Clinical trial NCT03568331
Conditions: Atopic Dermatitis
Keywords: Chronic Pruritus Eczema
Sponsor: Vanda Pharmaceuticals
Start date: 2018-07-09; Completion date: 2019-12-27
Enrollment: 375 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, randomized, double-blind, placebo-controlled study to be conducted in the United States in subjects with atopic dermatitis.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Tradipitant intervention 2: Placebo
Intervention descriptions: intervention 1: Oral Capsule intervention 2: Oral Capsule

Protocol documents:
Prot_000.pdf: 
 
 
TRADIPITANT 
VP-VLY-686-3101 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, EFFICACY STUDY OF THE NEUROKININ-1 
RECEPTOR ANTAGONIST VLY-686 IN PATIENTS WITH 
ATOPIC DERMATITIS 
 
Document Type:  
 
 
 
 
Clinical Study Protocol 
Sponsor:  
 
 
 
 
 
 
Vanda Pharmaceuticals Inc. 
 
 
 
 
 
 
 
 
 
 
2200 Pennsylvania Ave. NW 
 
 
 
 
 
 
 
 
 
 
Suite 300E 
 
 
 
 
 
 
 
 
 
 
Washington, DC 20037 
USA 
Study Product:  
 
 
 
 
tradipitant (VLY-686) 
Protocol Number: 
 
 
 
 
VP-VLY-686-3101 
Study Phase:  
 
 
 
 
 
III 
IND Number: 
 
 
 
 
 
122741 
NCT Number: 
 
 
 
 
 
NCT03568331 
 
 
Date: 12 August 2019 
Status: Final 


 
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SYNOPSIS  
Name of Sponsor/Company: 
Vanda Pharmaceuticals Inc. 
Name of Investigational Product: 
tradipitant (VLY-686) 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Efficacy Study of the 
Neurokinin-1 Receptor Antagonist VLY-686 in Patients with Atopic Dermatitis  
Study center(s): Multicenter in North America 
Studied period:  
Date first patient enrolled: July 2018 
Estimated study duration: 6 months 
Phase of development:  
III 
Number of patients (planned):  
Approximately 350 patients randomized (175 per arm, 1:1 randomization scheme), 
diagnosed with atopic dermatitis with treatment-resistant pruritus (i.e. pruritus duration of 
> 6 weeks despite the use of antihistamines or corticosteroids)  
Inclusion Criteria: 
1. Ability and acceptance to provide written informed consent; and sufficiently fluent 
in English to participate in the trial; 
2. Male and non-pregnant, non-lactating female patients aged 18 – 70 years 
(inclusive); 
a. Note: Principal investigators are advised to enroll a patient population that 
reflects the demographics of the overarching United States population. 
Demographics in this context refer to age, sex, race, and ethnicity.   
3. Diagnosed with atopic dermatitis 
a. ≥ 1% body surface area (BSA) of AD involvement at the screening and baseline 
visits; 
b. Presence of excoriations at screening and baseline visits (i.e. SCORing Atopic 
Dermatitis index excoriation score > 0) 
c. Note: Principal investigators are advised to enroll a patient population that 
reflects the severity distribution of the overarching atopic dermatitis population 
seen in the United States population. Severity in this context refers to mild, 
moderate, and severe atopic dermatitis. 
4. Suffering from chronic pruritus with pruritus being actively present for at least 6 
weeks prior to screening despite the use of antihistamines or corticosteroids; 
5. Worst Itch Numerical Rating Scale (WI-NRS) score ≥ 5 points at the screening and 
baseline visit; 


 
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6. Daily diary reporting Worst Itch Numerical Rating Score (WI-NRS) average score 
for maximum itch severity ≥ 7 points between screening and baseline visits;  
a. Note: WI-NRS average score for maximum itch severity will be determined 
based on the average of the 50% worst daily NRS scores for maximum itch 
severity (the daily scores ranging from 0 to 10) during the screening period 
(between visits 1 and 2). A minimum diary compliance of 70% during the 
screening phase (between Visits 1 and 2) is required before randomization.  For 
patients who do not have at least 70% diary compliance preceding the planned 
randomization date, randomization should be postponed until this requirement 
is met, but without exceeding the 45-day maximum duration for screening.  
7. Patients with Body Mass Index (BMI) of ≥18 and ≤40 kg/m2 (BMI = weight (kg)/ 
[height (m)]2);  
8. Patients must agree to the following study restrictions:   
a. Males of procreative capacity (not surgically sterile) will use an acceptable 
method of contraception from randomization through 1 month following the 
last dose of study medication. Examples of acceptable contraception for males 
include abstinence, use of a barrier method, or surgically-sterilized or post-
menopausal partner.  
b. Females of child-bearing potential (not surgically sterile or post-menopausal, 
defined as 12 months with no menses without a medical cause) will use an 
acceptable method of contraception from the earlier of screening or 1 month 
prior to randomization through 1 month after the last dose of study medication. 
Examples of acceptable methods of contraception for females include 
abstinence, the use of 2 independent barrier methods, hormonal contraception 
plus 1 barrier method, or surgically sterilized partner.  
9. Willing and able to comply with all study requirements and restrictions; 
10. Willing to not participate in any other interventional trial for the duration of their 
participation; 
11. Patients must be in good health as determined by past medical history, physical 
examination, electrocardiogram, clinical laboratory tests, and vital signs. 
 
Exclusion Criteria: 
1. Chronic pruritus due to condition other than atopic dermatitis (AD);  
2. Superinfection of AD; 
3. Unwilling or unable to follow medication restrictions described in Section 7.2, or 
unwilling or unable to sufficiently washout from use of restricted medication.  
4. Under medical treatment for a skin disease with a therapy listed in the prohibited 
medications section in Table 3 that may influence the results of the study; 
5. Have been treated with the following therapies: 


 
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a. An investigational drug, including placebo, within 8 weeks or within 5 half-
lives (if-known), whichever is longer, prior to the baseline visit or 
b. A biologic for less than 5 half-lives (if known) or 16 weeks prior to the baseline 
visit 
6. Recent history (within six months of screening) of drug or alcohol abuse as defined 
in DSM-5 Diagnostic Criteria for Drug and Alcohol Abuse and/or a positive drug or 
alcohol screen at the Screening visit and Baseline; 
7. Patient has ever made a suicide attempt and/or had suicidal ideation of type 4 or 5 
on the Columbia-Suicide Severity Rating Scale (C-SSRS) or patient is at risk of 
suicide at Screening or Baseline, in the opinion of the Investigator;  
8. Any medical procedure requiring general anesthetic within three months of the 
Baseline Visit or any procedure requiring sedation within one month of the baseline 
visit; 
9. Current clinically significant cardiovascular, respiratory, neurologic, hepatic, 
hematopoietic, renal, gastrointestinal or metabolic dysfunction unless currently 
controlled and stable, including (but not limited to) the following: 
a. Uncontrolled diabetes mellitus defined as HbA1c >7%; 
b. Positive hepatitis C antibody test (anti-HCF); 
c. Positive hepatitis B surface antigen (HBsAg); 
10. History (including family history) or current evidence of congenital long QT 
syndrome or known acquired QT interval prolongation; 
11. History of intolerance and/or hypersensitivity to medications similar to tradipitant 
and its accompanying excipients; 
12. Indication of impaired liver function (values for AST, ALT, or bilirubin > 2 times 
the Upper Limit of Normal (ULN); 
13. Has a creatinine level > 1.25x ULN  
14. Anyone affiliated with the site or sponsor and/or anyone who may consent under 
duress; 
15. Any other sound medical reason as determined by the Investigator including any 
condition which may lead to an unfavorable risk-benefit of study participation, may 
interfere with study compliance or may confound study results.  
Investigational product, dosage and mode of administration:  
A single oral capsule of tradipitant 85 mg or matching placebo will be orally administered 
twice daily for a total daily dose of 170 mg.  
Duration of treatment (Randomization Phase): 8 weeks 
 
Reference therapy, dosage and mode of administration:  
Placebo capsules will be provided in size and appearance identical to those containing VLY-
686 and will be administered orally. 


 
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Objectives:  
Primary Objective:  
• To evaluate the efficacy of VLY-686 in reducing worst itch in patients with 
chronic pruritus in atopic dermatitis as measured by Worst Itch Numerical 
Rating Scale (WI-NRS) at Week 8. 
 
Secondary Objectives: 
• To evaluate the efficacy of VLY-686 in improving disease severity in patients 
with atopic dermatitis as measured by the validated Investigator Global 
Assessment scale for Atopic Dermatitis (vIGA-AD). 
• To evaluate the efficacy of VLY-686 in improving disease severity in patients 
with atopic dermatitis as measured by the SCORing Atopic Dermatitis 
(SCORAD) index and Eczema Area and Severity Index (EASI). 
• To evaluate the proportion of patients with improvement of WI-NRS ≥ 4-point 
reduction. 
• To evaluate the proportion of patients with improvement on SCORAD index of 
at least 50%, 75% or 90% improvement. 
• To evaluate the proportion of patients with improvement on the EASI of at least 
50%, 75% or 90% improvement. 
• To assess the efficacy of tradipitant on global measures of improvement as 
measured by Clinical Global Impression of Change (CGI-C) and Patient Global 
Impression of Change (PGI-C). 
• To assess the efficacy of tradipitant on quality of life as measured by the Patient 
Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), 
Healthly Days Core Module (4 questions) (HRQOL-4), Insomnia Symptom 
Questionnaire (ISQ) and Patient Benefit Index - Pruritus (PBI-P). 
• To explore the safety and tolerability of multiple oral doses of VLY-686. 
 
Pharmacogenomic Sub-Study: 
• Identify genetic markers that correlate with response to tradipitant treatment. 
• Identify genetic markers that correlate with adverse events that may occur upon 
treatment with tradipitant. 
• To identify genetic markers that are associated with atopic dermatitis and/or 
pruritus and disorders/diseases associated with NK-1 receptors. 
• To identify genetic markers that are associated in the metabolism, distribution, 
and/or excretion of tradipitant and its metabolites.     
Overall Design: 
This is multicenter, randomized, double-blind, placebo-controlled study to be conducted in 
the United States. Approximately Three Hundred and Fifty (350) patients diagnosed with 
atopic dermatitis, who satisfy the selection criteria for the study, will be randomized to 
receive either tradipitant 85 mg or matching placebo BID. 


 
6 
 
The study is divided into two phases: the pre-treatment phase and the evaluation phase. The 
pre-treatment phase includes a screening and a baseline visit where patients’ eligibility for 
the study will be assessed. Washout of medications will occur during the screening phase.   
The evaluation phase includes 8 weeks of randomized, double-blind, placebo-controlled 
treatment. In-clinic evaluations will occur at Screening, Baseline, and Weeks 2, 4, 6, and 8.  
Criteria for evaluation: 
Efficacy:  
Efficacy assessments will include:  
• Worst Itch Numerical Rating Scale (WI-NRS) 
• SCORing Atopic Dermatitis (SCORAD) index  
• Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-
AD) 
• Eczema Area and Severity Index (EASI)  
• Clinical Global Impression of Change (CGI-C) 
• Patient Global Impression of Change (PGI-C) 
• Patient Oriented Eczema Measure (POEM) 
• Dermatology Life Quality Index (DLQI) 
• Patient Benefit Index – Pruritus (PBI-P) 
• Insomnia Symptom Questionnaire (ISQ) 
• Healthly Days Core Module (4 questions) (HRQOL-4)  
Safety:  
• Safety and tolerability assessments will include the recording of adverse events 
(AEs), physical examinations, clinical laboratory evaluations, vital signs, and 
electrocardiograms. 
• The Columbia-Suicide Severity Scale (C-SSRS) will be used to assess suicidal 
behavior and ideation.  
 
 
 


 
7 
 
Table 1: 
Schedule of Evaluations 
Phase 
Pre-Treatment  
Evaluation 
Visit 
V1 
Screening 
V2 
Baseline 
V3 
 
V4 
 
V5 
 
V6  
 
Study Day 
Up to 
Day -45 
Day 0 
Day 
141 
Day 
281 
Day 
421  
Day 561 
or ET 
Informed Consent Form (ICF)2 
X 
 
 
 
 
 
Eligibility assessment  
X 
X 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
Adverse Event (AE) Assessment3 
X 
X 
X 
X 
X 
X 
Serum β-HCG (for WOCBP) 
X 
 
 
 
 
X 
Urine pregnancy test (for WOCBP) 
 
X 
X 
X 
X 
 
HbA1c 
X 
 
 
 
 
 
Hepatitis B/C screen 
X 
 
 
 
 
 
Drug and alcohol screen 
X 
X 
X 
X 
X 
X 
Hematology, chemistry, and urinalysis 
X 
X 
 
X 
 
X 
IgE collection 
X 
X 
X 
X 
X 
X 
Cytokine Panel4 
X 
 
 
 
 
X 
Filaggrin Analysis 
X 
 
 
 
 
X5 
Pharmacogenetic (PG) sample 
X 
 
 
 
 
X5 
Pharmacokinetic (PK) sample 
 
X 
X 
X 
X 
X 
Resting 12-lead ECG 
X 
X 
X 
X 
X 
X 
Vital signs and body measurements6 
X 
X 
X 
X 
X 
X 
Physical Examination (PE)7 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity Rating 
Scale (C-SSRS)8 
X 
X 
X 
X 
X 
X 
Medical History of Pruritus 
Questionnaire 
 
X 
 
 
 
 
Medical History of Atopy 
Questionnaire 
X 
 
 
 
 
 
Pruritus Assessment (incl. NRS, VRS) 
X 
X 
X 
X 
X 
X 
SCORing Atopic Dermatitis 
(SCORAD) index 
X 
X 
X 
X 
X 
X 
Eczema Area and Severity Index 
(EASI) 
X 
X 
X 
X 
X 
X 


 
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Phase 
Pre-Treatment  
Evaluation 
Visit 
V1 
Screening 
V2 
Baseline 
V3 
 
V4 
 
V5 
 
V6  
 
Study Day 
Up to 
Day -45 
Day 0 
Day 
141 
Day 
281 
Day 
421  
Day 561 
or ET 
Validated Investigator Global 
Assessment scale for Atopic 
Dermatitis (vIGA-AD) 
X 
X 
X 
X 
X 
X 
Patient Benefit Index – Pruritus (PBI-
P)9 
 
X 
X 
X 
X 
X 
Patient Global Impression of Change 
(PGI-C) 
 
 
X 
X 
X 
X 
Clinical Global Impression of Change 
(CGI-C) 
 
 
X 
X 
X 
X 
Patient Oriented Eczema Measure 
(POEM) 
X 
X 
 
X 
 
X 
Dermatology Life Quality Index 
(DLQI) 
 
X 
X 
X 
X 
X 
X 
Insomnia Symptom Questionnaire 
(ISQ) 
X 
X 
 
X 
 
X 
Healthy Days Core Module (4 
questions) (HRQOL-4) 
X 
X 
 
X 
 
X 
Daily Diary 
 
Photography 
 
X 
 
X 
 
X 
Randomization 
 
X 
 
 
 
 
Study medication dispensation10 
 
X 
X 
X 
X 
 
Study medication collection & 
compliance 
 
 
X 
X 
X 
X 
Daily diary distribution and 
instruction 
X 
 
 
 
 
 
Patient daily diary review  
 
X 
X 
X 
X 
X 
1 within +/- 3 days 
2 Informed Consent will be obtained prior to performance of any study procedure(s) 
3 Adverse Event collection will begin at the time the ICF is signed 
4 If V1 cytokine panel sample is missed, sample should be drawn at the next in-clinic visit.  
5 Sample collected at V1. Sample collected at V6/EOS only if randomized under Protocol Amendment 1 and sample was not 
already collected at V2. 
6 Body height will only be collected at screening (V1), body weight will be collected at visits 1, 2, and 6. 
7 An abbreviated physcial axamination will be performed at V2 (Baseline) and post-baseline visits 3-5 ONLY if clinically 
indicated. 


 
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8 The Screening/Baseline C-SSRS will occur at V1 (Screening). The Since Last Visit C-SSRS will occur at all other visits. 
9 At V2 (Baseline), the Patient Needs Questionnaire (PBI-P(PNQ)) will be administered. The Patient Benefits Questionaire 
(PBI-P(PBQ)) will be administered at subsequent visits.  
10 Patients will be instructed to take their first dose of study medication on the evening of Day 0. 
 
ET = Early Termination; WOCBP = Women of Child-bearing Potential; ECG = electrocardiogram; C-SSRS = 
Columbia Suicide Severity Rating Scale; NRS = Numeric Rating Scale; VRS = Verbal Response Scale; HbA1c= 
Haemoglobin A1c or glycated haemoglobin; IgE= Immunoglobulin E 

SAP_001.pdf: 
 
 
TRADIPITANT 
VP-VLY-686-3101 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, EFFICACY STUDY OF THE NEUROKININ-1 
RECEPTOR ANTAGONIST VLY-686 IN PATIENTS WITH 
ATOPIC DERMATITIS 
 
Document Type:  
 
 
 
 
Statistical Analysis Plan 
Sponsor:  
 
 
 
 
 
 
Vanda Pharmaceuticals Inc. 
 
 
 
 
 
 
 
 
 
 
2200 Pennsylvania Ave. NW 
 
 
 
 
 
 
 
 
 
 
Suite 300E 
 
 
 
 
 
 
 
 
 
 
Washington, DC 20037 
USA 
Study Product:  
 
 
 
 
tradipitant (VLY-686) 
Protocol Number: 
 
 
 
 
VP-VLY-686-3101 
Study Phase:  
 
 
 
 
 
III 
IND Number: 
 
 
 
 
 
122741 
NCT Number: 
 
 
 
 
 
NCT03568331 
 
 
Date: 12 August 2019 
Status: Final 
 


 
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1. 
STATISTICS 
1.1. 
Sample Size and Accrual 
To detect a 1.2 point treatment difference in worst itch score, as measured by NRS, between 
VLY-686 and placebo with a standard deviation (SD) of 3, a sample size of 175 patients per arm 
(total 350 patients) provides approximately 96% power based on a two-sided Student’s T-Test 
with a 5% significance level. In addition, a total sample size of 350 patients (175 per arm) will 
also provide approximately 91% power to detect a 18% response difference,  according to 35% 
and 53% response rates on placebo and VLY-686 respectively in the phase II study,  based on a 
two-sided Fisher’s Exact Test with a 5% significance level.  
1.2. 
Statistical Methods and Analysis Plan 
This section describes the planned statistical analyses in general terms.  A complete description of 
the methodology will be specified in a statistical analysis plan (SAP). Any changes in the 
statistical methods described in this protocol that occur prior to database lock will be documented 
in the SAP and will not require a protocol amendment.  
 
1.2.1. 
General 
Statistical analyses will be performed using two-sided tests.   
 
Data will be summarized by treatment group (and by visit when applicable), with respect to 
demographic and baseline characteristics, efficacy variables, and safety variables. 
 
Summary statistics will include the mean, N, standard deviation, median, minimum, and 
maximum values for continuous variables, and frequencies and percentages for categorical 
variables. 
 
For the analyses of change from baseline, only patients with a baseline and at least one (1) post-
baseline measure will be included in the analysis. Unless otherwise specified, baseline is defined 
as the latest non-missing observation across all the visits in the screening phase, before the 
active study drug begins. Endpoint will be the latest non-missing observation across all the post-
baseline visits in the evaluation phase. 
 
Low enrolling sites will be pooled for analysis and the pooling algorithm will be determined 
prior to breaking the blind.  The goal of pooling low enrolling sites is to have a sufficient 
number of patients per treatment group within a site for the analysis models and for the 
evaluation of the treatment-by-site interaction for the primary endpoint.  Unless otherwise 
specified, the pooled sites will only be used in the analyses where the site has an effect.  The 
actual sites rather than the pooled sites will be specified in the data listings. 


 
3 
 
 
Details of the model and the analyses will be specified in the SAP.  All statistical analyses will 
be performed using SAS®, Version 9.1.3 or higher. 
 
1.2.2. 
Patient Populations for Analysis 
The following analysis populations will be defined for this study: 
Intent-to-Treat: will include any patient randomized into the study that receives a dose of 
study drug and that has completed at least one post-baseline efficacy measurement while on 
study medication;   
Safety: Any patient randomized into the study that receives a dose of study drug; 
Per-Protocol: Any patient who is randomized and receives the protocol required study drug 
exposure and required protocol processing.   
 
Efficacy analyses will be performed on the Intent-to-Treat population and the Per-Protocol 
population.  Safety summaries will be based on Safety set.  Patient characteristics will be presented 
for all patients randomized. 
 
1.2.3. 
Patient Disposition 
Study completion and reasons for discontinuation for all randomized patients in the double-blind 
phase will be summarized for each treatment group.    Discontinuations by reason will be tabulated 
by visit for each treatment group. 
 
Time to discontinuation due to adverse events, lack of efficacy and for any reason will be analyzed 
using Kaplan-Meier survival techniques; the log-rank test will be used for group comparison. 
 
1.2.4. 
Demography and Other Baseline Data 
Demographic data and patient characteristics at screening/baseline will be listed and summarized 
by treatment group for all randomized patients using descriptive statistics. 
 
Past and current medical history will be summarized by treatment group using the system organ 
class (SOC) as coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary.  
 
Past medical conditions will be defined as an onset date prior to randomization (Visit 2) and 
resolved (not on-going) as of Visit 2.  Current medical conditions, defined as an onset date on or 
after the date of randomization (Visit 2) or an onset date prior to randomization (Visit 2) and 


 
4 
 
unresolved (on-going) as of Visit 2, will be reported separately, but similarly to the past medical 
conditions.  If both a past and a current (on-going) medical condition record are indicated for a 
condition, the condition will be presented under current medical conditions only. 
 
1.2.5. 
Study Medication 
The number of patients at each visit will be summarized by treatment group.  
 
The compliance to study medication, as recorded in the CRF, will also be summarized by 
treatment group. The proportion of patients who are significantly noncompliant in the double-
blind phase, as noted in Section 7.3. of this protocol, will be summarized by treatment groups. 
 
1.2.6. 
Prior/Concomitant Therapy 
Any medications or therapy present before the first dose of study medication (Visit 2) will be 
considered as prior medications.  Concomitant medications (medications present while on study 
medication) will be recorded throughout the study and at early discontinuation.  These 
medications will be coded using the WHO-drug dictionary.  The number of patients from the 
Safety Population using prior or concomitant medications will be categorized by the WHO-drug 
category and preferred term, and presented for each treatment group.  In any given category (e.g., 
drug category) a patient will be counted only once. 
 
1.3. 
Efficacy Data Analysis 
1.3.1. 
Primary Outcome and Methodology 
The primary efficacy outcome measure for the double-blind phase will be the mean change from 
baseline in worst itch score, as measured by the Numerical Rating Scale (NRS) at Week 8. The 
primary statistical method will be the mixed effect model repeat measurement (MMRM). A 
detailed description of the primary analysis model and the corresponding sensitivity analysis will 
be included in the SAP.  
 
As stated previously, any changes in the statistical methods that occur prior to database lock will 
be documented in the SAP and will not require a protocol amendment. 
1.3.2. 
Secondary Efficacy Analysis 
The secondary efficacy outcomes include: 
• DDSS 
• Itch questionnaires including diary WI-NRS, site WI-NRS and VRS 
• Proportion of patients with improvement of WI-NRS ≥ 4-point reduction; 


 
5 
 
• SCORAD; 
• EASI;  
• Proportion of patients with improvement on SCORAD index of at least 50%, 75% or 
90% improvement. 
• Proportion of patients with improvement on the EASI of at least 50%, 75% or 90% 
improvement. 
• vIGA-AD; 
• PGI-C; 
• CGI-C; 
• PBI-P; 
• HRQOL-4; 
• POEM; 
• DLQI; 
• ISQ; 
• Pharmacokinetic-Pharmacodynamic correlation. 
 
Continuous endpoints will be summarized and analyzed in a similar manner as the primary 
endpoint. Categorical endpoints will be analyzed by a Cochran–Mantel–Haenszel (CMH) test. 
Details of the analysis will be described in the SAP. 
 
Time to event data will be analyzed using the Kaplan-Meier method, and the treatment group 
differences will be tested by the log-rank test. Details of the analysis will be described in the SAP. 
1.4. 
Safety Data Analysis 
The primary assessment of safety will be based on the frequency of treatment-emergent adverse 
events (TEAEs), serious adverse events (SAEs) and on the frequency of clinically notable 
abnormal vital signs, electrocardiograms (ECGs) and laboratory values. Other safety evaluations 
include changes in vital signs, changes in clinical laboratory evaluations, and changes in ECGs, 
physical exam findings during treatment, and suicide ideation (C-SSRS) and behavior events. 
 
1.4.1. 
Adverse Events 
Adverse events will be recorded throughout the study and at early discontinuation. Adverse 
events and medical conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary.  Treatment-emergent adverse events will be defined as 
those events, which are newly occurring or worsening from baseline.  In all cases only treatment 
emergent adverse events will be summarized.  


 
6 
 
 
Treatment-emergent adverse events will be summarized within each treatment group by primary 
system organ class and preferred term. (NOTE: In any given category [e.g. body system] a 
patient will only be counted once.) The incidence rates of TEAEs will be analyzed as described 
in the SAP.  Similar displays will be provided for SAE and prior (conditions ending prior to the 
first dose of study medication) and current (conditions present while on study medication) 
medical conditions. 
 
Adverse events will further be categorized by severity, relationship to study medication, and 
action taken. Other information collected will be listed, as appropriate. Any event starting more 
than 3 days after the final dose of study medication will be excluded from the above tables and 
only listed, unless the event caused discontinuation. 
 
The proportions of patients experiencing SAEs and AEs resulting in discontinuation from the 
study will be summarized by treatment groups.  
 
1.4.2. 
Laboratory Data 
Clinical Laboratory Data 
The summary statistics of raw data (hematology and chemistry) and change from baseline 
values will be presented, as well as shift tables from baseline to post-baseline values using 
normal ranges.  For urinalysis parameters, the number and percentage of patients falling under 
each category of the test will be presented. 
 
Clinical laboratory data will be summarized for each treatment group by presenting the 
proportions of patients with clinically notable abnormalities (Appendix 22.1). 
 
Clinically notable values will be identified according to the criteria identified in the FDA's 
"Supplementary Suggestions for Preparing an Integrated Summary of Safety Information in an 
Original NDA Submission and for Organizing Information in Periodic Safety Updates" (Revised 
2-APR-87) provided by the FDA Division of Neuropharmacological Drug Products (DNDP).  
Differences in incidence rates between the treatment groups will be tested as described in the 
SAP. 
 
1.4.3. 
Vital Signs and Body Measurements 
Data from vital signs and body measurements will be listed, clinically notable values (Appendix 
22.1) will be flagged, and any other information collected will be listed. Data will also be 
summarized by treatment group using mean change from baseline and proportions of patients with 
values outside the normal range, and values that were clinically notable.  


 
7 
 
 
1.4.4. 
Electrocardiogram (ECG) 
Results from the ECG will be listed for each patient. These data will also be summarized for each 
treatment group by presenting patients with newly occurring or worsening ECG abnormalities. 
 
1.4.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Results from the C-SSRS will be listed for each patient.  These data will also be summarized by 
treatment group and for suicidal ideation events, suicidal behaviors and completed suicides. In 
particular, for each of the following suicide related events, the number and percent of patients 
with the event will be enumerated by treatment group: completed suicide, nonfatal suicide attempt, 
interrupted attempt, aborted attempt, preparatory acts or behavior, active suicidal ideation with 
specific plan and intent, active suicidal ideation with some intent to act without specific plan, 
active suicidal ideation with any methods (no plan) without intent to act, non-specific active 
suicidal thoughts, and wish to be dead.  Details of the analysis will be provided in the SAP. 
 
1.5. 
Subgroup Analysis 
The subgroup analysis (such as, sex, age, baseline illness severity etc.) for efficacy variables and 
safety variables may be conducted as described in the SAP. 
 
1.6. 
Interim Analysis 
No interim analyses are planned. 
 
1.7. 
Deviations in Analysis from Statistical Plan and Other Issues 
During the analysis and reporting process, any deviations from the statistical plan designed for 
this protocol will be described and justified in the final report.