A Phase 4 clinical trial, also called post-marketing surveillance, is a study conducted after a drug has been approved and is on the market to continue monitoring its safety and effectiveness in the real world. T

임상 단계	주요 목적	데이터 출처/특징
Phase 1	안전성(Safety), 약동학(PK), 내약성(Tolerability)	소수 건강 지원자
Phase 2	효능 탐색(Efficacy), 용량 결정(Dose-finding)	환자군 대상
Phase 3	효과 입증(Confirmatory efficacy), 안전성 평가	대규모 환자군, 승인 전 마지막 단계
Phase 4	승인 후(Post-marketing) 효과 지속, 안전성, 현실 사용(RWD), 삶의 질(QOL) 등	실제 진료 환경(Real-world setting)

3. STUDY OBJECTIVES AND ENDPOINTS

3.1. Study Objectives

3.1.1. Primary Objective

The primary objective of this clinical study is:

To evaluate the persistence of effect of valbenazine in subjects with tardive dyskinesia (TD) who receive placebo in a double-blind, randomized withdrawal period following open-label treatment with valbenazine.
약 먹지 않아도 약 효과의 지속성을 평가하기 위함

3.1.2. Secondary Objectives

The secondary objectives of this clinical study are:

To evaluate the relationship between subject clinical characteristics and persistence of effect of valbenazine during the double-blind, placebo-controlled treatment period.
To evaluate the effect of valbenazine on measures of quality of life and disability when administered once daily for up to 16 weeks.
To evaluate the safety and tolerability of valbenazine administered once daily for up to 16 weeks.
군의 특성 사이 관계와 지속성 평가
삶의 질 측정, 장애에서 효과 평가
안전성 내약성 평가

4. STUDY DESIGN

4.1. Summary of Study Design

This is a Phase 4, randomized, double-blind, placebo-controlled study to evaluate the persistence of effect of valbenazine 40 mg and 80 mg.
Approximately 120 medically stable male and female subjects with clinical diagnoses of schizophrenia or schizoaffective disorder with neurolepticinduced TD or mood disorder with neuroleptic-induced TD will be enrolled.
The study includes an initial open-label treatment period for 8 weeks, followed by a doubleblind, placebo-controlled treatment period for 8 weeks, for a total of up to 16 weeks of treatment.
A final study visit will be conducted at Week 20 or upon early termination.
Eligible subjects will be enrolled in the study on Day 1.
Valbenazine will be self-administered at home (in the presence of the subject’s caregiver, if applicable) beginning on Day 1; the subject will be directed to take their dose at about the same time each day.
During the open-label treatment period, subjects will receive 40 mg for the first week followed by 80 mg for 7 weeks.
At the end of Week 8, subjects will be randomized 1:1 to valbenazine or placebo.
Subjects randomized to valbenazine will continue with the same dose as the last dose they received during the open-label treatment period.
Randomization will be stratified based on the use of concomitant antipsychotic medication; this will include up to 40 subjects who are not using antipsychotic medications (ie, have not used antipsychotic medication for at least 60 days prior to screening and have no plans for resuming antipsychotic treatment during the course of the study) and the remaining subjects will be using concomitant antipsychotic medications.
At any time during treatment (open-label and placebo-controlled treatment periods), subjects who are unable to tolerate the 80 mg dose will have their dose decreased to 40 mg (during the double-blind, placebo-controlled treatment period, this will be done in a blinded manner; subjects receiving placebo will continue to receive placebo).
Subjects who are unable to tolerate the 40 mg dose will be discontinued from the study.
stratified : 계층화된

4.2. Sample Size Considerations

Approximately 120 subjects will be enrolled in this study.
The 1:1 randomization to placebo or valbenazine during the double-blind, placebo-controlled treatment period will therefore provide a sample size of approximately 60 subjects in the placebo arm.
The standard deviation (SD) for the Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score change from the end of the open-label treatment period (end of Week 8) to visits during the double-blind, placebocontrolled treatment period in the placebo treatment arm is estimated to be 4.0 based on results from the previously reported Phase 3 study NBI-98854-1304.
With this SD and a sample size of 60, the overall width of a two-sided 95% confidence interval (CI) for the AIMS dyskinesia total score mean change will be approximately 2.0.
The width of the confidence interval will increase to approximately 2.2 if the placebo treatment arm sample size is 50 and to approximately 2.5 if the sample size is 40.

\(CI width = 2 \times Z_{1-\alpha /2)} \times \frac{SD}{\sqrt{n}}\)

95% CI = 1.96

SD = 4 from Phase 3 study

n = sample number 60 from placebo arm based on 1:1 randomization to placebo or valbenazine

import numpy as np

print("CI width = ", round(2 * 1.96 * 4 / np.sqrt(60),2))

CI width =  2.02

4.3. Randomization

At the end of Week 8, subjects will be randomized 1:1 to valbenazine or placebo.
Subjects randomized to valbenazine will continue with the same dose as the last dose they received during the open-label treatment period.
Randomization will be stratified based on the use of concomitant antipsychotic medication (yes vs. no).

4.4. Clinical Assessments

Assessments of persistence of effect after randomization will be based on:
- AIMS
- Adverse events (AEs) of TD
- Discontinuation from study during the double-blind, placebo-controlled treatment period due to lack of efficacy
Health-related quality of life and disability assessments include:
- EuroQol 5 Dimensions 5 Levels (EQ-5D-5L)
- Sheehan Disability Scale (SDS)
Safety assessments include:
- AEs
- Clinical laboratory tests (hematology, clinical chemistry, and urinalysis)
- Vital signs (including orthostatic blood pressures and pulse)
- Physical examinations
- 12-lead electrocardiograms (ECGs)
- Suicidal ideation and behavior – evaluated using the Columbia-Suicide Severity Rating Scale (C-SSRS)
- Brief Psychiatric Rating Scale (BPRS)
Blood samples for plasma valbenazine and metabolite concentration analyses are also collected.
Subjects/caregivers will be asked to record and provide dosing times from the evening before the treatment period visits when these samples are collected.
The schedule of assessments can be found in the protocol.

6. General Considerations For Data Analyses And Handling

All analyses described in this plan are considered a priori analyses in that they have been defined prior to locking the study database and unblinding the treatment group assignments.
Analyses defined subsequent to locking the database and unblinding will be considered post hoc analyses and will be applied as exploratory methodology.
Any post hoc analyses will be clearly identified in the clinical study report.
sap에 서술된 것은 데이터라킹, 언블라인딩 전에 정의된 a prior 분석
그 이후의 분석은 posthoc 분석으로 정의되며, 탐색적 분석이 될테고, csr에 명확히 명시될 예정

6.1. General Statistical Procedures

\(SEM = \frac{s}{\sqrt{n}}\)

Descriptive statistics will be used to summarize the data from this study.
The term “descriptive statistics” refers to the number of subjects, mean, median, SD, standard error of the mean (SEM), minimum, and maximum for numerical variables; and refers to the number and/or percentage of subjects for categorical variables.
Two-sided 95% confidence intervals will be presented for selected variables.
Additional descriptive statistics may be presented for selected variables.
Summary statistics will be displayed using the following decimal precision rules: the minimum and maximum will have the same number of decimal places as the data; the mean, median, SD, and SEM will have one more decimal place than the data being summarized.
Percentages will be displayed using one decimal place; percentages for 0 counts will be omitted.
These rules may be modified if warranted, based on practical considerations.
Some analyses may be combined in the same summary table.
Graphical displays of the analyses described in this SAP may also be produced.
omit: 빼내다

6.2. Analysis Sets

분석군 정의

6.2.1. Definition of Analysis Sets

For purposes of defining analysis sets, “enrolled subjects” refers to subjects enrolled into the study at the Day 1 visit (ie, are not screen failures) as specified by the subject enrollment electronic case report form (eCRF).

6.2.1.1. Safety Analysis Set

The safety analysis set will include all enrolled subjects who receive at least one dose of openlabel study drug and have any safety data collected after the first dose of study drug.
The safety analysis set will be used for summaries of safety data during the open-label period and for all summaries of plasma concentration data.
A single treatment group (Open-label Valbenazine) will generally be used for analyses of the open-label period.

6.2.1.2. Randomized Safety Analysis Set

The randomized safety analysis set will include all randomized subjects who receive at least one dose of randomized study drug and have any safety data collected after the first dose of randomized study drug.
The randomized safety analysis set will be used for all summaries of safety data during the placebo-controlled period.
Data from the preceding open-label period may be included in by-visit summaries.
Subjects will be grouped by randomized treatment.

6.2.1.3. Persistence of Effect Analysis Set

The persistence of effect (PE) analysis set will include all subjects who are randomized to a treatment group at Week 8, take at least one dose of randomized study drug and have at least one value for change from randomization baseline in the AIMS total score during the placebocontrolled period.
Treatment assignment for all summaries and analyses using the PE analysis set will be based on the randomization schedule.

6.2.1.4. Patient Reported Outcome Analysis Set

The patient reported outcome (PRO) analysis set will include all enrolled subjects who take at least one dose of study drug and have at least one health-related quality of life and/or disability assessment collected after baseline.
연구에 등록되어야 하며
최소 1회 이상 약을 복용해야하며
baseline이후 삶의 질 또는 장애 관련 설문 조사를 1회 이상 작성한 피험자

6.3. Baseline Definition

Two definitions of baseline will be used:
- Study baseline:
  - The assessments collected at the Day 1 study visit will serve as the study baseline value for all assessments.
    - If a value is not available at the Day 1 visit, then the last measurement collected on or prior to the date of the first dose of open-label study drug will serve as study baseline.
- Randomization baseline:
  - The assessments collected at the randomization visit (Week 8) will serve as the randomization baseline value for select assessments.
  - If a value is not available at the randomization visit, then the last measurement collected after the first dose of open-label study drug and on or prior to the date of the first dose of randomized study drug will serve as randomization baseline.
베이스라인이 두 개로 정의되었다.
- 스터디 베이스라인은 day1인 것으로 보아 약의 투여 전 후를 비교하려는 것으로 이해
- 랜덤 베이스라인은 week8 인 것으로 보아 시험군, 대조군 비교를 위한 것으로 이해

6.4. Derived and Transformed Data

6.4.1. Study Day

Study day is calculated relative to the date of the Day 1 visit.
If the date of interest occurs on or after the Day 1 visit, then the study day will be calculated as: date of interest – date of Day 1 visit + 1.
If the date of interest occurs prior to the Day 1 visit, then the study day will be calculated as: date of interest – date of Day 1 visit.
interest를 어디에 두냐에 따라 계산되는 값이 달라질 것.
이건 같은 공간적 시간적 개념으로 시작하는 시험이 아니기 때문에 환자마다 시작 날짜가 달라서 study day를 상대개념으로 정해놓으면 계산이 수월해질 것.

6.4.2. Change from Baseline

Change from baseline is calculated as (postbaseline value – baseline value).
Percent change from baseline is calculated as (change from baseline/baseline value * 100).
If either the baseline or postbaseline value is missing, the change from baseline and the percent change from baseline will also be missing.
The percent change from baseline will also be missing if the baseline value is equal to zero.

6.4.3. Handling of Early Termination Visit Data

An early termination (ET) visit occurs when a subject discontinues from the study prior to completing the scheduled Week 20 visit.
The data collected at ET visits will be included in summary tables and figures in accordance with the ET visit mapping scheme described in this section.
An ET visit will be mapped to the next scheduled study visit if it occurs within 14 days prior to and 13 days after the expected study day of the next scheduled visit (with the requirement that the scheduled visit prior to the ET visit was actually completed by the subject).
ET visits occurring after the Week 16 visit will be mapped to the Week 20 follow-up visit if it occurs after day 125.
Early termination visit data which are not mapped to a scheduled visit will not be included in by-visit analyses and summaries.
They will be included in any analyses that look across all available assessments during the treatment period, including unscheduled visits.
They will also be included in any applicable by-subject data listings.
조기종료et정의
- week 20 완료 전에 중단한 대상자
- 예정 시험일의 13일 전이나 14일 이내이면 다음 방문의 건으로 매핑
- week 16의 125일 이후 일어난거면 week20으로 간주
- by-visit 분석에는 포함되지 않고 계획된 방문에도 매핑되지 않음.

6.5. Handling of Missing Data

6.5.1. Missing Outcome Data

Unless otherwise specified, missing values will not be imputed for descriptive statistics.
For persistence of effect summaries based on the AIMS dyskinesia total score, the missing values for change from randomization baseline will be handled in a linear mixed-effect model with repeated measures (MMRM), where the values are assumed to be missing at random.
Missing data for other selected endpoints will be imputed using last observation carried forward(LOCF).
결측값은 대체되지 않고 요약될 것.
Primary endpoint인 aims 스코어에 대해 랜덤 베이스라인의 변화량의 결측값은 mmrm 방식으로 대체될 것인데, MMRM방식은 반복 측정 데이터를 분석할때 사용하는 통계모델로 결측치를 직접 대체하지 않고, 모델 내부에서 통계적으로 처리, 이 모델에서 사용하는 방식은 Missing at random 즉 무작위로 결측이 발색했다 가정함.
그 외 다른 endpoints 에서는 경측값이 locf 방식으로 대체될 것인데, 마지막 관측된 값으로 대체하는 방식임.

7. STUDY POPULATION

A summary of the number and percentage of subjects included in (and excluded from, as applicable) each analysis set (Section 6.2.1) will be provided.
The number and percentage of subjects excluded from each analysis set by reason for exclusion will also be provided.
A summary of subject disposition will be prepared that displays the number of subjects who were enrolled, who received at least one dose of study drug, who were randomized to each treatment group, who were randomized and completed the placebo-controlled withdrawal period, who were randomized and completed the follow-up period, and who were not randomized and discontinued study participation.
The number of subjects who discontinued from the study will also be displayed by reason for discontinuation.
The analysis set and subject disposition summaries will be based on all enrolled subjects and will include the following analysis groups:
- subjects enrolled but not randomized;
- subjects randomized to placebo;
- subjects randomized to valbenazine;
- all subjects.
A listing of randomized subjects will also be provided and will include subject ID, informed consent date, enrollment date, randomization date, concomitant antipsychotic use (yes vs. no), and randomized treatment group.
A separate summary of randomization by study site will be presented.
This summary will display the number of subjects randomized to each treatment group by site.

7.1. Protocol Deviations

Protocol deviations described in the study-specific Protocol Deviation Plan will be entered into the study electronic Trial Master File (eTMF) system and used to identify important protocol deviations (IPDs).

7.2. Demographic and Baseline Characteristics

Demographic and baseline characteristics data will be summarized using descriptive statistics for continuous variables, and frequency counts and percentages for categorical variables.

인구 통계학 요약 포함되는 것들

7.3. Medical History and Medical Conditions Present at Entry

Medical history will be summarized in frequency tables (number and percentage of subjects) by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT), with SOCs and PTs within each SOC sorted alphabetically.
Separate summaries will be presented for the safety analysis set and the randomized safety analysis set.
The randomized safety analysis set will be presented by treatment and will include an additional “All Subjects” column.

병력 사전은 어떤 것을 사용하고 어떻게 요약되는지

7.4. Study Drug Dosing, Compliance, and Dose Reductions

7.4.1. Compliance

순응도

Subjects will bring all unused study drug and empty study drug packaging material to the center at each study visit for drug accountability and reconciliation by study center personnel.
A compliance check will be performed by counting the capsules returned at each study visit.
The site will then enter whether the subject’s dosing compliance since the previous visit was ≥80% into the eCRF.
The number and percentage of subjects who are dosing compliant at each visit will be summarized using the safety analysis set (through Week 8) and the randomized safety analysis set (Week 8 through Week 16).

7.4.2. Dose Reductions

약물 감량

Subjects will receive 40 mg for the first week of treatment and 80 mg until the end of Week 8 in subjects randomized to receive placebo and until the end of Week 16 in subjects randomized to remain on valbenazine.
If a subject is unable to tolerate the 80 mg dose, the daily dosage will be reduced to 40 mg.
Subjects unable to tolerate the 40 mg dose (or placebo) will be discontinued from the study.
The number and percentage of subjects with a dose reduction at any time during the open-label treatment period will be presented using the safety analysis set.
The number and percentage of subjects with a dose reduction at any time during the placebo-controlled treatment period will be presented by treatment group using the randomized safety analysis set.

9. PERSISTENCE OF EFFECT OF VALBENAZINE

효과 지속성 분석

9.1. General Considerations

Unless otherwise specified, the PE analysis set will be used for all analyses described in this section.
Results will be displayed by randomized treatment group (Randomized Valbenazine vs Randomized Placebo).

9.2. Abnormal Involuntary Movement Scale

The severity of TD will be assessed using the AIMS. The AIMS examination will be administered by the investigator (or designee) in accordance with the AIMS administration procedure.
The AIMS administration will be video recorded (approximately 10 minutes) following standardized guidelines.
The investigator (or designee) will score items 8-10 and items 11-12 (binary dental status items). Items 1-7 will be scored by two blinded Central AIMS Video Raters using consensus scoring.

9.2.1. AIMS Individual Items

The score for Items 1 through 7 ranges from 0 (no dyskinesia) to 4 (severe dyskinesia) and includes facial and oral movements (Items 1 to 4), extremity movements (Items 5 to 6), and trunk movements (Item 7).
Items 8, 9 and 10 rate global judgments: Items 8 (severity of abnormal movements) and 9 (incapacitation due to abnormal movements) range from 0 (none, normal) to 4 (severe) and Item 10 being scored based only on the subject’s report of his/her awareness of abnormal movements from 0 (no awareness) to 4 (aware, severe distress).
Items 11 and 12 are yes/no questions concerning problems with teeth and/or dentures.
Descriptive statistics of the individual AIMS items 1 through 10 will be presented for study baseline, randomization baseline and for each study visit occurring thereafter.
Change from randomization baseline will be presented for the post-randomization visits.

기술 통계 및 변화량 분석(post randomization visit에 대해 기저치)

9.2.2. AIMS Dyskinesia Total Score

The AIMS dyskinesia total score is defined as the sum of the scores of AIMS items 1 through 7.
If any of the seven items have a missing value, the total score for that subject/visit will be set equal to missing.
The AIMS dyskinesia total score can therefore range from 0 to 28, with higher scores indicating greater severity.
The change from randomization baseline in AIMS dyskinesia total score during the placebocontrolled treatment period will be analyzed using a linear mixed-effect model of repeated measures (MMRM) that includes the fixed effects of treatment, visit, treatment-by-visit, concomitant antipsychotic use (yes vs. no), and study baseline AIMS dyskinesia total score as a covariate.
Within-subject variability will be accounted for using a random effect with an unstructured covariance matrix.
The least squares (LS) mean for each treatment group and the associated 95% confidence interval (CI) will be presented for each visit.
The primary measurement of persistence of effect will be based off the CI for the LS mean change from randomization baseline in the placebo group at Week 16.
Descriptive statistics of the AIMS dyskinesia total score will be presented for study baseline, randomization baseline and for each study visit occurring thereafter. Descriptive statistics for change from randomization baseline and change from study baseline will also be presented for the relevant postbaseline visits. The descriptive statistics for the change from randomization baseline will include a 2-sided 95% confidence interval for the mean.
Mean (±SEM) values of the observed values at each visit will be summarized in a line graph by treatment group. A similar graph will be presented for the changes from randomization baseline for the post-randomization visit.
The LS means (±SEM) from the MMRM analysis results will be summarized in a similar line graph.

사용되는 모델은 MMRM, 고정효과는 치료효과, 방문, 치료와 방문의 교호, 항정신병약 투약여부, 그리고 베이스라인AIMS총점수 공변량으로

환자 내 반복측정치 간의 상관성을 유연하게 고려하기 위해 unstructured covariance matrix (비구조화 공분산행렬) 사용

치료군간 lsmean이랑 95%신뢰구간 제시.

9.2.3. AIMS Responder Analysis

An AIMS responder is defined, on a per-visit basis, as a subject whose AIMS dyskinesia total score is reduced by at least 50% from study baseline. Descriptive statistics will be presented by visit and treatment group for the number and percentage of subjects classified as AIMS responders.

9.3. AEs of TD and Discontinuations

Additional measures of persistence of effect that will be summarized include AEs of TD and early discontinuations from the study due to lack of efficacy during the double-blind, placebocontrolled treatment period.
The summary will include the number and percentage of subjects who:
- 1. experience an AE of TD during the placebo-controlled treatment period;
- 1. discontinue from the study due to lack of efficacy during the placebo-controlled treatment period;
- 1. meet either of the previous criteria.
An AE of TD is defined as AEs with a MedDRA preferred term of “Tardive dyskinesia” or “Dyskinesia”.

9.4. Subgroup Analyses

The relationship between subject clinical characteristics and the persistence of effect of valbenazine during the double-blind, placebo-controlled treatment period will be evaluated.
The following clinical characteristics will be investigated:
- Primary psychiatric diagnosis (schizophrenia or schizoaffective disorder vs. mood disorder)
- Age group (<45 years vs. ≥45 years; <65 years vs. ≥65 years)
- Sex (male vs. female)
- Concomitant use of antipsychotic medications (yes vs. no, as indicated by investigator in IWRS)
- Treatment response status (yes vs. no, as indicated by AIMS Responder status [Section 9.2.3] at randomization baseline)
Each subgroup factor along with its 2-way and 3-way interactions with treatment group and visit will be added to the MMRM model specified for the AIMS dyskinesia total score in Section 9.2.2.
The LS mean for each combination of treatment group and subgroup stratum and the associated 95% CIs will be presented by visit.
Descriptive statistics for the observed AIMS dyskinesia total scores and changes from randomization will also be presented by visit and treatment for each stratum of the subgroups.
The MMRM results will not be presented if a subgroup has <10 subjects in any treatment and subgroup stratum combination or if the model fails to converge.
If needed to investigate a potential signal, descriptive statistics of the individual AIMS items or other assessments of persistence of effect may also be presented by subgroup.

서브그룹 분석

(생략)