The accelerometer-based Kinesia kinetic tremor combined score is the sum of Kinesia kinetic tremor scores across both sides of the body. Tremor is measured using a motion sensor that transmits raw data to a computer where it converts the tremor amplitude to a Kinesia score of 0 to 4 based on validated algorithms; the total score ranges from 0 to 8, higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.

Efficacy population (Part A; capsules) included all participants who received at least 1 dose of SAGE-217 capsule formulation in Part A and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

The accelerometer-based Kinesia kinetic tremor combined score is the sum of Kinesia kinetic tremor scores across both sides of the body. Tremor is measured using a motion sensor that transmits raw data to a computer where it converts the tremor amplitude to a Kinesia score of 0 to 4 based on validated algorithms; the total score ranges from 0 to 8, higher scores indicate more severe tremor. A negative change from Randomization indicates improvement.

The Efficacy Population included all participants who completed at least one dose of study drug in Part B and had at least one post-randomization efficacy evaluation.

The accelerometer-based Kinesia upper limb total score is the sum of the individual item scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Baseline indicates improvement.

The Efficacy Population consisted of all participants who completed at least 1 dose of study drug in Part C and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Baseline indicates improvement.

Efficacy population (Part A; capsules) included all participants who received at least 1 dose of SAGE-217 capsule formulation in Part A and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given timepoint.

The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4, with higher scores indicating more tremors/greater tremor amplitude. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Baseline indicates improvement.

Efficacy population (Part A; capsules) included all participants who received at least 1 dose of SAGE-217 capsule formulation in Part A and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given timepoint.

The TETRAS performance subscale upper limb total score is the sum of the TETRAS individual item scores from both sides of the body. The TETRAS individual item score included TETRAS Performance Subscale item 4a, 4b and 4c scores [4a: forward outstretched postural tremor (FOPT) and 4b: lateral "wing beating" postural tremor (LWBPT) scores and 4c: Kinetic tremor (KT) score] from both sides of the body. Each individual item score ranges from 0 to 4; The total upper limb score ranges from 0 to 24, higher scores indicate more severe tremor. A negative change indicates improvement.

Efficacy population (Part A; capsules) included all participants who received at least 1 dose of SAGE-217 capsule formulation in Part A and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

The TETRAS individual item score is the sum of the TETRAS Performance Subscale items 4a, 4b, or 4c scores [4a: forward outstretched postural tremor (FOPT), 4b: lateral "wing beating" postural tremor (LWBPT), 4c: kinetic tremor] from both sides of the body. Each TETRAS score ranges from 0 to 4; the total score ranges from 0 to 16; higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.

Efficacy population (Part A; capsules) included all participants who received at least 1 dose of SAGE-217 capsule formulation in Part A and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

The TETRAS Performance Subscale score includes 9 items. Out of these 9 items, Item 6 is Archimedes spirals (AS), Item 7 is Handwriting, and Item 8 is Dot approximation task (DAT). Each item was scored from 0 to 4, for both sides of the body, each item has a total score of 0 to 8, where higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.

Efficacy population (Part A; capsules) included all participants who received at least 1 dose of SAGE-217 capsule formulation in Part A and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Randomization indicates improvement.

The Efficacy Population included all participants who completed at least one dose of study drug in Part B and had at least one post-randomization efficacy evaluation.

The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Randomization indicates improvement.

The Efficacy Population included all participants who completed at least one dose of study drug in Part B and had at least one post-randomization efficacy evaluation.

The TETRAS performance subscale upper limb total score is the sum of the TETRAS individual item scores from both sides of the body. The TETRAS individual item score included TETRAS Performance Subscale item 4a, 4b and 4c scores [4a: forward outstretched postural tremor (FOPT) and 4b: lateral "wing beating" postural tremor (LWBPT) scores and 4c: Kinetic tremor (KT) score] from both sides of the body. Each individual item score ranges from 0 to 4; The total upper limb score ranges from 0 to 24, higher scores indicate more severe tremor. A negative change from Randomization indicates improvement.

The Efficacy Population included all participants who completed at least one dose of study drug in Part B and had at least one post-randomization efficacy evaluation.

The TETRAS individual item score is the sum of the TETRAS Performance Subscale item 4a and 4b scores [4a: forward outstretched postural tremor (FOPT) and 4b: lateral "wing beating" postural tremor (LWBPT) scores] from both sides of the body. Each TETRAS score ranges from 0 to 4; the total score ranges from 0 to 16, higher scores indicate more severe tremor. A negative change from Randomization indicates improvement.

The Efficacy Population included all participants who completed at least one dose of study drug in Part B and had at least one post-randomization efficacy evaluation.

The TETRAS kinetic tremor combined score is the sum of the TETRAS Performance Subscale item 4c (kinetic tremor) scores from both sides of the body. The TETRAS kinetic tremor score ranges from 0 to 4, the total score for both sides of the body ranges from 0 to 8, higher scores indicate more severe tremor. A negative change from Randomization indicates improvement.

The Efficacy Population included all participants who completed at least one dose of study drug in Part B and had at least one post-randomization efficacy evaluation.

The TETRAS Performance Subscale score includes 9 items. Out of these 9 items, Item 6 is Archimedes spirals (AS), Item 7 is Handwriting, and Item 8 is Dot approximation task (DAT). Each item was scored from 0 to 4, for both sides of the body, each item has a total score of 0 to 8, where higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.

The Efficacy Population included all participants who completed at least one dose of study drug in Part B and had at least one post-randomization efficacy evaluation.

The accelerometer-based Kinesia upper limb total score is the sum of Kinesia kinetic tremor scores across both sides of the body. The individual items included forward outstretched postural tremor (FOPT), lateral "wing beating" postural tremor (LWBPT), and kinetic tremor (KT) scores from both sides of the body. Each upper limb individual item question score for each side of the body ranges from 0 to 4. The Kinesia upper limb total score ranges from 0 to 24, with higher scores indicating more tremors/greater tremor amplitude. A negative change from Baseline indicates improvement.

The Efficacy Population consisted of all participants who completed at least 1 dose of study drug in the capsule formulation in Part C and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

The TETRAS performance subscale upper limb total score is the sum of the TETRAS individual item scores from both sides of the body. Each individual item score ranges from 0 to 4; The total upper limb score ranges from 0 to 24, higher scores indicate more severe tremor. A negative change indicates improvement.

The Efficacy Population consisted of all participants who completed at least 1 dose of study drug in the capsule formulation in Part C and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

The TETRAS individual item score is the sum of the TETRAS Performance Subscale item 4a and 4b scores [4a: forward outstretched postural tremor (FOPT) and 4b: lateral "wing beating" postural tremor (LWBPT) scores] from both sides of the body. Each TETRAS score ranges from 0 to 4; the total score ranges from 0 to 16, higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.

The Efficacy Population consisted of all participants who completed at least 1 dose of study drug in the capsule formulation in Part C and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

The TETRAS Performance Subscale score includes 9 items. Out of these 9 items, Item 6 is Archimedes spirals (AS), Item 7 is Handwriting, and Item 8 is Dot approximation task (DAT). Each item was scored from 0 to 4, for both sides of the body, each item has a total score of 0 to 8, where higher scores indicate more severe tremor. A negative change from Baseline indicates improvement.

The Efficacy Population consisted of all participants who completed at least 1 dose of study drug in the capsule formulation in Part C and had at least 1 postdose efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

An Adverse Event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. Adverse events that occurred after the first administration of study drug were denoted as TEAEs. A Serious Adverse Event (SAE) was an AE occurring during any study phase and at any dose of the study drug, comparator, or placebo, that fulfilled the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

The Safety Population consisted of all participants who were administered at least 1 dose of open-label study drug (Parts A and C) or double-blind study drug (Part B).

The C-SSRS consists of a baseline and post-baseline (PB) evaluation that assesses the lifetime experience of the participants with suicidal ideation and behavior. The data for suicidal ideation were summarized for participants who answered 'Yes'. Suicide ideation was categorized as 1) wish to be dead and 2) non-specific active suicidal thoughts.

The Safety Population consisted of all participants who were administered at least 1 dose of open-label study drug (Parts A and C) or double-blind study drug (Part B).

Vital signs included heart rate, respiratory rate, temperature, and blood pressure.

The Safety Population consisted of all participants who were administered at least 1 dose of open-label study drug (Parts A and C) or double-blind study drug (Part B).

Laboratory parameters included hematology, blood chemistry, and urinalysis.

The Safety Population consisted of all participants who were administered at least 1 dose of open-label study drug (Parts A and C) or double-blind study drug (Part B).

A 12-lead ECG was performed.

The Safety Population consisted of all participants who were administered at least 1 dose of open-label study drug (Parts A and C) or double-blind study drug (Part B).

The SSS was designed to quickly assess how alert a subject is feeling. Degrees of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of 1 indicates the subject is "feeling active, vital, alert, or wide awake" and the highest score of 7 indicates the participant is "no longer fighting sleep, sleep onset soon; having dream-like thoughts". Greater changes from baseline indicate greater sedation. A positive change from baseline indicates improvement.

The Safety Population consisted of all participants who were administered at least 1 dose of open-label study drug (Parts A and C) or double-blind study drug (Part B). Number analyzed is the number of participants with data available for analysis at the given time point. SSS was not evaluated in Part C.

Mood was assessed using the Bond-Lader VAS score. This is a 16-part self-administered questionnaire that employs a 100-mm VAS to explore different aspects of self-reported mood. Three factor scores for (alertness, contentedness, and calmness) were calculated using following equations based on normalized VAS scores:

• Alertness = 0.827X1 + 0.618X3 + 0.755X4 + 0.642X5 + 0.776X6 + 0.635X9 + 0.792X11 + 0.593X12 + 0.614X15;
• Contentedness = 0.677X7 + 0.697X8 + 0.823X13 + 0.738X14 + 0.594X16; and
• Calmness = 0.845X2 + 0.677X10,

where Xi represents a subject's item score after normalization, and i represents the item number from the entire scale (in order from 1-16). A negative change from baseline (CFB) indicated more alertness, more contentedness, and more calmness.

The Safety Population consisted of all participants who were administered at least 1 dose of open-label study drug (Parts A and C) or double-blind study drug (Part B). Number analyzed is the number of participants with data available for analysis at the given time point.

Participants responded to 5 DEQs based on how they are feeling after taking the study drug. DEQ-5 were as follows; Q1: Do you FEEL a drug effect right now? Q2: Are you HIGH right now? Q3: Do you DISLIKE any of the effects that you are feeling right now? Q4: Do you LIKE any of the effects that you are feeling right now? Q5: Would you like MORE of the drug you took, right now? The answers were recorded on a 100-mm VAS, with the answer for each being "Not at all" (0 mm) and "Extremely" (100 mm) at the extremes. There were options to record "Not applicable" for questions 3 and 4 if no drug effects were felt and for question 5 prior to administration of study medication, and these participants were excluded from the data summarization. Higher score on Q1 indicates a drug effect; on Q2 indicates feeling high; on Q3 indicates disliking the drug; and on Q4 and Q5 indicates liking the drug.

The Safety Population consisted of all participants who were administered at least 1 dose of open-label study drug (Parts A and C) or double-blind study drug (Part B). Number analyzed is the number of participants with data available for analysis at the given time point.