour IV infusion of SAGE-547 matching-placebo on Day 1 of Stage 1 (TP 1). After a washout period of approximately 7 days, participants received a 12-hour IV infusion of SAGE 547 at ascending doses of 29, 58, and 86 μg/kg/h, 4 hours each, on Day 10 of Stage 1 (TP 2).
Stage 2 (Open Label): SAGE-547	SAGE-547	Participants who completed Stage 1 were invited to receive a 10-hour IV infusion of SAGE 547, at ascending doses of 90 μg/kg/h for 1 hour, 120 μg/kg/h for 1 hour, and 150 μg/kg/h for 8 hours on Day 1 of Stage 2.

Primary Outcome Measures

Name	Time	Method
Stage 2: Change From Baseline in Vital Signs Parameter - Supine Diastolic Blood Pressure	Stage 2 Day 1: Pre-infusion (Baseline) and 2, 4, 6, 8, 10, 12, 14 and 24 hours post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in supine diastolic blood pressure is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Vital Signs Parameter - Supine Heart Rate	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion and 12-hour follow-up post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in supine heart rate is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Vital Signs Parameter - Standing Systolic Blood Pressure	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion and 12-hour follow-up post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in standing systolic blood pressure is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Percentage of Participants With a Response of 'Yes' to Any Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation or Suicidal Behavior Item at Any Visit	Stage 1: Pre-infusion on Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2)	The C-SSRS scale consisted of baseline evaluation that assessed lifetime experience of participants with suicidal ideation (SI) and suicidal behavior (SB) and postbaseline evaluation that focused on suicidality since last study visit. 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 \[from 1 (minor physical damage) to 5 (death), with 5 being most severe\]. C-SSRS SI items involved (a) wish to be dead, (b) non-specific active suicidal thoughts, (c) active SI with any methods (not plan) without intent to act, (d) active SI with some intent to act, without specific plan and (e) active SI with specific plan and intent. C-SSRS SB items involved (a) actual attempt, (b) engaged in non-suicidal self-injurious behavior, (c) interrupted attempt, (d) aborted attempt, (e) preparatory acts or behavior, (f) suicidal behavior. Only categories with data are reported.
Stage 2: Percentage of Participants With a Response of 'Yes' to Any Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation or Suicidal Behavior Item at Any Visit	Stage 2 Day 1: Pre-infusion and 10 hours and 7-day follow-up post-infusion	The C-SSRS scale consisted of baseline evaluation that assessed lifetime experience of participants with SI and SB and postbaseline evaluation that focused on suicidality since last study visit. 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 \[from 1 (minor physical damage) to 5 (death), with 5 being most severe\]. C-SSRS SI items involved (a) wish to be dead, (b) non-specific active suicidal thoughts, (c) active SI with any methods (not plan) without intent to act, (d) active SI with some intent to act, without specific plan and (e) active SI with specific plan and intent. C-SSRS SB items involved (a) actual attempt, (b) engaged in non-suicidal self-injurious behavior, (c) interrupted attempt, (d) aborted attempt, (e) preparatory acts or behavior, (f) suicidal behavior.
Stage 2: Change From Baseline in Vital Signs Parameter - Supine Heart Rate	Stage 2 Day 1: Pre-infusion (Baseline) and 2, 4, 6, 8, 10, 12, 14 and 24 hours post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in supine heart rate is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in Vital Signs Parameter - Standing Systolic Blood Pressure	Stage 2 Day 1: Pre-infusion (Baseline) and 2, 4, 6, 8, 10, 12, 14 and 24 hours post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in standing systolic blood pressure is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Vital Signs Parameter - Standing Diastolic Blood Pressure	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion and 12-hour follow-up post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in standing diastolic blood pressure is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in Vital Signs Parameter - Standing Diastolic Blood Pressure	Stage 2 Day 1: Pre-infusion (Baseline) and 2, 4, 6, 8, 10, 12, 14 and 24 hours post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in standing diastolic blood pressure is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Vital Signs Parameter - Standing Heart Rate	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion and 12-hour follow-up post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in standing heart rate is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Stage 1: Up to 30 days after last infusion (up to Day 40)	An adverse event (AE) is 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 AE with start date/time after the start of initial infusion in each stage. An SAE is defined as an AE or suspected adverse reaction, which in the view of either the Investigator or Sponsor, results in any of the following outcomes: death; is life-threatening; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant disability or incapacity; congenital anomaly or birth defect or other medically important condition.
Stage 1: Change From Baseline in Vital Signs Parameter - Supine Diastolic Blood Pressure	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion and 12-hour follow-up post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in supine diastolic blood pressure is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Potassium Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for potassium levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Calcium Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in calcium levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Calcium Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for calcium levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Chloride Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in chloride levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Chloride Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for chloride levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Bicarbonate Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in bicarbonate levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Bicarbonate Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for bicarbonate levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Protein Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in protein levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Stage 2: Up to 30 days after last infusion (up to Day 31)	An AE is 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 AE with start date/time after the start of initial infusion in each stage. An SAE is defined as an AE or suspected adverse reaction, which in the view of either the Investigator or Sponsor, results in any of the following outcomes: death; is life-threatening; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant disability or incapacity; congenital anomaly or birth defect or other medically important condition.
Stage 1: Change From Baseline (CFB) in Vital Signs Parameter - Supine Systolic Blood Pressure	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion and 12-hour follow-up post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in supine systolic blood pressure is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in Vital Signs Parameter - Supine Systolic Blood Pressure	Stage 2 Day 1: Pre-infusion (Baseline) and 2, 4, 6, 8, 10, 12, 14 and 24 hours post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in supine systolic blood pressure is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in Vital Signs Parameter - Standing Heart Rate	Stage 2 Day 1: Pre-infusion (Baseline) and 2, 4, 6, 8, 10, 12, 14 and 24 hours post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in standing heart rate is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Vital Signs Parameter - Temperature	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion and 12-hour follow-up post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in temperature is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in Vital Signs Parameter - Temperature	Stage 2 Day 1: Pre-infusion (Baseline) and 2, 4, 6, 8, 10, 12, 14 and 24 hours post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in temperature is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Vital Signs Parameter - Respiratory Rate	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion and 12-hour follow-up post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in respiratory rate is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in Vital Signs Parameter - Respiratory Rate	Stage 2 Day 1: Pre-infusion (Baseline) and 2, 4, 6, 8, 10, 12, 14 and 24 hours post-infusion	Vital signs included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate, standing systolic blood pressure, standing diastolic blood pressure, standing heart rate, temperature, and respiratory rate. CFB in respiratory rate is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Alanine Aminotransferase Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in alanine aminotransferase levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Alanine Aminotransferase Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for alanine aminotransferase levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Aspartate Aminotransferase Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in aspartate aminotransferase levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Aspartate Aminotransferase Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for aspartate aminotransferase levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Gamma Glutamyl Transferase Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in gamma glutamyl transferase levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Gamma Glutamyl Transferase Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for gamma glutamyl transferase levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Sodium Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in sodium levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Sodium Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for sodium levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Potassium Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in potassium levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Protein Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for protein levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Glucose Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in glucose levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Glucose Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for glucose levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Lactate Dehydrogenase Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in lactate dehydrogenase levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Lactate Dehydrogenase Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for lactate dehydrogenase levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Cholesterol Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in cholesterol levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Cholesterol Level	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for cholesterol levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Triglyceride Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in triglyceride levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Triglyceride Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for triglyceride levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Albumin Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in albumin levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Albumin Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for albumin levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Bilirubin Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in bilirubin levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Bilirubin Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for bilirubin levels are reported in this outcome measure.
Stage 2: Absolute Values of Serum Chemistry Parameter - Creatinine Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for creatinine levels are reported in this outcome measure.
Stage 2: Absolute Values of Serum Chemistry Parameter - Phosphate Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for phosphate levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Urate Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in urate levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Creatinine Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in creatinine levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Blood Urea Nitrogen Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in blood urea nitrogen levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Blood Urea Nitrogen Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for blood urea nitrogen levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Alkaline Phosphatase Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in alkaline phosphatase levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Alkaline Phosphatase Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for alkaline phosphatase levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Creatine Kinase Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in creatinine kinase levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Creatine Kinase Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for creatinine kinase levels are reported in this outcome measure.
Stage 1: Change From Baseline in Serum Chemistry Parameter - Phosphate Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. CFB in phosphate levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Serum Chemistry Parameter - Urate Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Serum chemistry parameters included alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, sodium, potassium, calcium, chloride, bicarbonate, protein, glucose, lactate dehydrogenase, cholesterol, triglycerides, albumin, bilirubin, creatinine, blood urea nitrogen, alkaline phosphatase, creatinine kinase, phosphate, and urate. Absolute values for urate levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Hemoglobin Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in hemoglobin levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Hemoglobin Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for hemoglobin levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Hematocrit Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in hematocrit levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Hematocrit Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for hematocrit levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Platelet Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in platelet levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Platelet Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for platelet levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Erythrocyte Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in erythrocyte levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Erythrocyte Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for erythrocyte levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Neutrophil Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in neutrophil levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Neutrophil Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for neutrophil levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Basophil Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in basophil levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Basophil Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for basophil levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Eosinophil Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in eosinophil levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Eosinophil Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for eosinophil levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Monocyte Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in monocyte levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Monocyte Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for monocyte levels are reported in this outcome measure.
Stage 2: Change From Baseline in ECG Parameter - Heart Rate	Stage 2 Day 1: Pre-infusion (Baseline) and 10 hours post-infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in heart rate is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Erythrocytes Mean Corpuscular Volume Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for erythrocytes mean corpuscular volume levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Mean Cell Hemoglobin Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in mean cell hemoglobin levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Mean Cell Hemoglobin	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for mean cell hemoglobin levels are reported in this outcome measure.
Stage 1: Change From Baseline in Electrocardiogram (ECG) Parameter - QT Interval	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8,12 hours during infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in QT interval is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in ECG Parameter - QT Interval	Stage 2 Day 1: Pre-infusion (Baseline) and 10 hours post-infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in QT interval is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in ECG Parameter - PR Interval	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8,12 hours during infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in PR interval is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in ECG Parameter - PR Interval	Stage 2 Day 1: Pre-infusion (Baseline) and 10 hours post-infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in PR interval is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in ECG Parameter - QRS Duration	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in QRS duration is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in ECG Parameter - QRS Duration	Stage 2 Day 1: Pre-infusion (Baseline) and 10 hours post-infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in QRS duration is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in ECG Parameter - QTcB Interval	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in QTcB interval is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in ECG Parameter - QTcB Interval	Stage 2 Day 1: Pre-infusion (Baseline) and 10 hours post-infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in QTcB interval is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in ECG Parameter - QTcF Interval	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in QTcF interval is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in ECG Parameter - QTcF Interval	Stage 2 Day 1: Pre-infusion (Baseline) and 10 hours post-infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in QTcF interval is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in ECG Parameter - Heart Rate	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 4, 8, 12 hours during infusion	ECG parameters included QT interval, PR interval, QRS duration, QTcB interval, QTcF interval, and heart rate. CFB in heart rate is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in Hematology Parameter - Lymphocyte Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in lymphocyte levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Lymphocyte Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for lymphocyte levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Leukocyte Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in leukocyte levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Absolute Values of Hematology Parameter - Leukocyte Levels	Stage 2: Any day in Screening period (Day -7 up to Day -1) and any day in 7-day follow up	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. Absolute values for leukocyte levels are reported in this outcome measure.
Stage 1: Change From Baseline in Hematology Parameter - Erythrocytes Mean Corpuscular Volume Levels	Day 1 of Stage 1 (Treatment Period 1) or on Day 10 of Stage 1 (Treatment Period 2): Pre-infusion (Baseline) and 12-hour follow-up post-infusion	Hematology parameters included hemoglobin, hematocrit, platelets, erythrocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, leukocytes, erythrocytes mean corpuscular volume, and mean cell hemoglobin. CFB in erythrocytes mean corpuscular volume levels is reported in this outcome measure. Baseline is defined as the pre-infusion value in each period/stage.

Secondary Outcome Measures

Name	Time	Method
Stage 1: Change From Baseline in Accelerometer Total Score Response	Stage 1 Days 1 and 10: Pre-infusion (Baseline) and 2, 4, 6, 8, 10 and 12 hours and 12-hour follow-up post-infusion	Accelerometer total score response was defined as ≥30% decrease from baseline to each time point in accelerometer total score. Accelerometer total score is sum of forward outstretched postural tremor, lateral wing-beating postural tremor, and kinetic tremor scores across both sides of the body (i.e., right and left). Accelerometer was used for transducer measurement of tremor amplitude. Participants wore wireless ring motion sensor. It measured linear acceleration and angular velocity (i.e., kinesia score). Information from motion sensor data was correlated to symptoms of tremor. Kinesia (accelerometer) scores ranged from 0 to 4 in 0.5 step increments. The total score ranges from 0 to 24, higher scores indicating more severe tremors. Negative change from baseline indicated decrease in tremor. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in Accelerometer Total Score Response	Stage 2 Day 1: Baseline and 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours	Accelerometer total score response was defined as ≥30% decrease from baseline to each time point in accelerometer total score. Accelerometer total score is sum of forward outstretched postural tremor, lateral wing beating postural tremor, and kinetic tremor scores across both sides of the body (i.e., right and left). Accelerometer was used for transducer measurement of tremor amplitude. Participants wore wireless ring motion sensor. It measured linear acceleration and angular velocity (i.e., kinesia score). Information from motion sensor data was correlated to symptoms of tremor. Kinesia (accelerometer) scores ranged from 0 to 4 in 0.5 step increments. The total score ranges from 0 to 24, higher scores indicating more severe tremors. Negative change from baseline indicated decrease in tremor. Baseline is defined as the pre-infusion value in each period/stage.
Stage 1: Change From Baseline in The Essential Tremor Rating Scale (TETRAS) Using Performance Subscale (PS) Part 4 Upper-Limb Total Scores	Stage 1 Days 1 and 10: Pre-infusion (Baseline) and 2, 4, 6, 8, 10 and 12 hours and 12-hour follow-up post-infusion	The TETRAS PS total score was calculated as the sum of items 4 (upper-limb), 6 (Archimedes spiral), 7 (handwriting), and 8 (dot approximation). TETRAS PS upper-limb total score was calculated as the sum of the 6 separate upper-limb maneuvers assessed by the clinician: forward-outstretched postural tremor \[right\], forward outstretched postural tremor \[left\], lateral wing-beating postural tremor \[right\], lateral wing-beating postural tremor \[left\], kinetic tremor \[right\], kinetic tremor \[left\], each on a 0 (no tremor) to 4 (maximum tremor) severity scale in 0.5-point increments. TETRAS Part 4 score for both upper limbs ranged from 0 to 24, higher scores indicated more severe tremor. A negative change from baseline indicated less tremor. Baseline is defined as the pre-infusion value in each period/stage.
Stage 2: Change From Baseline in TETRAS Using PS Part 4 Upper-Limb Total Scores	Stage 2 Day 1: Baseline and at 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours	The TETRAS PS total score was calculated as the sum of items 4 (upper-limb), 6 (Archimedes spiral), 7 (handwriting), and 8 (dot approximation). TETRAS PS upper-limb total score was calculated as the sum of the 6 separate upper-limb maneuvers assessed by the clinician: forward-outstretched postural tremor \[right\], forward outstretched postural tremor \[left\], lateral wing-beating postural tremor \[right\], lateral wing-beating postural tremor \[left\], kinetic tremor \[right\], kinetic tremor \[left\], each on a 0 (no tremor) to 4 (maximum tremor) severity scale in 0.5-point increments. TETRAS Part 4 score for both upper limbs ranged from 0 to 24, higher scores indicated more severe tremor. A negative change from baseline indicated less tremor.
Stage 1: Change From Baseline in Stanford Sleepiness Scale (SSS) Score	Stage 1 Day 1 and 10: Pre-infusion (Baseline) and 2, 4, 6, 8, 10 and 12 hours and 12-hour follow-up post-infusion	SSS is a participant-rated scale designed to quickly assess how alert a participant was feeling. Degrees of sleepiness and alertness were rated on a scale of 1 to 7, where the lowest score of '1' indicated the participant was 'feeling active, vital, alert, or wide awake' and the highest score of '7' indicated the participant was 'no longer fighting sleep, sleep onset soon; having dream-like thoughts'. Baseline is defined as the pre-infusion value in each period. A negative change from baseline indicated less sleepiness.
Stage 2: Change From Baseline in Stanford Sleepiness Scale (SSS) Score	Stage 2 Day 1: Baseline and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours	SSS is a participant-rated scale designed to quickly assess how alert a participant was feeling. Degrees of sleepiness and alertness were rated on a scale of 1 to 7, where the lowest score of '1' indicated the participant was 'feeling active, vital, alert, or wide awake' and the highest score of '7' indicated the participant was 'no longer fighting sleep, sleep onset soon; having dream-like thoughts'. Baseline is defined as the pre-infusion value in each period. A negative change from baseline indicated less sleepiness.
Stage 1: Maximum Peak Plasma Concentration (Cmax) of SAGE-547	Stage 1: Pre-infusion and after the start of infusion at 30 and 40 minutes and at 1, 1.5, 2, 4, 6, 8, 10, 12, 12.5, 12.75, 13, 13.5, 14, 16 and 24 hours
Stage 2: Maximum Peak Plasma Concentration (Cmax) of SAGE-547	Stage 2: Pre-infusion and at 30, 60, 90 and 120 minutes and at 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 10.5, 10.75, 11, 11.5, 12, 14, 16 and 24 hours after start of the infusion
Stage 1: Time to Maximum Peak Plasma Concentration (Cmax) of SAGE-547	Stage 1: Pre-infusion and after the start of infusion at 30 and 40 minutes and at 1, 1.5, 2, 4, 6, 8, 10, 12, 12.5, 12.75, 13, 13.5, 14, 16 and 24 hours
Stage 2: Time to Maximum Peak Plasma Concentration (Cmax) of SAGE-547	Stage 2: Pre-infusion and at 30, 60, 90 and 120 minutes and at 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 10.5, 10.75, 11, 11.5, 12, 14, 16 and 24 hours after start of the infusion
Stage 1: Area Under the Plasma Concentration Time Curve up to the Time of the Last Quantifiable Sample (AUClast) of SAGE-547	Stage 1: Pre-infusion and after the start of infusion at 30 and 40 minutes and at 1, 1.5, 2, 4, 6, 8, 10, 12, 12.5, 12.75, 13, 13.5, 14, 16 and 24 hours
Stage 2: Area Under the Plasma Concentration Time Curve up to the Time of the Last Quantifiable Sample (AUClast) of SAGE-547	Day 1: Pre-infusion and at 30, 60, 90 and 120 minutes and at 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 10.5, 10.75, 11, 11.5, 12, 14, 16 and 24 hours after start of the infusion
Stage 1: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of SAGE-547	Stage 1: Pre-infusion and after the start of infusion at 30 and 40 minutes and at 1, 1.5, 2, 4, 6, 8, 10, 12, 12.5, 12.75, 13, 13.5, 14, 16 and 24 hours
Stage 2: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of SAGE-547	Stage 2: Pre-infusion and at 30, 60, 90 and 120 minutes and at 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 10.5, 10.75, 11, 11.5, 12, 14, 16 and 24 hours after start of the infusion
Stage 1: Clearance (CL) of SAGE-547	Stage 1: Pre-infusion and after the start of infusion at 30 and 40 minutes and at 1, 1.5, 2, 4, 6, 8, 10, 12, 12.5, 12.75, 13, 13.5, 14, 16 and 24 hours	Clearance is defined as the volume of plasma from which a substance is completely removed per unit time.
Stage 2: Clearance (CL) of SAGE-547	Stage 2: Pre-infusion and at 30, 60, 90 and 120 minutes and at 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 10.5, 10.75, 11, 11.5, 12, 14, 16 and 24 hours after start of the infusion	Clearance is defined as the volume of plasma from which a substance is completely removed per unit time.
Stage 1: Terminal Half-Life (t½) of SAGE-547	Stage 1: Pre-infusion and after the start of infusion at 30 and 40 minutes and at 1, 1.5, 2, 4, 6, 8, 10, 12, 12.5, 12.75, 13, 13.5, 14, 16 and 24 hours	Terminal half-life is defined as the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.
Stage 2: Terminal Half-Life (t½) of SAGE-547	Stage 2: Pre-infusion and at 30, 60, 90 and 120 minutes and at 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 10.5, 10.75, 11, 11.5, 12, 14, 16 and 24 hours after start of the infusion	Terminal half-life is defined as the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.