Clinical trial NCT02970968
Conditions: Gastroparesis
Sponsor: Vanda Pharmaceuticals
Start date: 2016-11-01; Completion date: 2018-12-01
Enrollment: 152 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. One hundred fifty (150) subjects diagnosed with gastroparesis, who satisfy the selection criteria for the study, will be randomized to one of two treatment groups, active or placebo.

Detailed description:
This is a multicenter, randomized, double-blind, placebo-controlled study to be conducted in the United States. One hundred fifty (150) subjects diagnosed with gastroparesis, who satisfy the selection criteria for the study, will be randomized to one of two treatment groups, active or placebo.

The study is divided into two phases: the screening phase and the evaluation phase. The screening phase includes a screening visit to evaluate subjects' preliminary eligibility for the study. During the screening phase, subjects will collect diary data for at least 4 weeks. The evaluation phase includes 4 weeks of randomized double-blind treatment.

Arms: arm 1: VLY-686 (Tradipitant) oral capsule for 4 weeks. arm 2: Placebo oral capsule for 4 weeks.
Interventions: intervention 1: VLY-686 (Tradipitant) intervention 2: Placebo
Intervention descriptions: intervention 1: oral capsule intervention 2: placebo oral

Protocol documents:
Prot_SAP_000.pdf: 
  
1 
CONFIDENTIAL 
 
 
TRADIPITANT  
AMENDMENT NO. 9 TO VP-VLY-686-2301 
 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO ASSESS THE 
EFFICACY OF TRADIPITANT IN RELIEVING SYMPTOMS 
OF GASTROPARESIS  
 
Author: 
Gunther Birznieks  
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-686-2301 
Study Phase:  
 
 
 
 
 
IIa 
IND Number: 
 
 
 
 
 
131545 
 
 
Date:  26 November 2018 
Status: Final 
Number of Pages: 95 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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CONFIDENTIAL 
SIGNATURE PAGE FOR VANDA PHARMACEUTICALS INC. 
 
VP-VLY-686-2301 Amendment No. 9 
 
Approved by the following: 
 
Program Lead: 
 
  
 
Gunther Birznieks  
 Date 
 
Senior Vice President, Research 
& Development Committee 
 
 
  
 
 
  
Medical Director: 
 
  
 
Christos Polymeropoulos, M.D.  Date 
 
Medical Director 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Name of Sponsor/Company: 
Vanda Pharmaceuticals Inc. 
Name of Investigational Product: 
Tradipitant (VLY-686) 
Name of Active Ingredient: 
{2-[1-(3,5-Bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-
chlorophenyl)-methanone 
Title of Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Proof of Concept Study 
to Assess the Efficacy of Tradipitant in Relieving Symptoms of Gastroparesis 
Study center(s): approximately 30 centers in the United States 
Indication:  
Diabetic & Idiopathic Gastroparesis 
Phase of development:  
IIa 
Number of subjects (planned):  
Approximately 150 subjects randomized to 2 arms (75 per arm, 1:1 randomization scheme)  
Inclusion Criteria: 
1. Male and female subjects aged 18 – 70 years (inclusive); 
2. Diagnosed with idiopathic or diabetic gastroparesis with moderate to severe nausea:  
a. Demonstrated delayed gastric emptying of a solid meal via either scintigraphy or gastric 
breath test within 10 years of screening. If solid meal is not tolerated, a liquid meal may be 
used instead to demonstrate delayed gastric emptying via scintigraphy,   
b. Presence of nausea symptom for at least 6 months prior to screening, 
c. At least 24 screening diary entries,  
NOTE: CRITERIA 2D-E ARE CONFIDENTIAL AND SHOULD NOT BE SHARED 
WITH SUBJECTS, POTENTIAL SUBJECTS, OR ANYONE OUTSIDE OF THE 
IMMEDIATE STUDY TEAM. 
d. mGCSI individual nausea score ≥ 3 at Visit 1, and 
e. Average daily diary nausea severity ≥ 3 during the worst 50% days of nausea during 
the screening period; 
3. Patient’s gastroparesis symptoms persist despite diet and/or life-style modifications; 
4. Body Mass Index (BMI) of ≥18 and ≤38 kg/m2 (BMI = weight (kg)/ [height (m)]2);  
5. Subjects 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 sterilized or post-menopausal  partner;  
b. Females of child-bearing potential (not surgically sterile or post-menopausal, defined as 12 
months without menses) will use an acceptable method of contraception from 1 month prior 
to randomization (or screening, if earlier) through 1 month following the last dose of study 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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medication. Examples of acceptable methods of contraception for females include 
abstinence, double barrier method, IUD, hormonal contraception, or sterilized partner;  
6. Ability and acceptance to provide written informed consent;  
7. Willing to participate in the pharmacogenomics sample collection; 
8. Willing and able to comply with all study requirements and restrictions, including but not limited 
to:  
a. daily symptom diary completion, 
b. prohibited medications, and 
c. strict control of blood glucose (T1DM and T2DM patients); 
9. Willing to not participate in any other interventional trial for the duration of their participation. 
Exclusion Criteria: 
1. Another active disorder or treatment which could explain or contribute to symptoms in the 
opinion of the Investigator (including but not limited to gastric malignancy, neurological 
disorder, or heavy doses of strong anticholinergics);  
2. Gastrectomy, fundoplication, vagotomy, pyloroplasty, bariatric surgery, post-surgical cause of 
gastroparesis, or gastric stimulation device surgically implanted within the last year or if 
implanted more than a year ago, have changed stimulation settings within the last 3 months (ie 
gastric stimulation device must have a stable setting for at least 3 months); 
3. Gastric or parenteral feeding within 4 weeks of screening;  
4. Pregnancy or nursing;  
5. History of intolerance and/or hypersensitivity to medications similar to tradipitant and its 
accompanying excipients; 
6. History (including family history) or current evidence of congenital long QT syndrome or 
known acquired QT interval prolongation (including QTc > 450 in males or > 470 in females at 
screening); 
7. History of suicide attempt and/or suicidal ideation (of type 4 or 5 on the Columbia Suicide 
Severity Rating Scale (C-SSRS)) within 2 years of screening or subject is at risk of suicide at 
Screening or Baseline, in the opinion of the investigator;  
8. History of an eating disorder within 2 years of screening; 
9. Recent history (within six months of screening) of Alcohol Use Disorder or Substance Use 
Disorder as defined in DSM-5 or evidence of such abuse which may include a positive drug 
screen at the Screening visit; 
10. Uncontrolled thyroid disease;  
11. Unstable cardiac, respiratory, hepatic or renal disease; 
12. Evidence of uncontrolled blood glucose (including HbA1C >9 or metabolic crisis in past 60 
days); 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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13. Indication of impaired liver function (including values for AST, ALT, or bilirubin > 1.5 times 
the Upper Limit of Normal, unless isolated bilirubin > 1.5 x ULN due solely to Gilbert’s 
syndrome); 
14. Has a creatinine level > 1.5x ULN; 
15. Use of prohibited medication or medication with anti-nausea, antiemetic, neuromodulating, or 
prokinetic effect within 2 weeks of the screening visit EXCEPT when administered on a stable 
daily dosing schedule (stable for at least 3 months prior to the screening visit) or administered 
under protocol-specified rescue medication guidelines;  
16. Use of the following within 2 weeks of screening: another NK-1 antagonist or a second generation 
5-HT3 antagonist, phenergan more than 2 times per day, or opiods more than 2 times per week;  
17. Pyloric injection of neurotoxins (e.g. botulinum type A or B) within 3 months of the Screening 
Visit;  
18. Exposure to any investigational medication, including placebo or domperidone, within 60 days 
of the Baseline Visit;  
19. Anyone affiliated with the site or sponsor and/or anyone who may consent under duress; and  
20. Any other reason as determined by the Investigator 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:  
Oral 85 mg tradipitant and matching placebo capsules will be administered. Subjects will be randomized 
to one of two treatment arms to receive 85 mg tradipitant BID or placebo.  All subjects will be instructed 
to take 1 capsule in the morning and another approximately 12 hours later in the evening. 
Duration of treatment:  Double Blind Evaluation Phase: 4 weeks 
 
Open Label Extension (OLE) Phase : 8 weeks 
Continued Open Label Extension (COLE) Phase: additional 52 weeks 
Objectives:  
Primary:  
• 
To evaluate the efficacy of tradipitant relative to placebo in change from baseline in 
individual nausea severity scores reported daily.  
Secondary: 
• 
To evaluate the efficacy of tradipitant relative to placebo in change from baseline of other 
individual symptoms associated with gastroparesis 
• 
To evaluate the efficacy of tradipitant relative to placebo in change from baseline of the 
overall symptom burden associated with gastroparesis  
• 
To evaluate the efficacy of tradipitant relative to placebo in change from baseline of global 
improvement and quality of life measures  
• 
To explore the safety and tolerability of multiple oral doses of tradipitant.  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Overall Design: 
This is a multicenter, randomized, double-blind, placebo-controlled study to be conducted in the United 
States. One hundred fifty (150) subjects diagnosed with gastroparesis, who satisfy the selection criteria 
for the study, will be randomized to one of two treatment groups. Randomization will be stratified by 
disease etiology (idiopathic or diabetic), and enrollment for either of the etiologies will be capped at 60% 
of the total sample size. 
The study is divided into four phases: the screening phase, the evaluation phase, the open label extension 
phase, and the continued open label extension phase. The screening phase includes a screening visit to 
evaluate subjects’ preliminary eligibility for the study. During the screening phase, subjects will collect 
diary data for at least 4 weeks. The evaluation phase includes 4 weeks of randomized double-blind 
treatment. Daily diaries will be completed during all phases. Clinical evaluations will occur at Screening, 
Baseline, Week 2 and Week 4. At the end of the 28-day evaluation phase, those subjects who completed 
this phase will enroll into an 8-week open-label extension (OLE), where each subject will either continue 
(if previously on active) or be switched to (if previously on placebo) the same daily dose of tradipitant as 
the randomized portion of the study (85 mg bid, approximately 12 hours apart). Patients who complete 
the 8 week open-label extension phase will return for a 52 week continued open label extention phase 
(COLE).  
Primary Endpoint:  
Change from baseline to Day 28 in weekly average of daily individual nausea severity scores (0=none, 
1=very mild, 2= mild, 3=moderate, 4=severe, 5=very severe) 
 
Criteria for evaluation: 
Efficacy:  
Efficacy assessments will include:  
• 
Gastroparesis Core Symptom Daily Diary (GCSDD) 
• 
Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• 
Modified Patient Assessment of Upper GI Disorders – Symptoms (mPAGI-SYM) 
• 
Patient Global Impression – Change (PGI-C) 
• 
Patient Assessment of Upper Gastrointestinal Disorders – QOL (PAGI-QOL) 
• 
Gastroparesis Treatment Benefit Survey (GTBS) 
• 
Clinician Global Impression – Severity (CGI-S) 
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. 
Sample Size Discussion:  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Based on a two-sided t-test with the 5% significance level, the planned sample size of 75 subjects per arm 
provides 86% power to detect a mean difference of 0.8 point in the average of daily nausea severity 
assuming the standard deviation of 1.6 in each treatment group.  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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1. 
TABLE OF CONTENTS AND LIST OF TABLES 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS AND LIST OF TABLES ....................................................8 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................16 
3. 
INTRODUCTION ......................................................................................................20 
3.1. 
Background .................................................................................................................20 
3.2. 
Tradipitant Relevant Data Summary ..........................................................................21 
3.2.1. 
Nonclinical Pharmacology and Toxicology ...............................................................21 
3.2.2. 
Clinical ........................................................................................................................21 
4. 
TRIAL OBJECTIVES AND RATIONALE ..............................................................24 
4.1. 
Objectives ...................................................................................................................24 
4.1.1. 
Primary .......................................................................................................................24 
4.1.2. 
Secondary ...................................................................................................................24 
4.1.3. 
Exploratory .................................................................................................................24 
4.2. 
Rationale .....................................................................................................................24 
4.2.1. 
Study Rationale ...........................................................................................................24 
4.2.2. 
Rationale for Dose and Study Design .........................................................................25 
4.2.3. 
Risk and Benefit .........................................................................................................25 
5. 
INVESTIGATIONAL PLAN .....................................................................................26 
5.1. 
Overall Study Design and Plan: Description ..............................................................26 
5.1.1. 
Screening Phase ..........................................................................................................26 
5.1.1.1. 
Screening Visit (Visit 1) .............................................................................................26 
5.1.1.2. 
Baseline Visit (Visit 2) ...............................................................................................27 
5.1.2. 
Evaluation Phase .........................................................................................................28 
5.1.2.1. 
Visit 3 ..........................................................................................................................28 
5.1.2.2. 
End of Phase or Early Termination (Visit 4) ..............................................................28 
5.1.3. 
Open-Label Extenion Phase .......................................................................................28 
5.1.4. 
Continued Open-Label Extension Phase ....................................................................28 
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................32 
6.1. 
Subject Inclusion Criteria ...........................................................................................32 
6.2. 
Subject Exclusion Criteria ..........................................................................................33 
6.3. 
Subject Withdrawal Criteria .......................................................................................34 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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7. 
TREATMENT OF SUBJECTS – EVALUATION PHASE ......................................36 
7.1. 
Study Medication ........................................................................................................36 
7.1.1. 
Dosing .........................................................................................................................36 
7.1.2. 
Guidance for Taking Study Medication .....................................................................36 
7.2. 
Concomitant Medications ...........................................................................................36 
7.2.1. 
Prohibited Medications ...............................................................................................36 
7.2.2. 
Rescue Medication ......................................................................................................37 
7.2.2.1. 
Rescue Medication Guidelines ...................................................................................37 
7.2.3. 
Medication Washout ...................................................................................................38 
7.3. 
Treatment Compliance ................................................................................................38 
7.4. 
Treatment Assignment ................................................................................................38 
7.4.1. 
Subject ID Assignment ...............................................................................................38 
7.4.2. 
Subject Replacement ..................................................................................................39 
7.4.3. 
Randomization ............................................................................................................39 
8. 
STUDY MEDICATION MATERIALS AND MANAGEMENT .............................40 
8.1. 
Study Medication ........................................................................................................40 
8.2. 
Study Medication Packaging and Labeling ................................................................40 
8.3. 
Study Medication Storage ...........................................................................................40 
8.4. 
Study Medication Accountability ...............................................................................40 
9. 
STUDY ASSESSMENTS – EVALUATION PHASE ...............................................42 
9.1. 
Study Assessments per Visit .......................................................................................42 
9.1.1. 
Screening Visit (Visit 1) .............................................................................................42 
9.1.2. 
Baseline Visit (Visit 2, Study Day 0) .........................................................................42 
9.1.3. 
Visit 3 (Study Day 14 ± 3 days) .................................................................................43 
9.1.4. 
Visit 4 (Study Day 28 ± 3 days) .................................................................................44 
9.1.5. 
Unscheduled Visits .....................................................................................................45 
10. 
ASSESSMENT OF EFFICACY ................................................................................46 
10.1. 
Patient Reported Outcome (PRO) Assessments .........................................................46 
10.1.1. 
Gastroparesis Core Symptom Daily Diary (GCSDD) ................................................46 
10.1.2. 
Modified Gastroparesis Cardinal Symptom Index (mGCSI) .....................................46 
10.1.3. 
Modified Patient Assessment of Gastrointestinal Disorders – Symptoms 
(mPAGI-SYM) ...........................................................................................................46 
10.1.4. 
Patient Global Impression-Change (PGI-C) ...............................................................47 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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10.1.5. 
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life 
(PAGI-QOL) ...............................................................................................................47 
10.1.6. 
Gastroparesis Treatment Benefit Survey (GTBS) ......................................................47 
10.2. 
Clinician Global Impression of Severity (CGI-S) ......................................................47 
10.3. 
Pharmacokinetic Assessment ......................................................................................47 
11. 
ASSESSMENT OF SAFETY .....................................................................................48 
11.1. 
Safety Parameters .......................................................................................................48 
11.1.1. 
Safety ECG .................................................................................................................48 
11.1.2. 
Laboratory Evaluations ...............................................................................................48 
11.1.2.1. 
Additional Laboratory Evaluations .............................................................................49 
11.1.3. 
Vital Signs and Body Measurements ..........................................................................49 
11.1.3.1. 
Vital Signs ..................................................................................................................49 
11.1.3.2. 
Body Measurements ...................................................................................................50 
11.1.4. 
Medical History and Physical Examinations ..............................................................50 
11.1.5. 
Pregnancy ...................................................................................................................50 
11.1.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................51 
11.1.7. 
Definitions Related to Safety ......................................................................................51 
11.1.7.1. 
Adverse Event .............................................................................................................51 
11.1.7.2. 
Serious Adverse Event ................................................................................................51 
11.1.7.3. 
Adverse Event Follow-Up ..........................................................................................52 
11.1.7.4. 
Adverse Event Reporting Period ................................................................................52 
11.1.7.5. 
Pre-Existing Condition ...............................................................................................53 
11.1.8. 
Relationship to Study Medication ..............................................................................53 
11.1.9. 
Recording Adverse Events .........................................................................................53 
11.1.9.1. 
Adverse Events During Study Period .........................................................................53 
11.1.9.2. 
Post-Study Adverse Event ..........................................................................................54 
11.1.9.3. 
Abnormal Laboratory Values .....................................................................................54 
11.1.10. 
Reporting Adverse Events ..........................................................................................54 
11.1.10.1. Study Sponsor Notification by Investigator ...............................................................54 
11.1.10.2. Reporting of Events to Regulatory Authorities and IRB/EC ......................................55 
11.1.11. 
Unblinding Procedures ...............................................................................................55 
12. 
PHARMACOGENOMICS ASSESSMENT ..............................................................56 
13. 
STATISTICS ..............................................................................................................57 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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13.1. 
Sample Size and Accrual ............................................................................................57 
13.2. 
Statistical Methods and Analysis Plan ........................................................................57 
13.2.1. 
General ........................................................................................................................57 
13.2.2. 
Subject Populations for Analysis ................................................................................58 
13.2.3. 
Subject Disposition .....................................................................................................58 
13.2.4. 
Demography and Other Baseline Data .......................................................................58 
13.2.5. 
Study Medication ........................................................................................................59 
13.2.6. 
Prior/Concomitant Therapy ........................................................................................59 
13.3. 
Efficacy Data Analysis ...............................................................................................59 
13.3.1. 
Primary Outcome  and Methodology .........................................................................59 
13.3.2. 
Secondary Efficacy Analysis ......................................................................................60 
13.4. 
Safety Data Analysis ...................................................................................................60 
13.4.1. 
Adverse Events ...........................................................................................................61 
13.4.2. 
Laboratory Data ..........................................................................................................61 
13.4.3. 
Vital Signs and Body Measurements ..........................................................................62 
13.4.4. 
Electrocardiogram (ECG) ...........................................................................................62 
13.4.5. 
C-SSRS .......................................................................................................................62 
13.5. 
Subgroup Analysis ......................................................................................................62 
13.6. 
Interim Analysis ..........................................................................................................62 
13.7. 
Deviations in Analysis from Statistical Plan and Other Issues ...................................62 
14. 
DIRECT ACCESS TO SOURCE DOCUMENTS .....................................................63 
14.1. 
Definition of Source Document ..................................................................................63 
14.2. 
Study Monitoring ........................................................................................................63 
14.3. 
Audits and Inspections ................................................................................................63 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................65 
15.1. 
Data Collection ...........................................................................................................65 
15.2. 
Clinical Data Management .........................................................................................65 
15.3. 
Database Quality Assurance .......................................................................................65 
16. 
ETHICS ......................................................................................................................66 
16.1. 
Ethics Review .............................................................................................................66 
16.2. 
Ethical Conduct of the Study ......................................................................................66 
16.3. 
Written Informed Consent ..........................................................................................66 
17. 
DATA HANDLING AND RECORD KEEPING ......................................................67 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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17.1. 
Retention of Records ..................................................................................................67 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................68 
18.1. 
Changes to the Protocol ..............................................................................................68 
18.2. 
Discontinuation of Study ............................................................................................68 
18.3. 
Publication of Results .................................................................................................69 
18.4. 
Investigator Agreement ..............................................................................................70 
19. 
REFERENCES ...........................................................................................................71 
20. 
APPENDICES ............................................................................................................73 
20.1. 
Open-Label Extension Phase ......................................................................................73 
20.1.1. 
Phase Objective ..........................................................................................................73 
20.1.2. 
Phase Rationale ...........................................................................................................73 
20.1.3. 
Study Design for OLE Phase ......................................................................................73 
20.1.4. 
Selection and Withdrawal Criteria of Subjects for the OLE Phase ............................76 
20.1.4.1. 
Inclusion Criteria ........................................................................................................76 
20.1.4.2. 
Early Withdrawal of Subjects .....................................................................................76 
20.1.5. 
Study Medication ........................................................................................................77 
20.1.5.1. 
Dosing .........................................................................................................................77 
20.1.5.2. 
Guidance for Taking Study Medication .....................................................................77 
20.1.6. 
Concomitant Medication During the OLE Phase .......................................................77 
20.1.6.1. 
Prohibited Medication ................................................................................................77 
20.1.6.2. 
Rescue Medication ......................................................................................................77 
20.1.7. 
Treatment Compliance ................................................................................................78 
20.1.8. 
Treatment Assignment ................................................................................................78 
20.1.9. 
Study Drug, Packaging, and Labeling ........................................................................78 
20.1.10. 
Assessments Performed During the OLE ...................................................................78 
20.1.10.1. Visit 4a (Only for subjects that completed the Double-Blind Phase prior to 
the OLE being available) ............................................................................................78 
20.1.10.2. Visit 5 (Study Day 56 +/- 3 days) ...............................................................................79 
20.1.10.3. Visit 6 (Day 84/EOS ± 3 days or ET) .........................................................................80 
20.1.11. 
Efficacy Assessments .................................................................................................80 
20.1.12. 
Safety Assessments .....................................................................................................80 
20.1.13. 
Statistical Methods ......................................................................................................81 
20.2. 
Continued Open Label Extension Phase .....................................................................82 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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20.2.1. 
Phase Objectives .........................................................................................................82 
20.2.1.1. 
Primary .......................................................................................................................82 
20.2.1.2. 
Secondary ...................................................................................................................82 
20.2.2. 
Phase Rationale ...........................................................................................................82 
20.2.2.1. 
Study Rationale ...........................................................................................................82 
20.2.2.2. 
Rationale for Dose and Study Design .........................................................................82 
20.2.2.3. 
Risk Benefit ................................................................................................................83 
20.2.3. 
Investigational Plan ....................................................................................................83 
20.2.3.1. 
Overall Phase Design and Plan: Description ..............................................................83 
20.2.3.2. 
Screening Visit COLE-Visit 1-A (Day 0) ..................................................................84 
20.2.3.3. 
Screening Visit COLE-Visit 1-B (Day 0) ...................................................................84 
20.2.3.4. 
COLE Visit 2-Visit 6 (Day 28, Day 84, Day 140, Day 196, Day 280  ± 5 
days) ............................................................................................................................85 
20.2.3.5. 
Monthly Call to Subjects to Assess Health (Day 56, Day 112, Day 224, Day 
252, Day 308, Day 336,  ± 3 days) .............................................................................85 
20.2.3.6. 
End of Study or Early Termination COLE Visit 7 (Day 364 ± 7 days) .....................85 
20.2.4. 
Selection and Withdrawal Criteria of Subjects for the OLE Phase ............................87 
20.2.4.1. 
Inclusion Criteria ........................................................................................................87 
20.2.4.2. 
Early Withdrawal of Subjects .....................................................................................87 
20.2.5. 
Treatment of Subjects .................................................................................................88 
20.2.5.1. 
Dosing .........................................................................................................................88 
20.2.5.2. 
Guidance for Taking Study Medication .....................................................................88 
20.2.6. 
Concomitant Medication During the COLE Phase ....................................................89 
20.2.6.1. 
Prohibited Medication ................................................................................................89 
20.2.6.2. 
Rescue Medication ......................................................................................................89 
20.2.7. 
Treatment Compliance ................................................................................................89 
20.2.8. 
Treatment Assignment ................................................................................................90 
20.2.9. 
Study Drug, Packaging, and Labeling ........................................................................90 
20.2.10. 
Study Medication Materials and Management ...........................................................90 
20.2.11. 
Study Assessments per Visit .......................................................................................90 
20.2.11.1. COLE Screening Visit A or B (Visit 1, COLE Day 0) ...............................................90 
20.2.11.2. COLE Visit 2-Visit 6 (COLE Day 28, Day 84, Day 140, Day 196, Day 280, 
± 5 days) .....................................................................................................................91 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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20.2.11.3. COLE Visit 7/End of Study/Early Termination (COLE Day 365, ± 7 days) .............92 
20.2.11.4. Unscheduled Visits .....................................................................................................92 
20.2.11.5. Monthly Calls to Patients (COLE Day 56, Day 112, Day 224, Day 252, Day 
308, Day 336, ± 3 days) ..............................................................................................93 
20.2.12. 
Efficacy Assessments .................................................................................................93 
20.2.13. 
Safety Assessments .....................................................................................................93 
20.2.14. 
Statistical Methods ......................................................................................................93 
20.3. 
Laboratory Ranges Used to Identify Clinically Notable Abnormal 
Laboratory Values ......................................................................................................93 
20.4. 
Vital Signs Values ......................................................................................................94 
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................16 
Table 2: 
VP-VLY-686-2301 Treatment Arms ..........................................................................26 
Table 3: 
Schedule of Evaluations .............................................................................................30 
Table 4: 
Medications Allowed for Rescue Use ........................................................................38 
Table 5: 
Clinical Laboratory Tests ...........................................................................................48 
Table 6: 
SAE Criteria and Definitions ......................................................................................51 
Table 7: 
SAE Reporting Information ........................................................................................55 
Table 8: 
Schedule of Evaluations for OLE ...............................................................................74 
Table 9: 
Schedule of Evaluations for COLE ............................................................................85 
 
 
 
 
 
 
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation 
Description 
AD 
Atopic Dermatitis 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase (also known as SGPT) 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase (also known as SGOT) 
AUC  
Area Under the Plasma Concentration-time Curve  
AUC0-∞ 
Area under the concentration/time curve extrapolated to infinity 
AUC0-24 
Area under the concentration/time curve extrapolated to 24 hours post dosing 
BID 
Twice a day  
BMI 
Body Mass Index 
bpm 
Beats per Minute 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CFR 
Code of Federal Regulations 
CINV 
Chemotherapy-Induced Nausea and Vomiting 
CGI-S 
Clinician Global Impression of Severity 
CL/F 
Oral Clearance 
Cmax 
The highest observed plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Cardiovascular 
DNDP 
Division of Neuropharmacological Drug Products 
dL 
Deciliter 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Abbreviation 
Description 
DNA 
Deoxyribonucleic Acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
EC 
Ethical Committee  
EC50 
half maximal effective concentration 
EC90 
90 percent effective concentration 
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic Acid 
e.g. 
For example 
eCLcr 
Estimated Creatinine Clearance 
EOS 
End of Study 
ET 
Early Termination 
FDA 
Food and Drug Administration 
g 
Gram(s) 
GCP 
Good Clinical Practice 
GCSDD 
Gastroparesis Core Symptom Daily Diary 
GCSI 
Gastroparesis Cardinal Symptom Index  
GGT 
Gamma-Glutamyltransferase 
GI 
Gastrointestinal 
GTBS 
Gastroparesis Treatment Benefit Survey 
HDL 
High Density Lipoprotein 
HDPE 
High-Density Polyethylene 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ID 
Identification 
i.e. 
In other words 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
kg 
Kilogram 
LDH 
Lactate Dehydrogenase 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Abbreviation 
Description 
LDL 
Low Density Lipoprotein 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mGCSI 
Modified Gastroparesis Cardinal Symptom Index 
mPAGI-SYM 
Modified Patient Assessment of Upper Gastrointestinal Disorders - Symptoms 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeters of mercury 
MMRM 
Mixed Model Repeated Measures 
ms 
Milliseconds 
NDA 
New Drug Application 
NK 
Neurokinin 
NKA 
Neurokinin A 
NKB 
Neurokinin B 
NOAEL 
No-Observed Adverse Effect Level 
OC 
Observed Cases 
OLE 
Open-label Extension 
OTC 
Over the Counter 
PAGI-QOL 
Patient Assessment of Upper Gastrointestinal Disorders - Quality of Life 
PAGI-SYM 
Patient Assessment of Upper Gastrointestinal Disorders - Symptom Severity 
Index 
PD 
Pharmacodynamic 
PE 
Physical Examination 
PET 
Positron Emission Tomography 
PG 
Pharmacogenomic 
pg 
Picograms 
PGI-C 
Patient Global Impression of Change 
pH 
Hydrogen ion concentration 
PK 
Pharmacokinetic 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Abbreviation 
Description 
PONV 
Post-Operative Nausea and Vomiting 
QD 
One a day 
QT 
Time Between the Start of the Q Wave and the End of the T Wave in the Heart’s 
Electrical Cycle 
RBC 
Red blood cell 
REML 
Restricted Maximum Likelihood 
RO 
Receptor Occupancy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase (also known as AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (also known as ALT) 
SOC 
System Organ Class 
SOPs 
Standard Operating Procedures 
SP 
Substance P 
T1/2 
Time Required for the Plasma Drug Concentration to Decrease by One Half 
T1DM 
Type 1 Diabetes Mellitus 
T2DM 
Type 2 Diabetes Mellitus 
T4 
Thyroxine 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to Reach Cmax 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
U.S. 
United States 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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3. 
INTRODUCTION 
This document is a protocol for a human research study.  This study is to be conducted according 
to United States (U.S.) and international standards of Good Clinical Practice (GCP) (Food and 
Drug Administration [FDA] and International Conference on Harmonization [ICH] guidelines), 
applicable local government regulations, and Institutional research policies and procedures.  
 
3.1. 
Background 
 
Gastroparesis is a chronic disorder characterized by objective evidence of delayed gastric 
emptying, symptoms associated with gastric retention, and absence of mechanical obstruction 
[1]. The true prevalence of gastroparesis is unknown, but its US prevalence is estimated to be as 
high as 5 million [2].  The two primary etiologies of gastroparesis are Diabetes Mellitus and 
idiopathic disease together representing over 60% of all cases [3][4]. Nausea is the most 
commonly reported symptom of gastroparesis, and has been reported in >90% of patients in 
various studies [5][6].  Vomiting is the second most commonly reported symptom with reports of 
incidence varying between 66 and 88 percent [5]. Other commonly reported symptoms of 
gastroparesis include early satiety, postprandial fullness, and abdominal pain [7]. 
 
Despite the severity of symptoms and associated distress among gastroparesis patients, there are 
currently no treatments for the symptoms of gastroparesis approved for chronic use.  
Gastroparesis continues to represent a large unmet need.  In a large cohort study of 262 
gastroparesis patients, less than one-third demonstrated clinically meaningful improvements at 
48 weeks despite treatment interventions [8]. 
 
The mammalian tachykinins (neurokinin [NK]) are a family of peptide neurotransmitters that 
share a common C-terminal sequence. This group includes substance P (SP), neurokinin-A 
(NKA), and neurokinin-B (NKB). SP, the most abundant NK, preferentially binds to the 
neurokinin type-1 (NK-1) receptor and is involved in the regulation of many physiological 
processes [9].  NK-1 receptors have been mapped in the central nervous system and were found 
to have a broad distribution in the brain, including the mid-brain, basal ganglia, hypothalamus, 
and limbic system. Neurokinin receptors are also widely distributed in the gut, the bronchial tree, 
and the vascular system [10].  
 
Tradipitant (VLY-686), formerly known as LY686017, is a potent and selective inhibitor of 
human cell membrane NK-1 receptor binding in vitro. In preclinical and clinical studies, 
tradipitant produces a long-lasting blockade of brain NK-1 receptors. Although the distinct 
pathways of nausea and vomiting are largely undetermined, a definitive role of SP acting at NK-
1 receptors in the nucleus tractus solitarus has been confirmed [11].  Previous clinical studies 
have demonstrated the efficacy of NK-1 antagonism in the prevention of chemotherapy induced 
and post-operative nausea and vomiting (CINV and PONV) [12].  
Tradipitant is currently being assessed clinically to determine its efficacy in treating the 
symptom of nausea in patients suffering from gastroparesis.  
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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3.2. 
Tradipitant Relevant Data Summary 
For a thorough review, refer to the tradipitant Investigator’s Brochure. 
 
3.2.1. 
Nonclinical Pharmacology and Toxicology 
Several in vitro and in vivo safety pharmacology studies (in rodents and dog) were performed to 
assess the effect of tradipitant on the cardiovascular (CV), gastrointestinal (GI), respiratory, and 
central nervous (CNS) systems. The safety parameters evaluated in these studies were also 
monitored clinically. It was concluded that secondary pharmacological effects related to CNS, 
respiratory, GI, or CV functioning would not be expected at clinical doses ≤800 mg. 
 
Animal toxicology studies (a single-dose study in rats; a 13-week repeat-dose study in mice; 1-, 
3-, and 6-month repeat-dose studies in rats; 1- and 3-month repeat-dose studies in dogs; a fertility 
and embryo-fetal development study in rats; an embryo-fetal development study in rabbits; and 
in vitro and in vivo genetic tests) showed no treatment-related mortality or marked toxicity up to 
and including the no-observed adverse effect level of dosing (NOAEL) of       1500 mg/kg. 
Tradipitant was not teratogenic and did not induce changes in reproduction or fertility at doses 
≤1000 mg/kg. Liver and thyroid enlargement and elevation of serum gamma- 
glutamyltransferase (GGT) were observed in the rat studies and associated with hepatocellular 
hypertrophy and thyroid hyperplasia, yet there was no evidence of hepatocellular injury. In the 6-
month study, these changes were reversible after a 4-week recovery period. These findings were 
considered secondary to microsomal enzyme induction. In dogs, elevation of serum alkaline 
phosphatase (ALP) and alanine aminotransferase (ALT) were observed and considered 
consistent with hepatic microsomal enzyme induction because they were not accompanied by 
histologic evidence of liver injury. Exposure-based margins of safety for oral administration of 
≤100 mg of tradipitant to humans are 23-fold and 2.9-fold, relative to rats after a single dose and 
6 months of treatment, respectively; 40-fold, relative to mice after 13 weeks of treatment; and 
66-fold, relative to dogs after 3 months of treatment.  
 
Liver enzymes will be monitored in the planned clinical studies. No risk of particular severity or 
seriousness is anticipated. Results of an in vitro 3T3 neutral red uptake phototoxicity test indicate 
that VLY-686 is predicted to have no phototoxic potential.   
 
3.2.2. 
Clinical 
The clinical development of tradipitant was initiated by Eli Lilly in 2003.  In addition to clinical 
pharmacology studies, Eli Lilly completed clinical trials testing for efficacy in translational 
models for irritable bowel syndrome, anxiety, and alcohol dependence.  Vanda Pharmaceuticals 
Inc. has completed additional clinical pharmacology studies as well as a clinical trial testing for 
efficacy in chronic pruritus associated with atopic dermatitis.  
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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• Study H8R-EW-HJAC was a dose-escalation study in healthy male subjects designed 
to assess the safety and pharmacokinetics of tradipitant. Doses ranged from 1 to     
800 mg. A sub-proportional increase in exposure was observed with an increase in 
dose, most notably at doses greater than 30 mg. The oral clearance (CL/F) increased 
with dose level and, in general, the median terminal half-life (T1/2) was similar across 
all doses, suggesting dose-dependent changes in bioavailability. 
• Study H8R-EW-HJAD was a multiple-dose study with an escalating dosing regimen 
(1, 10, 30, and 100 mg once-daily dosing) over 28 days designed to assess the safety 
and tolerability of tradipitant. Consistent with the biphasic elimination of tradipitant, 
steady-state was reached within 7 days of daily dosing, and the exposure accumulated 
about 40% relative to a single dose of 1 mg. PET imaging with the 
radiopharmaceutical [11C]GR205171 was used to quantify the relationships between 
oral doses, plasma concentration, and the occupancy of cerebral NK-1 receptors by 
tradipitant, demonstrating a dose- and concentration-dependent increase in frontal 
cortex receptor occupancy (RO). The maximum percent RO was 93% and was 
determined 24 hours after the last 100 mg dose on Day 28. The RO did not decrease 
substantially from 24 to 72 hours during the wash-out phase following 100 mg. The 
plasma concentration required to produce half maximal RO (EC50) and 90% maximal 
RO (EC90) was estimated to be about 2 ng/mL and 27 ng/mL, respectively.  
• Study H8R-EW-HJAE was a single-dose, randomized, 2-way crossover study in 
healthy male subjects designed to assess the effect of a high-fat meal on the 
pharmacokinetics of tradipitant. Administration of 10 mg of tradipitant in the fed state 
increased Cmax and AUC0–∞ approximately 2- and 1.5-fold, respectively, and delayed 
the median Tmax by 2 hours relative to the fasted state. 
• Study H8R-MC-HJAK was an open-label study in healthy male subjects to assess 
metabolism and disposition of a single oral dose of [14C]VLY-686. It demonstrated 
that tradipitant was extensively metabolized via hepatic mechanisms. In addition to 
tradipitant, 24 metabolites were detected by radioactivity and/or by mass 
spectrometry in various matrices. Over 13 days, the mean total recovery of 
radioactivity was approximately 88%, with 81% of the dose recovered in feces and 
7% of the dose recovered in urine. The fecal profiles showed that a very small 
percentage of excreted radioactivity was due to tradipitant, suggesting that drug had 
been absorbed and that its metabolites had been excreted, presumably via the bile.  
• Study H8R-MC-HJAP was performed to characterize any potential PK, 
pharmacodynamic (PD), or adverse effect interactions between tradipitant and 
ethanol. Ethanol co-administered with tradipitant has a small but clinically irrelevant 
effect on tradipitant PK (9.3% increase for Cmax and 14% increase for AUC0-24). 
There was no clear or consistent effect of tradipitant given at a dose of 50 mg daily 
for 7 days on postural stability or cognition functions compared to placebo and no 
clear or consistent adverse interaction effects between tradipitant and ethanol on 
postural stability or cognitive function in healthy subjects. Overall, there was no 
indication in this study that tradipitant given at dose of 50 mg daily for 7 days had an 
adverse PK or PD interaction with ethanol. 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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• Study VP-VLY-686-1101 was conducted to investigate the anti-pruritic potential of 
oral doses of VLY-686 20 mg, 50 mg or 100 mg compared to placebo after 
intradermal injections of the pruritogen, substance P.  Due to the baseline itch 
severity scores before treatment with placebo being significantly higher than the 
baseline scores before the 3 ascending doses of VLY-686, the results of this study are 
uninterpretable.  The VLY-686 plasma concentrations versus time curves could not 
be extrapolated to infinity for any subject as sampling times only went out to 24 hours 
post-dose.  Therefore, AUC0-∞, T1/2 and λZ could not be calculated.  In general, the 
PK characteristics for VLY-686 observed in this study were similar to those observed 
in Study H8R-EW-HJAC.   
• Study VP-VLY-686-1102 was a single-site, open-label, single-sequence study in 24 
healthy male and female subjects to assess the effect of tradipitant administration on 
CYP3A4 using midazolam pharmacokinetics as a marker. Midazolam 10 mg was 
administered alone and then with 85 mg tradipitant following 12 days of Q12H 
tradipitant dosing.  There was no alteration in the pharmacokinetics of midazolam. 
This suggests that tradipitant has no net effect on the CYP3A4/5 enzyme.  Overall, 
the study data indicate that repeated oral doses of 85 mg tradipitant administered 
Q12H is generally safe and well-tolerated in male and female healthy subjects. 
• Study VP-VLY-686-2101 was a proof of concept study conducted in atopic 
dermatitis patients with chronic pruritus. Although a statistically significant 
difference from placebo was not seen in the overall intent to treat population, a 
PK/PD correlation was demonstrated in the tradipitant treated group.  Based on this 
PK analysis, individuals with higher tradipitant exposure at the time of their pruritus 
assessment had a statistically and clinically meaningful difference from placebo as 
measured on a 100 mm Visual Analog Scale (VAS) for itch.  
• Study VP-VLY-686-2102 was a Phase II proof of concept study in atopic dermatitis 
patients with chronic pruritus.  This study was designed to assess the decrease in VAS 
in patients treated with tradipitant over an 8 week period of 85 mg BID dosing 
compared to placebo in 150 patients.  Although the primary efficacy endpoint 
comparison did not reach statistical significance, several secondary analyses did. 
Tradipitant demonstrated clinically meaningful improvements in worst itch and 
disease severity in patients with atopic dermatitis. 
• Study VP-VLY-3101 is an ongoing Phase III study in atopic dermatitis patients with 
chronic pruritus. This study is designed to assess the decrease in daily worst itch in 
patients treated with tradipitant over an 8 week period of 85 mg BID dosing 
compared to placebo in 300 patients. 
 
In clinical studies, tradipitant has been administered as a single dose up to 800 mg, up to 12 days 
at a daily dose of 170 mg, and up to 4 weeks at a daily dose of 100 mg.  Following 12 days of 
twice daily 85 mg tradipitant administration in 24 healthy volunteers, the median time to 
maximum plasma concentration ranged from 2 to 6 hours and the geometric mean (%CV) 
elimination half-life was 34 (41%) hours. 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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4. 
TRIAL OBJECTIVES AND RATIONALE 
4.1. 
Objectives 
4.1.1. 
Primary 
• To evaluate the efficacy of tradipitant relative to placebo in change from baseline in 
individual nausea severity scores reported daily.  
 
4.1.2. 
Secondary 
• To evaluate the efficacy of tradipitant relative to placebo in change from baseline of 
other individual symptoms associated with gastroparesis 
• To evaluate the efficacy of tradipitant relative to placebo in change from baseline of 
the overall symptom burden associated with gastroparesis  
• To evaluate the efficacy of tradipitant relative to placebo in change from baseline of  
global improvement and quality of life measures  
• To explore the safety and tolerability of multiple oral doses of tradipitant. 
 
4.1.3. 
Exploratory 
• To identify genetic markers that correlate with response to tradipitant treatment. 
• To identify genetic markers that correlate with adverse events that may occur upon 
treatment with tradipitant. 
• To identify genetic markers that are associated with gastroparesis and/or gastroparesis 
symptoms and 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.   
 
4.2. 
Rationale 
4.2.1. 
Study Rationale 
The underlying pathophysiology of gastroparesis is complex and remains largely unknown.  
Prokinetic therapy has been the traditional mainstay of gastroparesis treatments, but studies 
continue to demonstrate a lack of correlation between reduction in gastric emptying delays and 
relief of gastroparesis symptoms [5]. 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Two case reports have documented the efficacy of open-label NK-1 antagonist therapy in severe, 
refractory gastroparesis cases [13][14].  Thus, NK-1 receptor antagonists, like tradipitant, are 
promising potential therapeutics for treating nausea associated with gastroparesis. 
 
4.2.2. 
Rationale for Dose and Study Design 
In a multiple-dose PET clinical study, frontal cortex receptor occupancy was recorded at 93% 
following 7 days of 100 mg daily dosing.  Based on the PET study findings, it is estimated that a 
dose of approximately 85 mg daily would achieve 90% brain receptor occupancy 24-hours post 
steady-state dosing.  A target brain NK-1 receptor occupancy of 90% is based on a published 
study comparing the efficacy of two different doses in aprepitant, an NK-1 antagonist approved 
for CINV and PONV, in which a greater antiemetic effect was observed at a dosing regimen 
which reached 90% receptor occupancy than a dosing regimen reaching 80% receptor occupancy 
[12].   
 
While it is hypothesized that a daily dose of 85 mg will provide adequate central receptor 
occupancy coverage to centrally mediate nausea and vomiting, there is some evidence to suggest 
that the antiemetic effects of NK-1 antagonism may also have a peripherally-mediated 
component involving modulation of abdominal vagal afferent activity [15].   Additionally, the 
pharmacokinetic profile of tradipitant administered to individuals with delayed gastric emptying 
has not been fully characterized and therefore it is not known if delayed gastric emptying will 
significantly impact the dose-exposure relationship seen in healthy volunteers.  These two factors 
lead to the possibility that a higher daily dose of tradipitant might be necessary to achieve 
maximal efficacy and importantly, a more frequent dosing regimen may be warranted.  As 85 mg 
BID was well tolerated in previous studies, this current proof of concept study will test 85 mg 
BID and matching placebo.   
 
The completed nonclinical and clinical safety studies with tradipitant showed a favorable safety 
profile. Clinical laboratory tests, vital signs, 12-lead ECG, and physical examination (PE) data 
showed no clinically significant alterations due to administration of tradipitant.  Additionally, 
preclinical studies showed no evidence of a drug-related QT prolongation. 
 
4.2.3. 
Risk and Benefit 
The potential benefit for subjects, if randomized to tradipitant, is the possibility of experiencing 
decreased symptoms of gastroparesis while participating in this study. Nonclinical and clinical 
data to date have not indicated any likely toxicity at doses to be used in this study, and the drug 
has been well-tolerated in previous clinical studies.  The most commonly reported adverse events 
(≥ 2% and 1.25x placebo) in previous clinical studies were somnolence, dizziness, fatigue, and 
dry mouth.  Nonetheless, as tradipitant is an experimental compound, there may be unforeseen 
risks associated with its use.  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Study Design and Plan: Description 
This is a randomized, double-blind, placebo-controlled study to be conducted in the United 
States. Approximately one hundred fifty (150) patients diagnosed with gastroparesis of either 
diabetic or idiopathic origin satisfying the selection criteria for the study will be randomized 1:1 
to tradipitant treatment or matching placebo (Table 2). Randomization will be stratified by 
disease etiology (idiopathic or diabetic), and enrollment for each etiology will be capped at 60% 
of the total sample size. 
 
Table 2: 
VP-VLY-686-2301 Treatment Arms 
Arm 
Total Daily Dose 
AM Dose 
PM Dose 
Tradipitant BID 
170 mg 
85 mg tradipitant 
85 mg tradipitant 
Placebo 
0 mg 
Placebo 
Placebo 
 
The study is divided into four phases: the screening phase, the evaluation phase, the open label 
extension phase, and the continued open label extension phase. The screening phase includes 
screening and baseline visits where eligibility for the study will be assessed. The evaluation 
phase includes 4 weeks of placebo-controlled, double-blind, randomized treatment. Daily diaries 
will be collected throughout both phases of the study. At the end of the 28-day evaluation phase, 
those subjects who completed this phase enroll into an 8-week open-label extension (OLE) 
where each subject will receive the same dose of tradipitant utilized in the randomized segment 
of the study (85 mg bid, approximately 12 hours apart). Subjects who complete the 8 week open 
label phase can return and enroll into a 52-week continued open label extension phase (COLE).  
 
5.1.1. 
Screening Phase 
The screening phase includes the screening and baseline visits. Informed consent must be 
obtained prior to the initiation of any study related screening procedures.  The screening phase 
will be at least 28 days.   
The screening phase may be extended to up to 35 days to allow for additional screening diary 
data collection. The screening phase may also be extended to allow for medication washout prior 
to the collection of baseline diary data.   
A full list of assessments performed at each visit are listed in Table 3 and Section 9. 
 
5.1.1.1. 
Screening Visit (Visit 1) 
During the Screening Visit (Visit 1), safety and efficacy assessments will be performed to assess 
the subject’s initial eligibility after the subject signs the informed consent form.  Collection of 
adverse event information will begin at the time the ICF is signed.  Subjects will be trained and 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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provided access to diary which will be used to collect daily symptoms. Subjects will complete 
their first diary entry at the visit as part of the training process. Subjects will be instructed to 
complete the diary once daily for at least 28 days prior to the baseline visit.  In order to avoid 
subject reporting bias which could negatively impact the results of the study, inclusion 
criteria 2d and 2e should NEVER be shared with subjects or potential subjects.  
The Screening Visit may be repeated following medication washout and prior to baseline diary 
collection at the discretion of the Investigator and/or Medical Monitor.   
Subjects who do not meet eligibility criteria will be considered screen failures.  Screen failures 
may be given the opportunity for reconsideration at a later time (re-screening) at the discretion of 
the Investigator and approval by the Sponsor.  
 
5.1.1.1.1. Visit 1 Instruction if Patient Lacks Scintigraphy or Breath Test 
A potential subject without a prior scintigraphy or breath test evaluation to serve as objective 
evidence of delayed gastric emptying, or with a scintigraphy or breath test evaluation that 
demonstrates delayed gastric emptying that is outside the 10-year window can still be considered 
as symptomatically suffering from gastroparesis and scheduled for a Visit 1 provided they meet 
all other Visit 1 criteria, including: 
-history of nausea for the past 6 months 
-at least one other symptom of gastroparesis, such as vomiting, postprandial fullness, or 
abdominal pain 
 
If evaluation at Visit 1 confirms the subject meets all other criteria (including moderate to high 
nausea on mGCSI as determined by a score of ≥ 3), the subject may begin completing their daily 
diary according to the normal screening process described in Section 5.1.1.1.  
The subject will also be scheduled to return for an unscheduled visit to take place within 2 weeks 
of their Visit 1, in order for the site to perform a breath test or scintigraphy to confirm the 
subject’s objective evidence of delayed gastric emptying. The choice of utilizing breath test or 
scintigraphy will be at the investigator’s discretion. If this test confirms delayed gastric 
emptying, the subject will continue participation in the study according to the normal screening 
procedures. Subjects whose test does not confirm delayed gastric emptying will be considered 
screen failures. 
 
5.1.1.2. 
Baseline Visit (Visit 2)  
On Day 0 (Visit 2/Baseline), assessments will be performed and diary data will be reviewed to 
assess the subject’s continued eligibility. Subjects continuing to meet all eligibility criteria will 
be randomized to one of two treatment arms (Table 2), and will be given enough study 
medication to last until the next visit.  Study staff should be careful to review eligibility criteria 
that is specific to the Baseline Visit including diary review to determine eligibility based on 
symptom severity.  Subjects must have at least 24 daily screening diary entries prior to 
randomization.  The screening may be extended for a total of up to 35 days to accommodate this. 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Subjects who are randomized will be instructed to begin taking study medication in the evening 
of Day 0 (Baseline/Visit 2).  Twice daily dosing will begin the day following the baseline visit.  
 
5.1.2. 
Evaluation Phase 
5.1.2.1. 
Visit 3 
Subjects will return to the clinic on Day 14 (± 3 days) for Visit 3 for safety and efficacy 
assessments.  Diary and medication compliance will be reviewed.  Unused study medication will 
be collected and subjects will be dispensed enough study medication to last until Visit 4. 
 
5.1.2.2. 
End of Phase or Early Termination (Visit 4) 
At the End of Study Visit (Day 28 ± 3 days) or at the time of early termination, subjects will 
return to the clinic for safety and efficacy assessments.  Diary and medication compliance will be 
reviewed.  
 
5.1.3. 
Open-Label Extenion Phase 
 All subjects who complete the short-term double-blind phase will continue treatment with 
tradipitant for an additional 8-weeks of treatment in the OLE phase. Subjects who have 
completed the trial prior to the OLE becoming available can come back and sign an additional 
informed consent and be evaluated for eligibility to participate in this phase during V4a. The site 
will record that the subject has completed the double-blind phase of the study and indicate if the 
subject will continue into the OLE. If the subject will continue into the OLE, enough open label 
medication will be dispensed to the subject to last until the next schedule visit. Patients who have 
previously completed this study can come back to for visit V4a to allow all original V1 screening 
labs and other safety assessments as well as the open label informed consent to be collected prior 
to OLE dosing. 
A detailed description of this OLE phase can be found in Appendix 20.1  
 
5.1.4. 
 Continued Open-Label Extension Phase  
All subjects who complete the short-term double-blind phase and the 8 week open label 
extension phase can continue treatment with tradipitant for an additional 52-weeks of treatment 
in the COLE phase. Subjects who have completed the trial prior to the COLE becoming available 
can come back and sign an additional informed consent and be evaluated for eligibility to 
participate in this phase during Visit COLE-V1-B. The site will record that the subject has 
completed the double-blind and open label extension phases of the study and indicate if the 
subject will continue into the COLE. If the subject will continue into the COLE, enough open 
label medication will be dispensed to the subject to last until the next schedule visit. Patients who 
have previously completed this study can come back to for visit COLE-V1-B to allow all 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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original V1 screening labs and other safety assessments as well as the continued open label 
informed consent to be collected prior to COLE dosing. 
A detailed description of this COLE phase can be found in Appendix 20.2  
 
   
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Table 3: 
Schedule of Evaluations 
Visit 
V1 
Screening 
V2 
Baseline 
V3 
 
V4 
EOP 
Study Day 
≥28 days prior 
to Day 0 
Day 0 
Day 141 
Day 281  
Informed Consent Form (ICF) 2 
X 
 
 
X 
Eligibility assessment 
X 
X 
 
X 
Subject demography and medical history  
X 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
Adverse Event (AE) Query3 
X 
X 
X 
X 
Collection of menstrual cycle information 
X 
X 
X 
X 
Serum β-HCG (for WOCBP) 
X 
 
 
X 
Urine pregnancy test (for WOCBP) 
 
X 
X 
 
TSH, T4 
X 
X 
X 
X 
Urine Drug Screen 
X 
X 
X 
X 
HbA1c, hematology, chemistry, and urinalysis 
X 
X 
X 
X 
Pharmacogenomic (PG) sample 
 
X 
 
 
Pharmacokinetic (PK) sample 
 
X 
X 
X 
12-lead resting ECG 
X 
X 
X 
X 
Vital signs and body measurements4 
X 
X 
X 
X 
Physical Examination (PE) 
X 
 
 
X 
C-SSRS5 
X 
X 
X 
X 
mGCSI6 & mPAGI-SYM 
X 
X 
X 
X 
Gastroparesis Treatment Benefit Survey (GTBS) 
X 
 
 
 
PAGI-QOL 
 
X 
 
X 
Patient Global Impression of Change (PGI-C) 
 
 
X 
X 
Clinical Global Impression of Severity (CGI-S) 
 
X 
X 
X 
Randomization 
 
X 
 
 
Study medication dispensation 
 
X 
X 
X 
Study medication collection & compliance 
 
 
X 
X 
Subject diary instruction 
X 
 
 
 
Subject diary review 
 
X 
X 
X 
EOP 
 
 
 
X 
Gastroparesis Core Symptom Daily Diary (GCSDD) 
                                          
1 within +/- 3 days 
2 Informed consent will be obtained prior to the performance of any study procedure(s) 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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3 Adverse event collection will begin at the time the ICF is signed.  
4 Vital sign collection at all visits. Height collection at V1. Body weight collection at V1, V2, and V4. 
5 The Screening/Baseline C-SSRS will occur at V1.  The Since Last Visit C-SSRS will occur at all other visits.  
6 mGCSI questions on symptom changes  (Part II) will only be administered at V3 and V4.  
EOP= End of Phase;; WOCBP = Women of Child-bearing Potential; ECG = electrocardiogram; C-SSRS = 
Columbia Suicide Severity Rating Scale; mGCSI = modified Gastroparesis Cardinal Symptom Index; PAGI-QOL = 
Patient Assessment of Upper Gastrointestinal Symptoms – Quality of Life 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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6. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1. 
Subject Inclusion Criteria 
Subjects will be considered eligible for participation in the study if the following criteria are 
satisfied:   
1. Male and female subjects aged 18 – 70 years (inclusive); 
2. Diagnosed with idiopathic or diabetic gastroparesis with moderate to severe nausea:  
a. Demonstrated delayed gastric emptying of a solid meal via either scintigraphy or 
gastric breath test within 10 years of screening. If solid meal is not tolerated, a 
liquid meal may be used instead to demonstrate delayed gastric emptying via 
scintigraphy,  
b. Presence of nausea symptom for at least 6 months prior to screening, 
c. At least 24 screening diary entries, 
NOTE:  CRITERIA 2D-E ARE CONFIDENTIAL AND SHOULD NOT BE SHARED 
WITH SUBJECTS, POTENTIAL SUBJECTS, OR ANYONE OUTSIDE OF THE 
IMMEDIATE STUDY TEAM. 
d. mGCSI individual nausea score ≥ 3 at Visit 1, and 
e. Average daily diary nausea severity ≥ 3 during the worst 50% days of nausea 
during the screening period; 
3. Patient’s gastroparesis symptoms persist despite diet and/or life-style modifications; 
4. Body Mass Index (BMI) of ≥18 and ≤38 kg/m2 (BMI = weight (kg)/ [height (m)]2);  
5. Subjects 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 sterilized or post-menopausal  partner;  
b. Females of child-bearing potential (not surgically sterile or post-menopausal, 
defined as 12 months without menses) will use an acceptable method of 
contraception from 1 month prior to randomization (or screening, if earlier) through 
1 month following the last dose of study medication. Examples of acceptable 
methods of contraception for females include abstinence, double barrier method, 
IUD, hormonal contraception, or sterilized partner;  
6. Ability and acceptance to provide written informed consent;  
7. Willing to participate in the pharmacogenomic sample collection; 
8. Willing and able to comply with all study requirements and restrictions, including but not 
limited to:  
a. Daily symptom diary completion,  
b. Prohibited medications, and 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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c. Strict control of blood glucose (T1DM and T2DM patients); 
9. Willing to not participate in any other interventional trial for the duration of their 
participation. 
 
6.2. 
Subject Exclusion Criteria 
Subjects will be excluded from the study if any of the following criteria apply: 
1. Another active disorder or treatment which could explain or contribute to symptoms in 
the opinion of the Investigator (including but not limited to gastric malignancy, 
neurological disorder, or heavy doses of strong anticholinergics);  
2. Gastrectomy, fundoplication, vagotomy, pyloroplasty, bariatric surgery, post-surgical 
cause of gastroparesis, or gastric stimulation device surgically implanted within the last 
year or if implanted more than a year ago, have changed stimulation settings within the last 
3 months (ie gastric stimulation device must have a stable setting for at least 3 months); 
3. Gastric or parenteral feeding within 4 weeks of screening;  
4. Pregnancy or nursing;  
5. History of intolerance and/or hypersensitivity to medications similar to tradipitant and its 
accompanying excipients; 
6. History (including family history) or current evidence of congenital long QT syndrome or 
known acquired QT interval prolongation (including QTc > 450 in males or > 470 in 
females at screening); 
7. History of suicide attempt and/or suicidal ideation (of type 4 or 5 on the Columbia Suicide 
Severity Rating Scale (C-SSRS)) within 2 years of screening or subject is at risk of suicide 
at Screening or Baseline, in the opinion of the investigator;  
8. History of an eating disorder within 2 years of screening; 
9. Recent history (within six months of screening) of Alcohol Use Disorder or Substance Use 
Disorder as defined in DSM-5 or evidence of such abuse which may include a positive 
drug screen at the Screening visit; 
10. Uncontrolled thyroid disease; 
11. Unstable cardiac, respiratory, hepatic or renal disease; 
12. Evidence of uncontrolled blood glucose (including HbA1C >9 or metabolic crisis in past 
60 days); 
13. Indication of impaired liver function (including values for AST, ALT, or bilirubin > 1.5 
times the Upper Limit of Normal, unless isolated bilirubin > 1.5 x ULN due solely to 
Gilbert’s syndrome); 
14. Has a creatinine level > 1.5x ULN; 
15. Use of prohibited  medication (Section 7.2.1) or medication with anti-nausea, antiemetic, 
neuromodulating, or prokinetic effect within 2 weeks of the screening visit EXCEPT 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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when administered on a stable daily dosing schedule (stable for at least 3 months prior to 
the screening visit) or administered under protocol-specified rescue medication 
guidelines;  
16. Use of the following within 2 weeks of screening: another NK-1 antagonist or a second 
generation 5-HT3 antagonist, phenergan more than 2 times per day, or opioids more than 
2 times per week;  
17. Pyloric injection of neurotoxins (e.g. botulinum type A or B) within 3 months of the 
Screening Visit;  
18. Exposure to any investigational medication, including placebo or domperidone, within 60 
days of the Baseline Visit;  
19. Anyone affiliated with the site or sponsor and/or anyone who may consent under duress; 
and  
20. Any other reason as determined by the Investigator which may lead to an unfavorable risk-
benefit of study participation, may interfere with study compliance, or may confound study 
results.  
 
6.3. 
Subject Withdrawal Criteria 
The term “discontinuation” refers to the randomized subject’s premature withdrawal from the 
study before completing all scheduled evaluations. 
 
Subjects may voluntarily withdraw from the study at any time for any reason. Subjects may also 
be discontinued from the study for any of the following reasons: 
• If in the Investigator’s judgment, continuation in the study may prove harmful to the 
subject.  Such a decision may be precipitated by adverse events, including changes in 
vital signs, physical examination, ECG, or laboratory tests.  The Investigator will 
maintain autonomy in making medical/safety decisions regarding the subject’s 
continued participation in the trial.  Clinically notable abnormalities in vital signs or 
laboratory tests are provided in Appendices Section 20.4 and Section 20.3, 
respectively, to guide clinical focus regarding a subject’s continued participation; 
• Noncompliance; 
 
For subjects withdrawing from the study prematurely, all efforts will be made to perform the 
Visit 4 Early Termination procedures.  
 
Documented reason:  It will be documented whether or not each subject completed the clinical 
study.  For subjects who do not complete the clinical study, the primary reason for 
discontinuation will be documented in the CRF.  Possible reasons for discontinuation include: 
1. Protocol deviation (including noncompliance to study requirements) 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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2. Adverse event(s) (including abnormal laboratory values, and abnormal test procedures) 
3. Pregnancy 
4. Lost to follow-up 
5. Death 
6. Subject withdrew consent 
7. Unsatisfactory therapeutic effect 
8. Other (specify). 
 
Subjects who discontinue because of an AE, abnormal laboratory value, or abnormal test result 
will be followed until resolution or for 30 days, whichever is less. Events which are stable after 
30 days will not require additional follow up.  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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7. 
TREATMENT OF SUBJECTS – EVALUATION PHASE 
7.1. 
Study Medication 
7.1.1. 
Dosing 
Randomized subjects will be dispensed study medication under double-blind conditions.  Each 
subject will be dispensed one bottle of study medication at Visit 2 and another bottle at Visit 3. 
Subjects will be instructed to take one capsule of study medication every day in the morning, and 
one capsule of study medication every day in the evening approximately 12 hours later. Each 
capsule will contain either 85 mg of tradipitant or matching placebo.  
 
7.1.2. 
Guidance for Taking Study Medication 
Subjects should be instructed to take study medication approximately every 12 hours at the same 
times each day. The morning dose of study medication should be taken at least 30 minutes before 
breakfast and the evening dose of study medication should be taken at least 30 minutes prior to 
dinner or bedtime.  Study medication should be taken on an empty stomach whenever possible. 
In the event that a patient vomits within 15 minutes of taking study medication and an intact 
capsule can be identified in the emesis, a second capsule should be administered.   
 
7.2. 
Concomitant Medications 
The administration of concomitant medication (including OTC medication) will be clearly 
documented on the concomitant medication CRF page.  
In general, concomitant medications that may interfere with the assessment of the efficacy 
and safety of tradipitant are not allowed in this protocol or are allowed with specific 
provisions.  
Prohibited medications and treatments are prohibited from the screening visit (or 4 weeks prior 
to the Randomization Visit when a washout is required) through the end of study participation. 
Questions regarding the use of concomitant medications not listed should be directed to the 
Medical Monitor. 
 
7.2.1. 
Prohibited Medications 
The following medications are prohibited from use during the screening and treatment periods of 
the study. This list is not exhaustive.  In the event that a study subject is on any medication or 
treatment that is not listed but that may interfere with the assessment of the efficacy and safety of 
tradipitant, the eligibility of the subject and/or use of the potential medication should be reviewed 
with the Medical Monitor and the Sponsor 
• NK-1 antagonists (including but not limited to aprepitant, netupitant, rolapitant) 
• Second generation 5-HT3 antagonists (including palonosetron)  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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• Any medication with anti-nausea, antiemetic, neuromodulating, or prokinetic effects 
that is not taken on a stable daily dosing schedule (stable for at least 3 months prior to 
the screening visit) is prohibited from the screening visit through the end of study 
with the exception of protocol-defined rescue medication defined in Section 7.2.2. 
• Phenergan (or promethazine) administration more than 2 times per day or Phenergan 
use that is not considered rescue use. 
• Opioid administration more than 2 times per week. 
• Marijuana (illicit or medical) use (including a positive drug screen for marijuana)  
 
The following medications are prohibited from use beginning one week before randomization 
through the end of the treatment period: 
• Drugs with a narrow therapeutic index: carbamazepine, cyclosporine, digoxin, 
ethosuximide, lithium, phenytoin, procainamide, quinidine, sirolimus, tacrolimus, 
theophylline, warfarin 
• Strong CYP3A4 inhibitors (listed by class):  
Class 
Prohibited medications 
Antibiotics  clarithromycin, telithromycin 
Antifungals  itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals 
boceprevir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, 
topinavir 
Other  
conivaptan 
grapefruit juice 
nefazodone 
 
7.2.2. 
Rescue Medication 
Anti-nausea or antiemetic medication that is not administered on a stable daily dosing regimen is 
considered rescue medication. Patients may use rescue medication per the Rescue Medication 
Guidelines. 
 
7.2.2.1. 
Rescue Medication Guidelines 
1. Only medications listed in Table 4 can be used as rescue medication.   
2. Patients should have previous experience with use of the medication.  
3. Rescue medication administration should be documented in the patient diary 
4. Patient use of rescue medication will be reviewed at study visits 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Table 4: 
Medications Allowed for Rescue Use  
The following medications are allowed for rescue use  
ondansetron, prochlorperazine, promethazine 
7.2.3. 
Medication Washout 
In the event that a medication washout period is required, Visit 1 should be conducted to 
establish preliminary eligibility prior to initiating washout.  The Investigator should discuss an 
appropriate washout period duration with the Medical Monitor as well as whether a repeat 
Screening Visit is warranted.    
Diary data collection should begin following the medication washout period.   
 
7.3. 
Treatment Compliance 
Compliance in this study will be assessed by the Investigator.  The Investigator will consider 
patient interviews as well as returned capsules when assessing compliance.    Subjects who were 
not fully compliant will be re-educated by the Investigator or study staff on the importance of 
taking the study medication daily at the scheduled time. 
 
Any overdose that occurs during study participation must be recorded on the overdose CRF. An 
overdose (intentional or accidental) is defined as the following:  >3 capsules of double-blind 
study medication taken within a 24-hour period (except when re-administered within the 
guidance of Section 7.1.2). 
 
7.4. 
Treatment Assignment  
7.4.1. 
Subject ID Assignment 
Subject Identification (ID) - Each subject who signs an informed consent form should receive a 
subject identification number.  The subject identification number (ID) consists of a 3-digit site 
number (Site No.) and a 4-digit subject number (Subject No.).  The Site No. and Subject No. will 
be separated by a hyphen.  
 
Site No. - Vanda (or designee) will assign a unique, three-digit number to the site. 
 
Subject No. – Subject numbers will be assigned to each subject starting with 1001 (i.e. 1001, 1002, 
1003 …). The ID for a subject who discontinues from the study for any reason after having been 
assigned an ID will not be reassigned.  
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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7.4.2. 
Subject Replacement 
Subjects who discontinue prior to study completion will not be replaced.  
 
7.4.3. 
Randomization  
Randomization will be performed through a centralized, web-based, validated system that 
automates the assignment of subjects to randomization numbers.  The randomization scheme will 
be reviewed and approved by Vanda or designee.  For study medication dispensation, the 
Investigator or designee will access the randomization system to determine which study 
medication bottle the subject will be assigned. 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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8. 
STUDY MEDICATION MATERIALS AND MANAGEMENT 
8.1. 
Study Medication 
Tradipitant capsules are white opaque, hard gelatin capsules provided as a strength of 85 mg. 
The 85 mg capsule formulation also contains spray-dried lactose monohydrate, microcrystalline 
cellulose (Avicel PH102 and PH200), povidone, croscarmellose sodium, sodium lauryl sulfate, 
and magnesium stearate as excipients. Placebo capsules will be provided in size and appearance 
identical to those containing tradipitant.  
 
8.2. 
Study Medication Packaging and Labeling 
Medication labels will comply with US regulations. The storage conditions for the study 
medication will be described on the medication label.  
 
Study medication capsules will be provided in high-density polyethylene (HDPE) bottles with a 
child-resistant cap containing desiccant. Each bottle will contain 36 capsules. At each visit, 
subjects will be given enough study medication to last until the next visit (one bottle will be 
dispensed at Visit 2 and collected at Visit 3, a second bottle will be dispensed at Visit 3 and 
collected at Visit 4). Subjects should be instructed to bring the study medication bottle along 
with any unused capsules to the site at his/her next visit.  Each bottle will have a two-part label.  
The second part of the label will be attached to the subject’s source documents before the bottle 
is dispensed to the subject. 
 
8.3. 
Study Medication Storage 
Study medication should be stored at 20-25 °C with excursions permitted to 15-30 °C.  Capsules 
should not be crushed or broken, but should be swallowed whole.  Study medication will be 
dispensed to only randomized subjects at the study site.   
 
8.4. 
Study Medication Accountability 
Vanda Pharmaceuticals Inc. is responsible for assuring that the quality of the study medication is 
adequate for the duration of the study. 
 
Study medication should be used in accordance with the protocol, under the supervision of the 
Investigator or delegated by the Investigator to the site pharmacist or other personnel trained to 
store and dispense investigational medications.   
 
The Investigator or designee is responsible for logging receipt of each shipment of study 
medication, confirming the actual shipment contents, and indicating the status of each bottle.  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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The Investigator must agree to supply study medication only to subjects enrolled in the study.  It 
is the responsibility of the Investigator to ensure that a current record of study drug disposition is 
maintained.  Records or logs must comply with applicable regulations and guidelines, and should 
include: 
• Amount of study medication received  
• Medication bottle number 
• Dates of medication inventory movement 
• Amount dispensed 
• Initials of person responsible for each medication inventory entry 
 
Accurate recording of all study medication administration (including dispensing and dosing) will 
also be made in the appropriate section of the subject’s CRF and source documents. 
 
Vanda or its designee will instruct the Investigator on the return or destruction of unused study 
medication.  If any study medication was lost or damaged, its disposition should be documented 
in the subject’s source documents as well as the drug accountability record.  Study medication 
supplies will be retained at the clinical site until instructions for return or destruction of the 
supplies are received from Vanda or its designee. 
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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9. 
STUDY ASSESSMENTS – EVALUATION PHASE 
9.1. 
Study Assessments per Visit  
9.1.1. 
Screening Visit (Visit 1) 
The following will be performed after the subject signs the informed consent form: 
• Review of inclusion/exclusion criteria 
• Collection of demographic information, medical history, and prior and concurrent 
medications;  vital sign and body measurements 
• Physical examination (PE) (excluding genitourinary examination unless clinically 
indicated) 
• ECG 
• Screening/Baseline C-SSRS questionnaire 
• Clinical laboratory assessments: hematology, chemistry (including estimated 
creatinine clearance (eCLcr; based on the Cockcroft-Gault equation), urinalysis, 
HbA1c, thyroid stimulating hormone (TSH), thyroxine (T4), urine drug screen,  
• Serum pregnancy test and collection of menstrual cycle information (for females of 
child-bearing potential) 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) Part I 
• Modified PAGI-SYM (mPAGI-SYM) 
• Gastroparesis Treatment Benefit Survey (GTBS) 
Collection of adverse event information will begin at the time the ICF is signed.  Subjects will be 
given a diary and instructed to begin completing the screening portion of their diary for at least 4 
weeks prior to the baseline visit.   Diary data will be assessed at Visit 2 to confirm patient 
eligibility for randomization (see Section 6.1). 
 
9.1.2. 
Baseline Visit (Visit 2, Study Day 0) 
On Day 0 (Visit 2/Baseline), the following assessments will be performed to assess the subject’s 
continued eligibility:  
• Review of inclusion/exclusion criteria 
• Adverse event query 
• Collection of concomitant medications  
• vital signs and weight measurements 
• Since last visit C-SSRS  
• Urine pregnancy test and collection of menstrual cycle information (for females of 
child-bearing potential) 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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• Gastroparesis Core Symptom Daily Diary (GCSDD) review: To be considered eligible 
for randomization, subjects must: 
− meet diary eligibility criteria (Section 6.1 )  
− have at least 24 daily diary entries  
− have a daily diary completion rate ≥ 24/35 (68%) 
 
Individuals continuing to meet eligibility criteria will be randomized, and the following 
assessments will also be performed during this visit:  
• ECG;  
• Clinical laboratory assessments (HbA1C, hematology, chemistry (including eCLcr; 
based on the Cockcroft-Gault equation), urinalysis, thyroid stimulating hormone 
(TSH), thyroxine (T4), and urine drug screen) 
• PG sample  
• Baseline Pharmacokinetic (PK) sample 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) Part I 
• Modified PAGI-SYM (mPAGI-SYM) 
• Patient Assessment of Upper Gastrointestinal Disorder  Quality of Life (PAGI-QOL) 
• Clinical Global Impression of Severity (CGI-S) 
• Study medication instruction and dispensation (first dose will be administered on 
evening of Day 0) 
 
9.1.3. 
Visit 3 (Study Day 14 ± 3 days) 
• Urine pregnancy test and collection of menstrual cycle information (for females of 
child-bearing potential)  
• Pharmacokinetic (PK) sample 
• Semi-supine routine vital signs (body temperature, respiratory rate, blood pressure, and 
pulse)  
• ECG 
• Clinical laboratory assessments (HbA1C, hematology, chemistry (including eCLcr; 
based on the Cockcroft-Gault equation), urinalysis, thyroid stimulating hormone 
(TSH), thyroxine (T4), and urine drug screen) 
• Adverse Event query 
• Concomitant medication review 
• Since last visit C-SSRS 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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• Diary review 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• Modified PAGI-SYM (mPAGI-SYM) 
• Patient Global Impression of Change (PGI-C) 
• Clinical Global Impression of Severity (CGI-S) 
• Study medication collection and review 
• Study medication instruction and dispensation 
 
9.1.4. 
Visit 4 (Study Day 28 ± 3 days)  
• Full PE (excluding pelvic, rectal and breast examinations unless clinically indicated) 
• Laboratory evaluations (HbA1C, hematology, chemistry (including eCLcr; based on 
the Cockcroft-Gault equation), urinalysis, thyroid stimulating hormone (TSH), 
thyroxine (T4), and urine drug screen) 
• Serum pregnancy test and collection of menstrual cycle information (for females of 
child-bearing potential)  
• Pharmacokinetic blood sample  
• ECG 
• Semi-supine routine vital signs (body temperature, respiratory rate, blood pressure, and 
pulse) and weight  
• Adverse Event query 
• Concomitant medication review 
• Since last visit C-SSRS 
• Review diary 
• Collect diary 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• Modified PAGI-SYM (mPAGI-SYM) 
• Patient Global Impression of Change (PGI-C) 
• Patient Assessment of Upper Gastrointestinal Disorder  Quality of Life (PAGI-QOL) 
• Clinical Global Impression of Severity (CGI-S) 
• Study medication collection and review  
• Records EOP 
• Review of Inclusion criteria (only for subjects that are continuing to the OLE phase) 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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• Dispense Study Drug (only for subjects that are continuing to the OLE phase) 
 
9.1.5. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the discretion of the Investigator.  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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10. 
ASSESMENTS OF EFFICACY 
The following rating scales will be used in this study to assess efficacy: 
• Gastroparesis Core Symptom Daily Diary (GCSDD) 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• Modified PAGI-SYM (mPAGI-SYM) 
• Patient Global Impression – Change (PGI-C) 
• Patient Assessment of Upper Gastrointestinal Disorders – QOL (PAGI-QOL) 
• Gastroparesis Treatment Benefit Scale (GTBS) 
• Clinician Global Impression – Severity (CGI-S) 
 
10.1. 
Patient Reported Outcome (PRO) Assessments  
10.1.1. 
Gastroparesis Core Symptom Daily Diary (GCSDD) 
Subjects will complete a daily symptom questionnaire at least 28 days prior to randomization 
through the end of study. The diary questionnaire will include questions related to the experience 
of gastroparesis core symptoms over the previous 24 hours.  The severity of nausea, early satiety, 
post-prandial fullness, bloating, and abdominal pain will be rated by severity on a Likert scale 
from 0 = none to 5 = very severe.  The frequency of vomiting, duration of nausea, and the use of 
rescue medication will also be collected.  
 
10.1.2. 
Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
The modified Gastroparesis Cardinal Symptom Index is a patient reported outcome administered 
in-clinic with a 2-week recall period. Part I of the questionnaire consists of the traditional GCSI 
and severity rating of upper abdominal pain as well as severity of overall symptoms. The 
questionnaire uses the same 0-5 scale utilized in both the GCSI and the PAGI-SYM [16].    Part 
II of the questionnaire will be administered at post-treatment visits (Visit 3 and Visit 4), and uses 
a 7-point rating scale for the subject to rate their own improvement in their core gastroparesis 
symptoms relative to baseline.  Symptoms are rated as: 1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very 
much worse.  
10.1.3. 
Modified Patient Assessment of Gastrointestinal Disorders – Symptoms 
(mPAGI-SYM) 
The modified PAGI-SYM is a patient reported outcome administered in-clinic with a 2-week 
recall period. This questionnaire will include PAGI-SYM items not included in the mGCSI. The 
questionnaire uses the same 0-5 scale utilized in both the GCSI and the PAGI-SYM [16].    
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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10.1.4. 
Patient Global Impression-Change (PGI-C) 
The PGI-C is a 7 point rating scale where the subject rates their own improvement in overall 
symptoms relative to the baseline assessment. It is rated as: 1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very 
much worse.  
 
10.1.5. 
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-
QOL) 
The 30-tem Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-
QOL©) questionnaire is a valid and reliable instrument assessing quality of life in patients with 
gastroparesis. The questionnaire covers five domains: Daily Activities, Clothing, Diet and Food 
Habits, Relationship, and Psychological Well-Being and Distress [16].  Affect to overall quality 
of life and well-being over the past two weeks is rated on a scale of 0 = “None of the time” to 5 = 
“All of the time” for each item.  
 
10.1.6. 
Gastroparesis Treatment Benefit Survey (GTBS)  
The Gastroparesis Treatment Benefit Survey (GTBS) is administered prior to the initiation of 
therapy.  The GTBS requires the subject to rate the relative importance of the relief of each of 
the core symptoms from  0 = ‘not at all important’ to 4 = ‘very important’. The GTBS is 
designed to be used in conjunction with Gastroparesis Core Symptom Daily Diary (GCSDD) 
data to provide symptom-specific and overall benefit scores which place higher weight on the 
relief of symptoms most important to the individual patient. 
 
10.2. 
Clinician Global Impression of Severity (CGI-S) 
The CGI-S is a 7-point scale in which the clinician rates the severity of the patient's illness at the 
time of assessment, relative to the clinician's past experience with patients who have the same 
diagnosis. Considering total clinical experience, a patient is assessed on severity of illness at the 
time of rating 1: normal, not at all ill; 2: borderline ill; 3: mildly ill; 4: moderately ill; 5: 
markedly ill; 6: severely ill; or 7: extremely ill. 
 
10.3. 
Pharmacokinetic Assessment 
A single blood sample will be collected at each visit as a secondary measure of overall study 
medication compliance. Samples will be tested for plasma concentrations of tradipitant and 
major metabolites.  Pharmacokinetic analyses may be provided in a separate report.  
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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11. 
ASSESSMENT OF SAFETY 
11.1. 
Safety Parameters 
Safety assessments should be conducted as specified in the Schedule of Evaluations (Table 3). 
These assessments include: the regular monitoring and recording of all AEs and serious adverse 
events (SAEs); regular monitoring of hematology, blood chemistry and urinalysis values, vital 
signs, body measurements and suicidal ideation and behavior; and the performance of physical 
examinations and electrocardiograms.  Any amendments to this protocol that change the 
schedule of visits and procedures will be included in the clinical study report for this protocol. 
 
11.1.1. 
Safety ECG 
A full standard 12-lead ECG will be performed (after the subject has rested in supine position for 
approximately 10-15 minutes) and centrally read at as specified in Table 3. 
   
11.1.2. 
Laboratory Evaluations 
The Schedule of Evaluations (Table 3) shows the days at which blood will be collected for 
clinical laboratory tests and urine for the urinalysis.   
 
The table below, Table 5, presents the clinical laboratory tests to be performed.   
 
Clinical laboratory tests will be performed by a certified laboratory that will forward laboratory 
data to both the site and Vanda or its designee.   
 
Values considered to be potentially clinically notable are provided in Appendix 20.3 for the 
Investigator’s guidance. Any laboratory test result from an enrolled subject that the Investigator 
considers clinically significant may be repeated once to rule out laboratory error.  For tests where 
a persistent abnormality is considered to be drug related, repeat analyses will be performed until 
the cause is determined and either a return to normality occurs or the Investigator deems the 
abnormality to be of no clinical significance.  Any laboratory test result that the Investigator 
considers clinically significant must also be recorded as an adverse event. 
 
Table 5: Clinical Laboratory Tests 
Category 
Parameters 
Hematology  
Red blood cell count (RBC), hemoglobin, hematocrit, platelets, and 
white blood cell (WBC) count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) 
Chemistry 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Category 
Parameters 
Electrolytes 
sodium, potassium, chloride, magnesium, bicarbonate 
Liver function test 
alkaline phosphatase, aspartate aminotransferase (AST [SGOT]), 
alanine aminotransferase (ALT [SGPT]), total bilirubin, gamma-
glutamyltransferase (GGT) 
Renal function parameters 
blood urea/blood urea nitrogen (BUN), creatinine, eCLcr 
Other 
glucose, calcium, albumin, total cholesterol, high density lipoprotein 
(HDL), low density lipoprotein (LDL), triglycerides, phosphorus, lactate 
dehydrogenase (LDH), total protein, uric acid, creatine kinase 
Urinalysis 
 
Gross and chemical exam 
color, appearance, specific gravity, pH, protein, glucose, ketone, blood, 
nitrite 
Reflexive microscopic exam  
(will be done if any of the 
urinalysis 
testing 
is 
not 
negative) 
RBC, WBC, epithelial cells, bacteria, casts, crystals 
 
11.1.2.1. Additional Laboratory Evaluations 
• Serum pregnancy test at Visits 1, 4/4a,6, COLE-V1, and COLE-V7 
• Urine pregnancy test at Visits 2 , 3, 5, 6, and COLE V2-V6. 
• Drugs of abuse at all visits  
• Thyroid stimulating hormone (TSH) at all visits 
• Thyroxine (T4) at all visits 
• HbA1c measurement at all visits  
 
11.1.3. 
Vital Signs and Body Measurements 
11.1.3.1. Vital Signs 
Vital signs will be taken as specified in the Schedule of Evaluations (Table 3). Measurements 
will include the following: 
• Oral body temperature 
• Respiratory rate 
• Semi-supine blood pressure (systolic and diastolic)  
• Semi-supine pulse/ heart rate  
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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After the subject signs the informed consent, vital sign values that the Investigator considers 
clinically significant will be recorded as AEs.  Vital sign values considered to be potentially 
clinically notable are provided in Appendix 20.4 for the Investigator’s guidance.  The recording 
must be in the form of a clinical sign, symptom, or diagnosis, and not a mere description of the 
vital sign abnormality.  Measurements will be repeated at medically appropriate intervals until 
they return to acceptable levels. 
 
11.1.3.2. Body Measurements  
Body measurements include the following assessments: 
• Body weight (at Visit 1, Visit 2, and Visit 4) 
• Height (at Visit 1 only) 
 
11.1.4. 
Medical History and Physical Examinations 
A medical history will be taken at Visit 1 (Screening).  A full PE (excluding pelvic, rectal and 
breast examinations unless clinically indicated) will be performed at Visit 1 (Screening), Visit 
4/a, and Visit 6.  Documentation of the PE will be included in the source documentation at the 
investigational site.   
 
11.1.5. 
Pregnancy 
Before enrolling a woman of child-bearing potential (WOCBP) in this clinical study, Investigators 
must review the following information with the subject: 
• Informed consent requirements 
• Risk of pregnancy 
• Contraceptives in current use 
• Drug interactions with hormonal contraceptives 
• Pregnancy prevention during the study (including abstinence) 
 
All WOCBP (defined as any female unless surgically sterile or postmenopausal at least 12 months) 
should be instructed to contact the Investigator immediately if they suspect they might be pregnant 
while participating in this study.  Any pregnancy that occurs during study participation must be 
reported to Vanda (or designee) within 24 hours of learning of its occurrence and must be followed 
to determine outcome.  If a subject becomes pregnant, she will be discontinued from the study. 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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11.1.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a semi-structured clinical interview designed to systematically assess and track 
suicidal adverse events (behavior and ideation) throughout different settings including clinical 
trials.  This scale was developed by researchers at Columbia University and will be administered 
in this study as specified in the Schedule of Evaluations (Table 3).  The Screening/Baseline 
version of the C-SSRS will be completed at Visit 1 and the Since Last Visit version of the C-
SSRS will be completed at Visits 2-4. Results from the C-SSRS will be listed for each subject.  
These data will also be summarized for each treatment group and for suicidal ideation events, 
suicidal behaviors and completed suicides. 
 
11.1.7. 
Definitions Related to Safety 
11.1.7.1. Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation 
subject that does not necessarily have causal relationship with treatment.  An AE can therefore 
be any unfavorable and unintended sign (including clinically significant abnormal laboratory 
finding), symptom, or disease temporally associated with clinical study whether or not related to 
the investigational product. 
 
Clinically significant findings or changes in assessments should be recorded as AEs. Every 
attempt should be made to describe the AE in the form of a diagnosis.  If a clear diagnosis has 
been made, individual signs and symptoms will not be recorded unless they represent atypical or 
extreme manifestations of the diagnosis, in which case they should be reported as separate 
events.  If a clear diagnosis cannot be established, each sign and symptom must be reported 
individually.    
 
11.1.7.2. Serious Adverse Event 
AEs are classified as serious or non-serious.  A serious adverse event is defined as any untoward 
medical occurrence that occurs during clinical study that meets one of the following criteria as 
shown in Table 6. 
 
Table 6: 
SAE Criteria and Definitions 
SAE Criteria 
Definition 
Death of Subject 
An event that results in the death of the subject. 
Life-Threatening 
An event that, in the opinion of the Investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if 
it had occurred in a more severe form. 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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SAE Criteria 
Definition 
Hospitalization 
An event that results in an admission to the hospital for any length 
of time. This does not include an emergency room visit or 
admission to an out-patient facility. 
Prolongation of Hospitalization 
An event that occurs while the subject is hospitalized and prolongs 
the subject’s hospital stay. 
Congenital Anomaly/Birth Defect 
An anomaly detected at or after birth, or any anomaly that results 
in fetal loss. 
Persistent or Significant 
Disability/Incapacity 
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include transient interruptions of daily activities or 
experiences of relatively minor medical significance such as 
headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle).                                                               
Important Medical Event Requiring 
Medical or Surgical Intervention to 
Prevent Serious Outcome1 
An important medical event that, based on medical judgment, may 
not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of a subject, life-threatening, subject 
hospitalization, prolongation of existing hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity). 
1 Important Medical Events may be classified as serious or non-serious events at the discretion of the Investigator. 
 
All AEs that do not meet the above criteria should be classified as non-serious adverse events.  
Elective surgeries requiring hospitalization and hospitalizations for social reasons are not 
considered SAEs. 
 
11.1.7.3. Adverse Event Follow-Up 
Subjects with non-serious AEs that are ongoing at the subject’s last study visit must be followed 
until resolution or for 30 days after the subject’s last study visit, whichever comes first.  Non-
serious AE that are reported during the 7 days following the subject’s last study visit will be 
recorded on the Adverse Events CRF and followed until resolution or for up to the 30 days after 
the subject’s last study visit, whichever comes first.  SAEs will be followed until the event resolves 
or the event or sequelae stabilize.  SAEs that are reported within 30 days of the subject’s last study 
visit should be reported as indicated in Section 11.1.10. 
 
11.1.7.4. Adverse Event Reporting Period 
AEs are to be recorded in the source documents from the time of the subject’s informed consent 
signature until the end of the subject’s study participation.  Each AE, both serious and non-serious, 
will also be reported on the Adverse Events CRF.  CRF Completion Instructions will be provided 
to each investigational site.  If the subject reports or the Investigator learns of a new AE(s) up to 7 
days after the subject’s last study visit or a new SAE(s) up to 30 days after the subject’s last study 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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visit, the investigational site personnel will ensure that these data are recorded on the Adverse 
Events CRF for the study.  The period during which an SAE must be reported may be extended if 
there is a strong suspicion that the event being reported is related to the study medication or a study 
procedure. 
 
11.1.7.5. Pre-Existing Condition 
A pre-existing condition is one that is present at the start of the study.  A pre-existing condition 
should be recorded as an adverse event if the frequency, intensity, or the characteristics of the 
condition worsen during the study period. 
 
11.1.8. 
Relationship to Study Medication 
Each AE is to be reported on the AE CRF.  The Investigator is responsible for making an 
assessment of the likelihood that an AE is causally related to the study medication.  The 
Investigator should choose one of the five choices of causality. 
• Certain: occurs in a reasonable time after study drug administration and cannot be 
explained by concurrent disease or drugs.  The event should respond to withdrawal of 
study drug (de-challenge) and recur with re-challenge when clinically plausible. 
• Probable: occurs in a reasonable time after study drug administration and it is unlikely 
to be to be attributed to concurrent disease or drugs, and it has a response to de-
challenge.  Re-challenge information is not required to fulfill this definition. 
• Possible: occurs in a reasonable time after study drug administration, but could be 
related to concurrent disease or drugs. De-challenge information may be lacking or 
unclear. 
• Unrelated: the event has an improbable temporal relationship (too soon, or too late 
after study drug, or study drug is not taken) and is plausibly related to other drugs or 
underlying disease. 
• Unassessable:  available information is insufficient, contradictory, and cannot be 
supplemented or verified at the time of the report. This assessment will be considered 
as “related” for all expedited reports until an alternative assessment is made. 
Adverse Event causality of “certain”, “probable”, “possible”, and “unassessable” will be 
considered related to study medication. 
 
11.1.9. 
Recording Adverse Events 
11.1.9.1. Adverse Events During Study Period 
At each study visit, the Investigator must seek information on AEs by questioning the subject 
and, as appropriate, by examining the subject.  Information on all AEs should be recorded 
immediately in the source document, and also in the appropriate AE module of the CRF.  All 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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signs, symptoms, and abnormal diagnostic procedure results that are considered clearly related 
should be grouped and recorded in the source document as one diagnosis.  All AEs occurring 
during the study period must be recorded. 
 
11.1.9.2. Post-Study Adverse Event 
At the last scheduled visit, the Investigator should instruct each subject to report any subsequent 
event(s) that the subject or the subject’s personal physician believes might reasonably be related 
to participation in this study.  The Investigator should notify the study sponsor of any death or 
AE occurring at any time after a subject has discontinued or terminated study participation that 
may reasonably be related to this study.  The Investigator should also notify the sponsor if they 
become aware of the development of cancer or a congenital anomaly in any offspring conceived 
subsequent to a subject’s study participation. 
 
11.1.9.3. Abnormal Laboratory Values 
Abnormal laboratory values or test results should not generally be considered adverse events, 
unless deemed clinically significant by the Investigator.  Assessment of signs or symptoms or 
requirement for therapeutic intervention should be considered when determining clinical 
significance.  Record clinical significant laboratory values on the Adverse Events CRF using an 
appropriate diagnostic description.   
 
11.1.10. 
Reporting Adverse Events 
11.1.10.1. Study Sponsor Notification by Investigator 
All SAEs should be reported on the electronic CRF within 24 hours to the Vanda Drug Safety 
designee using the AE electronic CRF page. 
 
The initial report should contain as much information about the event as possible.  Follow-up 
reports will provide any information missing at the time of the initial report (e.g., an end date for 
the adverse event or laboratory values received after the report).  In addition, significant new 
information on ongoing SAEs should be reported promptly to Vanda (or designee). 
  
The initial and follow-up reports should identify subjects by a unique subject ID rather than by 
subjects’ names, personal identification numbers, and/or address.   
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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At the time of the initial report, the information listed in Table 7 should be provided. 
 
Table 7: 
SAE Reporting Information 
• Event term 
• Event date of onset 
• Brief narrative with relevant 
medical history 
• Action taken regarding study medication 
administration  
• Seriousness criteria met 
• Initial PI assessment of relationship to 
study medication  
 
 
11.1.10.2. Reporting of Events to Regulatory Authorities and IRB/EC 
Investigator or designee will submit events to the IRB/EC according to individual committee 
requirements. Vanda or designee will submit expedited reports of relevant events to Regulatory 
Authorities as required by local and federal regulations.  Events will be reviewed for medical 
sense, expectedness, and causality.  
 
11.1.11. 
Unblinding Procedures 
The subjects and the medical staff will not be aware of which treatment is being administered.  
Data will remain blinded until clinical data have been reviewed, at which time the randomization 
schedule may be released for the purposes of assessment of drug safety and efficacy. 
 
Only if a subject’s medical condition warrants, such as a medical emergency for which treatment 
requires knowledge of what study medication was given, may the Investigator break the blind to 
determine if the subject received tradipitant or placebo.  If possible, the Medical Monitor should 
be consulted prior to unblindng. If a subject’s condition is so severe that time would not permit 
consulting with the Medical Monitor, the subject’s assigned treatment can be unblinded by the 
Investigator using the IWRS system.  In the event that it becomes necessary to unblind a 
subject’s treatment assignment during the study, the Investigator should contact the Medical 
Monitor immediately, if not prior to unblinding, and explain the reason for unblinding.  
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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12. 
PHARMACOGENOMICS ASSESSMENT 
The pharmacogenomic assessment is an exploratory assessment.  The intent of the assessment is 
to identify genetic factors that may predict response to treatment with tradipitant and/or relative 
susceptibility to side effects.  In addition, the sample may be used to identify genetic markers 
that may be associated with gastroparesis, disorders associated with NK-1 receptors, or in the 
metabolism, distribution, and/or excretion of tradipitant and its metabolites.   Information 
regarding this collection and assessment will be provided in the informed consent form.  
 
All subjects enrolled in VP-VLY-686-2301 will have a pharmacogenomics sample collected. A 
blood sample will be drawn at Baseline (or any other visit if the blood draw is missed) to obtain 
sufficient DNA for the pharmacogenomic assessment.  The blood is drawn into an EDTA tube 
which will be gently inverted several times to prevent clotting. The sample(s) will then be placed 
in a -70 °C or -20 °C freezer at the site.  The sample(s) will be shipped on dry ice to a central 
laboratory for DNA extraction.  The sample will remain under control of the Sponsor and may be 
stored for up to 15 years.  
 
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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13. 
STATISTICS 
13.1. 
Sample Size and Accrual 
Based on a two-sided t-test with the 5% signicance level, the planned sample size of 75 subjects  
per arm (a total of 150 subjects) provides around 86% power to detect a mean difference of 0.8 
point in the average of nausea severity score assuming the standard deviation of 1.6 in each 
treatment group.     
 
13.2. 
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.  
 
13.2.1. 
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. 
 
Continuous efficacy variables will be analyzed using a mixed-effect model for repeated measures 
(MMRM) and/or an analysis of covariance (ANCOVA) model. The models will be described in 
the SAP. 
 
For the analyses of change from baseline, only subjects 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 subjects per treatment group within a site for the analysis models and for the evaluation of the 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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treatment-by-site interaction for the primary endpoint.  Unless otherwise specified, the pooled 
sites will only be used in the analyses where site is included.  The actual sites rather than the 
pooled sites will be specified in data listings. 
 
Categorical variables will be analyzed using the Cochran-Mantel-Haenszel (CMH) test blocking 
on sites, and Fisher’s exact test will be used when site is not adjusted (mainly for safety 
assessment). 
 
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. 
 
13.2.2. 
Subject Populations for Analysis 
The following analysis populations will be defined for this study: 
Intent-to-Treat: will include any subject 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 subject randomized into the study that receives a dose of study drug; 
Per-Protocol: Any subject 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.  Subject characteristics will be 
presented for all subjects randomized. 
 
13.2.3. 
Subject Disposition 
Study completion and reasons for discontinuation for all randomized subjects 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. 
13.2.4. 
Demography and Other Baseline Data 
Demographic data and subject characteristics at screening/baseline will be listed and summarized 
by treatment group for all randomized subjects using descriptive statistics. 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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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 
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. 
 
13.2.5. 
Study Medication 
The number of subjects 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 subjects who are significantly noncompliant in the double-
blind phasewill be summarized by treatment groups. 
 
13.2.6. 
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 subjects 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 subject will be counted only once. 
 
13.3. 
Efficacy Data Analysis 
13.3.1. 
Primary Outcome  and Methodology 
The primary efficacy outcome measure will be change from baseline to Day 28 in the weekly 
average of daily nausea severity score.  A repeated measures analysis employing a restricted 
maximum likelihood (REML)-based, mixed-effects model approach (MMRM) will be used to 
analyze the primary efficacy outcome.  The MMRM model will include the fixed, categorical 
effects of treatment group assignment, visit, treatment group-by-visit interaction and pooled site 
as well as the fixed, continuous covariates of baseline symptom score and the baseline symptom 
score-by-visit interaction. A detailed description of the MMRM model will be included in the 
SAP.  
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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In addition to the MMRM  model, an analysis of covariance (ANCOVA) model will also be 
applied. The last-observation-carried-forward (LOCF) will be used to impute any subsequent 
missing data. The model will have baseline as a covariate, and the fixed, categorical effects of 
treatment group assignment, pooled site.  An observed cases (OC) analysis will also be 
performed.  
 
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. 
  
13.3.2. 
Secondary Efficacy Analysis 
The secondary efficacy outcomes include: 
• Other Gastroparesis Core Symptoms: vomiting, early satiety, post-prandial fullness, 
and upper abdominal pain;  
• mGCSI 
• mPAGI-SYM 
• PGI-C 
• PAGI-QOL 
• GTBS 
• CGI-S 
 
Continuous endpoints will be summarized and analyzed in a manner similar to the primary 
endpoint. Details of the analysis will be described in the SAP. 
 
Categorical variables will be evaluated as 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. 
 
13.4. 
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 and behavior events. 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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13.4.1. 
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.  
 
Treatment-emergent adverse events will be summarized within each treatment group by primary 
system organ class (SOC) and preferred term. (NOTE: In any given category [e.g. body system] 
a subject 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 subjects experiencing SAEs and AEs resulting in discontinuation from the 
study will be summarized by treatment groups.  
 
13.4.2. 
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 subjects 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 subjects with clinically notable abnormalities (Appendix 20). 
 
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. 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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13.4.3. 
Vital Signs and Body Measurements 
Data from vital signs and body measurements will be listed, clinically notable values (Appendix 
20.2) 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 subjects 
with values outside the normal range, and values that were clinically notable.  
 
13.4.4. 
Electrocardiogram (ECG) 
Results from the ECG will be listed for each subject. These data will also be summarized for 
each treatment group by presenting subjects with newly occurring or worsening ECG 
abnormalities. 
 
13.4.5. 
C-SSRS 
Results from the C-SSRS will be listed for each subject.  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 subjects 
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. 
 
13.5. 
Subgroup Analysis 
The subgroup analysis (such as, gender, age, etiology, baseline illness severity etc.) for efficacy 
variables and safety variables may be conducted as described in the SAP. 
 
13.6. 
Interim Analysis 
No interim analyses are planned. 
 
13.7. 
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. 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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14. 
DIRECT ACCESS TO SOURCE DOCUMENTS 
14.1. 
Definition of Source Document 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents and data records 
(ICH E6, Section 6.10) include, but are not limited to: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, X-rays, subject files, and records kept at the pharmacy, at the laboratories, and 
at medical or technical departments involved in the clinical trial.  The Investigator is required to 
maintain adequate and accurate source documents that record all observations and other data 
pertinent to this study. 
 
14.2. 
Study Monitoring 
The Sponsor’s or CRO’s monitor will maintain contact with the Investigator and designated staff 
between study visits.  Monitoring visits to each investigational site will be conducted by the 
assigned monitor as frequently as stipulated in the monitoring plan.  The Investigator must 
designate an adequate space to conduct the monitoring visit and will allocate adequate time for 
Vanda’s monitoring activities.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the monitor.   
 
The purposes of clinical trial monitoring are to verify that: 
• the rights and well-being of the human subjects are protected; 
• reported trial data are accurate, complete and verifiable from source documents; and 
• trial conduct is in compliance with the currently approved protocol/amendment(s), 
with GCP, and with applicable regulatory requirement(s). 
 
14.3. 
Audits and Inspections 
In addition to routine monitoring procedures, Vanda may request an independent Good Clinical 
Practice Quality Assurance contractor to perform audits of clinical research activities to evaluate 
compliance with principles of Good Clinical Practice.  The Investigator will ensure that the 
compliance or quality assurance reviewer is allowed to: 
• review all of the study-related documents (e.g., study records and source documents) 
and study related facilities (e.g., pharmacy, diagnostic laboratory) 
• discuss the conduct of the study with the Investigator 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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A regulatory authority may also wish to conduct an inspection (during the study or even after its 
completion).  If an inspection is requested by a regulatory authority, the Investigator must inform 
the CRO and Vanda immediately that this request has been made, and promptly forward copies 
of the audit reports to Vanda. 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, Standard 
Operating Procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.  Site visit audits will be made periodically by the Sponsor’s (or CRO’s) qualified 
compliance auditing team, which is an independent function from the study conduct team. 
 
15.1. 
Data Collection 
The study CRF is the primary data collection instrument for the study.  All data requested on the 
CRF must be recorded.  All missing data must be explained.  A detailed guideline on the 
completion of the CRF will be provided to the site.  Monitors will highlight any discrepancies 
found in the documentation of study conduct and ensure that appropriate site personnel address 
the discrepancies.   
 
15.2. 
Clinical Data Management 
 Data from the CRFs and other external data (e.g. laboratory data) will be entered into a clinical 
database as specified in the Sponsor (or CRO’s) data management plan.  Quality control and data 
validation procedures will be applied to ensure the validity and accuracy of the clinical database. 
 
15.3. 
Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be documented and returned to the investigational site for resolution.  
Only authorized personnel will make corrections to the clinical database, and all corrections will 
be documented in an audit trail.   
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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16. 
ETHICS 
16.1. 
Ethics Review 
This protocol and any amendments will be submitted to a properly constituted EC or IRB, in 
agreement with local legal prescriptions (ICH 3.1-3.4), for formal approval of the study conduct.   
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the 
EC/IRB for the study.  The formal consent of a subject by the investigative site, using the 
EC/IRB-approved consent form, must be obtained before that subject is submitted to any study 
procedure.  This consent form must be signed by the subject, or subject’s legally acceptable 
surrogate, and the Investigator-designated research professional obtaining the consent. 
 
16.2. 
Ethical Conduct of the Study 
This study is to be conducted according to US and international standards of Good Clinical 
Practice, as described in the following documents: 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US Code of Federal Regulations (CFR) dealing with clinical studies (21 CFR including 
parts 50 and 56). 
3. Declaration of Helsinki (current) 
The Investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice. 
 
16.3. 
Written Informed Consent 
Prior to any study procedures being performed, subjects and persons conducting the consent 
process will be required to sign and date the IRB/EC approved informed consent, and each 
subject will be given a copy. In addition, this information should be recorded in the subject’s 
medical record.  The written consent document will embody the elements of informed consent as 
described in the Declaration of Helsinki, US 21 CFR Part 50.25, ICH GCP, and in accordance 
with any local regulations. The Investigator is responsible for the preparation, content, and 
IRB/EC approval of the consent form.  The consent form must be approved by the IRB/EC and 
be acceptable to the study Sponsor or designee. The consent form must be written in language 
fully comprehensible to the prospective subject.  The Investigator or designee will give the 
subject adequate opportunity to read the consent form and to discuss any questions. 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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17. 
DATA HANDLING AND RECORD KEEPING 
Throughout this study, all data will be linked to the electronic CRF via the unique subject 
identification number.  However, subjects’ initials and date of birth may also be collected in 
accordance with local and/or country regulations, and used to assist the Sponsor or designee with 
verification of data.  This data will be blinded in corresponding analyses. Medical records of 
consented subjects will be reviewed by Sponsor or designee including, but not limited to, 
laboratory test results, ECG reports, hospital admission and discharge summaries for admissions 
occurring during a subject’s participation in the study, and autopsy reports for deaths occurring 
during the study. The Sponsor and/or designee accessing the records will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subject identities.  
Should access to such medical records require a waiver or authorization separate from the 
statement of informed consent, the Investigator will obtain such permission in writing from the 
subject before the subject is entered into the study.  
 
Samples collected for pharmacogenomic study will be double-coded by the following process: 
(1) The sample is collected at the site in a tube labeled with a barcode - code #1.      (2) The 
sample is then sent to a central lab for storage and DNA extraction.  An aliquot of the DNA 
sample is sent to Vanda where it will be identified with a new unique code – code #2.  The 
sample is now double-coded.  This maximizes subject confidentiality.   
 
The DNA sample and any information generated from this sample will be labeled with the 
second code and no personal identifiers.  In addition, all genetic information will be stored in a 
separate secured database, independent from the clinical data database.  Only authorized 
personnel from Vanda will have access to the genetic data.  In addition, the FDA or other 
regulatory agencies may request copies of the genetic data for auditing purposes.  Unless ordered 
by a court of law, only the above mentioned agencies and personnel will have access to the 
genetic data. 
 
17.1. 
Retention of Records 
It is the Investigator’s responsibility to retain essential study documents for at least 2 years after 
the last approval of a marketing application in his/her country for the investigational product and 
until there are no pending or contemplated marketing applications in his/her country, or at least 2 
years have elapsed since the formal discontinuation of clinical development of the investigational 
product and they have written approval from the sponsor to dispose of the study documents.  
These documents should be retained for a longer period if required by an agreement with the 
sponsor or if legally required.  In such an instance, it is the responsibility of the sponsor to 
inform the Investigator/institution as to when these documents no longer need to be retained. The 
Investigator must receive Sponsor approval prior to destroying any records associated with the 
study.  


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Changes to the Protocol 
Except for a change that is intended to eliminate an immediate hazard to subjects, the approved 
protocol shall be conducted as described.  Any significant protocol deviation must be documented 
in the source documents. 
 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by Vanda prior to IRB/EC and regulatory agency submission. The Investigators must 
sign the amendment before implementation.   
 
Substantial amendments require approval from the regulatory authority and/or the responsible 
ethics committee. Amendments to the trial are regarded as “substantial” where they are likely to 
have a significant impact on:  
• the safety or physical or mental integrity of the subjects, or  
• the scientific value of the trial, or  
• the conduct or management of the trial, or  
• the quality or safety of any IMP used in the trial.  
 
In addition, if amendments affect the informed consent, a revised informed consent has to be 
submitted to the responsible ethics committee, before changes in study procedures are 
implemented.  These requirements for approval should in no way prevent any immediate action 
from being taken by the Investigator or by Vanda in the interests of preserving the safety of all 
subjects included in the study. If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons, the Vanda monitor and the IRB/EC 
at the center should be notified. 
 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or Ethical Committee approval but the Ethical Committee must be kept informed of 
such administrative changes.  
 
18.2. 
Discontinuation of Study  
Vanda reserves the right to discontinue any study for administrative reasons at any time. If 
appropriate, reimbursement for reasonable expenses will be made. 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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18.3. 
Publication of Results 
Manuscript(s) for publication, texts of presentations, abstracts of papers, and similar material 
should be submitted to Vanda for review and comment at least sixty (60) days prior to submission 
for publication, public dissemination or review by a program committee.  Upon request from 
Vanda, the site shall remove any confidential information (other than study results) prior to 
submitting or presenting the materials.  Vanda shall notify the Investigator in writing within sixty 
(60) days of receipt of such draft whether it contains information deemed to be confidential or 
information that if published within thirty (30) days would have an adverse effect on Sponsor’s 
business interests, including but not limited to a patent application in which Vanda owns an 
interest.  In the latter case, Vanda may request a delay and Investigator agrees to delay publication 
or presentation for a period not exceeding ninety (90) days.  An independent joint publication may 
be authored by Investigators from the multiple sites.  The Investigator, therefore, agrees not to 
independently publish the results of the study before the publication of such multi-site paper, if 
applicable.  No party heretofore mentioned shall use any other party’s name, or Vanda’s name, in 
connection with any advertising, publication, or promotion without prior written permission. 
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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18.4. 
Investigator Agreement 
This protocol is being provided to me for conducting a clinical trial for Vanda.  The information 
contained in the protocol is confidential and proprietary to Vanda.  Study documents provided by 
Vanda (protocols, Investigator’s Brochures, and other material) will be stored appropriately to 
ensure their confidentiality.  
I may disclose the contents of this protocol to study personnel under my supervision and my 
Institutional Review Board or Ethical Committee for the purpose of conducting this trial only. 
The information provided by Vanda to me may not be disclosed to others without direct written 
authorization from Vanda, except to the extent necessary to obtain informed consent from 
subjects who wish to participate in the trial.  
I have read the protocol and agree that it contains all necessary details for carrying out the study 
as described.  I will conduct this protocol as outlined and according to the moral, ethical, and 
scientific principles governing the Declaration of Helsinki and the principles of GCP and 
applicable local requirements. 
I understand that should the decision be made by Vanda to terminate prematurely or suspend the 
clinical trial at any time, with or without cause, such decision will be communicated to me in 
writing.  Conversely, if I decide to withdraw from execution of the clinical trial, I will 
immediately communicate such decision in writing to Vanda. 
By my signature below, I attest that I have read, and understood, and agree to abide by the 
conditions, instructions, and restrictions contained in this protocol.  
 
Investigator 
Name: ______________________________________ 
Signature: ____________________________________ 
Date: ________________________________________ 
 
Protocol Number: VP-VLY-686-2301 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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19. 
REFERENCES 
 
[1] 
W. L. Hasler, “Gastroparesis: symptoms, evaluation, and treatment,” Gastroenterol.Clin 
North Am, vol. 36, no. 0889–8553 (Print), pp. 619–47, ix, Sep. 2007. 
[2] 
H. P. Parkman, M. Camilleri, G. Farrugia, R. W. McCallum, A. E. Bharucha, E. A. 
Mayer, J. F. Tack, R. Spiller, M. Horowitz, A. I. Vinik, J. J. Galligan, P. J. Pasricha, B. 
Kuo, L. A. Szarka, L. Marciani, K. Jones, C. R. Parrish, P. Sandroni, T. Abell, T. Ordog, 
W. Hasler, K. L. Koch, K. Sanders, N. J. Norton, and F. Hamilton, “Gastroparesis and 
functional dyspepsia: Excerpts from the AGA/ANMS meeting,” Neurogastroenterol. 
Motil., vol. 22, no. 2, pp. 113–133, 2010. 
[3] 
A. E. Bharucha, “Epidemiology and natural history of gastroparesis,” Gastroenterol.Clin 
North Am, vol. 44, no. 1558–1942 (Electronic), pp. 9–19, Mar. 2015. 
[4] 
M. Camiller, H. P. Parkman, M. A. Shafi, T. L. Abell, and L. Gerson, “Clinical 
Guideline : Management of Gastroparesis,” Am J Gastroenterol, vol. 108, no. 1, pp. 18–
38, 2013. 
[5] 
L. A. Nguyen and W. J. Snape, “Clinical presentation and pathophysiology of 
gastroparesis,” Gastroenterology Clinics of North America, vol. 44, no. 1. pp. 21–30, 
2015. 
[6] 
W. L. Hasler, “Emerging drugs for the treatment of gastroparesis,” 
Expert.Opin.Emerg.Drugs, vol. 19, no. 1744–7623 (Electronic), pp. 261–279, Jun. 2014. 
[7] 
H. P. Parkman, K. Yates, W. L. Hasler, L. Nguyen, P. J. Pasricha, W. J. Snape, G. 
Farrugia, K. L. Koch, J. Calles, T. L. Abell, R. W. McCallum, L. Lee, A. Unalp–Arida, J. 
Tonascia, and F. Hamilton, “Similarities and Differences Between Diabetic and Idiopathic 
Gastroparesis,” Clin. Gastroenterol. Hepatol., vol. 9, no. 12, pp. 1056–1064, 2011. 
[8] 
P. J. Pasricha, K. P. Yates, L. Nguyen, J. Clarke, T. L. Abell, G. Farrugia, W. L. Hasler, 
K. L. Koch, W. J. Snape, R. W. McCallum, I. Sarosiek, J. Tonascia, L. A. Miriel, L. Lee, 
F. Hamilton, and H. P. Parkman, “Outcomes and Factors Associated with Reduced 
Symptoms in Patients with Gastroparesis,” Gastroenterology, vol. 149, no. 7, pp. 1762–
1774e4, 2015. 
[9] 
M. Otsuka and K. Yoshioka, “Neurotransmitter functions of mammalian tachykinins,” 
Physiol Rev., vol. 73, no. 0031–9333 (Print), pp. 229–308, Apr. 1993. 
[10] L. Quartara and C. A. Maggi, “The tachykinin NK1 receptor. Part II: Distribution and 
pathophysiological roles,” Neuropeptides, vol. 32, no. 0143–4179 (Print), pp. 1–49, Feb. 
1998. 
[11] S. M. Stahl, “The ups and downs of novel antiemetic drugs, part 2: An illustration,” J. 
Clin. Psychiatry, vol. 64, no. 6, pp. 626–627, 2003. 
[12] M. Bergstrom, R. J. Hargreaves, H. D. Burns, M. R. Goldberg, D. Sciberras, S. A. Reines, 
K. J. Petty, M. Ogren, G. Antoni, B. Langstrom, O. Eskola, M. Scheinin, O. Solin, A. K. 
Majumdar, M. L. Constanzer, W. P. Battisti, T. E. Bradstreet, C. Gargano, and J. Hietala, 
“Human positron emission tomography studies of brain neurokinin 1 receptor occupancy 
by aprepitant,” Biol.Psychiatry, vol. 55, no. 0006–3223 (Print), pp. 1007–1012, May 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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2004. 
[13] K. Chong and K. Dhatariya, “A case of severe, refractory diabetic gastroparesis managed 
by prolonged use of aprepitant.,” Nat. Rev. Endocrinol., vol. 5, no. 5, pp. 285–8, 2009. 
[14] J. Fahler, G. C. Wall, and B. I. Leman, “Gastroparesis-associated refractory nausea treated 
with aprepitant,” Annals of Pharmacotherapy, vol. 46, no. 12. 2012. 
[15] M. Minami, “[Cytokines and chemokines: mediators for intercellular communication in 
the brain].,” Yakugaku Zasshi, vol. 121, no. 12, pp. 875–85, 2001. 
[16] A. M. Rentz, P. Kahrilas, V. Stanghellini, J. Tack, N. J. Talley, C. de la Loge, E. Trudeau, 
D. Dubois, and D. A. Revicki, “Development and psychometric evaluation of the patient 
assessment of upper gastrointestinal symptom severity index (PAGI-SYM) in patients 
with upper gastrointestinal disorders,” Qual Life Res, vol. 13, no. 10, pp. 1737–1749, 
2004. 
 
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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20. 
APPENDICES 
 
20.1. 
Open-Label Extension Phase 
20.1.1. 
Phase Objective 
The objective of the open-label extension (OLE) phase is to explore the long-term safety of daily 
dosing with tradipitant over an additional 8 weeks of treatment. 
 
20.1.2. 
Phase Rationale 
The purpose of the open-label extension phase is to explore the long-term safety of tradipitant in 
subjects diagnosed with gastroparesis over an additional 8 weeks. This phase may allow subjects 
previously randomized to the tradipitant arm in the evaluation phase the opportunity to continue 
treatment with tradipitant.  For subjects previously randomized to the placebo arm, this phase may 
afford them the opportunity to explore the potential benefits of a new drug treatment not otherwise 
available to them.   
 
20.1.3. 
Study Design for OLE Phase 
The OLE phase consists of an additional 8-weeks of treatment where all subjects will receive the 
same daily dose of tradipitant in an open-label fashion. Subjects who received tradipitant during 
the evaluation phase will continue to receive tradipitant. Subjects who received placebo during the 
evaluation phase will also receive tradipitant.  
 
Subjects will go to the clinic during the OLE on the days specified in the Schedule of Evaluations 
for OLE (Table 8) for routine safety assessments which may include a urine pregnancy test for 
women of child-bearing potential (WOCBP), urine drug screen, vital signs measurements, safety 
labs, physical exam, an ECG and collection of adverse event including suicidality ideation and 
behavior and concomitant medication information. Refer to Table 8 and Section 20.1.10  for details 
of which assessments are done per Study Visit. Study medication will be dispensed at some of 
these visits and compliance will also be assessed.  End-of-study (EOS) assessments and an 
additional gastric emptying breath test will be performed at Visit 6 (Study Day 84 ± 3 days) or at 
the time of early discontinuation. EOS assessments include safety evaluations such as serum 
pregnancy test for females, physical examination (PE), vital signs, ECG, collection of adverse 
event including suicidality ideation and behavior and clinical laboratory assessments (Table 8).  
 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Table 8: 
Schedule of Evaluations for OLE 
Visit 
V4a1 
V5 
 
V6 
EOP 
Study Day 
 
Day 562 
Day 842  
Informed Consent 
X 
 
 
Prior/concomitant medications 
X 
X 
X 
Adverse Event (AE) Query3 
X 
X 
X 
Collection of menstrual cycle information 
X 
X 
X 
Serum β-HCG (for WOCBP) 
X 
 
X 
Urine pregnancy test (for WOCBP) 
 
X 
 
TSH, T4 
X 
X 
X 
Urine Drug Screen 
X 
X 
X 
HbA1c, hematology, chemistry, and 
urinalysis 
X 
X 
X 
12-lead resting ECG 
X 
X 
X 
Vital signs and body measurements4 
X 
X 
X 
Physical Examination (PE) 
X 
 
X 
Gastric Emptying Breath Test (GEBT) 
 
 
X 
C-SSRS5 
X 
X 
X 
Clinical Global Impression of Severity 
(CGI-S) 
X 
X 
X 
PGI-C 
 
X 
X 
mGCSI & mPAGI-SYM 
X 
X 
X 
PAGI-QOL 
X 
 
X 
Gastroparesis Core Symptom Daily Diary 
(GCSDD)  
 
 
Subject diary review 
 
X 
X 
Study medication dispensation 
X 
X 
 


VP-VLY-686-2301                                                                               Vanda Pharmaceuticals Inc. 
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Visit 
V4a1 
V5 
 
V6 
EOP 
Study Day 
 
Day 562 
Day 842  
Study medication collection & compliance 
 
X 
X 
EOP 
 
 
X 
1 Only for subjects that completed the Double-Blind Phase prior to the OLE being available. 
2 within +/- 3 days 
3 Adverse event collection will begin at the time the ICF is signed. 
4 Vital sign collection at all visits. Height collection at V1 only. 
5 The Screening/Baseline C-SSRS will occur at V1.  The Since Last Visit C-SSRS will occur at all other visits.  
EOS = End of Study; ET = Early Termination; WOCBP = Women of Child-bearing Potential; ECG = 
electrocardiogram; C-SSRS = Columbia Suicide Severity Rating Scale 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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20.1.4. 
Selection and Withdrawal Criteria of Subjects for the OLE Phase 
20.1.4.1. Inclusion Criteria 
A subject is eligible for enrollment into the OLE phase of this study if he/she meets the following 
criteria: 
• Has completed the randomization phase through Visit 4 (Study Day 28);  
• Is willing to provide an additional written informed consent for the OLE phase if 
enrolled in study prior to OLE becoming available. 
20.1.4.2. Early Withdrawal of Subjects 
The term “discontinuation” refers to the randomized subject’s premature withdrawal from the 
study before completing all scheduled evaluations. 
 
Subjects may voluntarily withdraw from the OLE at any time for any reason. Subjects may also 
be discontinued from the study for any of the following reasons: 
• If in the Investigator’s judgment, continuation in the study may prove harmful to the 
subject.  Such a decision may be precipitated by adverse events, including changes in 
vital signs, physical examination, ECG, or laboratory tests.  The Investigator will 
maintain autonomy in making medical/safety decisions regarding the subject’s 
continued participation in the trial.  Clinically notable abnormalities in vital signs or 
laboratory tests are provided in Appendices 20.4  and 20.3, respectively, to guide 
clinical focus regarding a subject’s continued participation; 
• Noncompliance; 
 
Documented reason:   
It will be documented whether or not each subject completed the clinical study.  If, for any subject, 
study treatment or observations were discontinued, the reason will be recorded (only 1 choice is 
acceptable) on the electronic case report form (electronic CRF).  Acceptable reasons for a subject 
discontinuing participation in this clinical study are as follows: 
1. Protocol deviation (including noncompliance to study requirements) 
2. Adverse event(s) (including abnormal laboratory values, and abnormal test procedures) 
3. Pregnancy 
4. Lost to follow-up 
5. Death 
6. Subject withdrew consent 
7. Unsatisfactory therapeutic effect 


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8. Other (specify). 
20.1.5. 
Study Medication 
20.1.5.1. Dosing 
Subjects will be dispensed study medication under open-label conditions at the study visits 
indicated in the Schedule of Evaluations for OLE (Table 8).  Subjects will be instructed to take 
one capsule of study medication every day in the morning, and one capsule of study medication 
every day in the evening approximately 12 hours later. Each capsule will contain either 85 mg of 
tradipitant. 
 
20.1.5.2. Guidance for Taking Study Medication 
Subjects should be instructed to take study medication approximately every 12 hours at the same 
times each day. The morning dose of study medication should be taken at least 30 minutes 
before breakfast and the evening dose of study medication should be taken at least 30 minutes 
prior to dinner or bedtime. Study medication should be taken on an empty stomach whenever 
possible. 
In the event that a patient vomits within 15 minutes of taking study medication and an intact 
capsule can be identified in the emesis, a second capsule should be administered. 
 
20.1.6. 
 Concomitant Medication During the OLE Phase 
The administration of concomitant medication (including OTC medication) will be clearly 
documented on the concomitant medication CRF page. 
In general, concomitant medications that may interfere with the assessment of the efficacy and 
safety of tradipitant are not allowed in this protocol or are allowed with specific provisions. 
 
20.1.6.1. Prohibited Medication 
Prohibited medications and treatments are prohibited from the screening visit (or 4 weeks prior to 
the Randomization Visit when a washout is required) through the end of study participation. 
Questions regarding the use of concomitant medications not listed should be directed to the 
Medical Monitor. 
All medications prohibited during the randomization phases (Section 7.2.1) will also be prohibited 
during this phase. 
 
20.1.6.2. Rescue Medication 
Anti-nausea or antiemetic medication that is not administered on a stable daily dosing regimen is 
considered rescue medication. Patients may use rescue medication per the Rescue Medication 
Guidelines (Section 7.2.2.1). 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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20.1.7. 
Treatment Compliance 
Compliance in this study will be assessed by the Investigator. The Investigator will consider patient 
interviews as well as returned capsules when assessing compliance. Subjects who were not fully 
compliant will be re-educated by the Investigator or study staff on the importance of taking the study 
medication daily at the scheduled time.  
Any overdose that occurs during study participation must be recorded on the overdose CRF. An 
overdose (intentional or accidental) is defined as the following: >3 capsules of open label study 
medication taken within a 24-hour period (except when re-administered within the guidance of 
Section 7.1.2). 
 
20.1.8. 
Treatment Assignment 
At study Visits 4/4a, and 5, (Table 3 and Table 8), study personnel will dispense enough OLE 
medication to the subject to last until the next scheduled visit.  
 
20.1.9. 
Study Drug, Packaging, and Labeling 
Tradipitant capsules are white opaque, hard gelatin capsules provided as a strength of 85 mg. The 
85 mg capsule formulation also contains spray-dried lactose monohydrate, microcrystalline 
cellulose (Avicel PH102 and PH200), povidone, croscarmellose sodium, sodium lauryl sulfate, 
and magnesium stearate as excipients. 
 
Study medication capsules will be provided in high-density polyethylene (HDPE) bottles with a 
child-resistant cap containing desiccant. Each bottle will contain 36 capsules. Each bottle will 
have a two-part label. The second part of the label will be attached to the subject’s source 
documents before the bottle is dispensed to the subject. 
 
Study medication should be stored at 20-25 °C with excursions permitted to 15-30 °C. Capsules 
should not be crushed or broken, but should be swallowed whole. Study medication will be 
dispensed to only randomized subjects at the study site. 
 
20.1.10. 
Assessments Performed During the OLE 
20.1.10.1.  Visit 4a (Only for subjects that completed the Double-Blind Phase prior to the 
OLE being available) 
• Signing of the Informed Consent 
• Review of concomitant medication 
• Adverse event query 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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• Serum pregnancy test and collection of menstrual cycle information (for females of 
child-bearing potential) 
• Clinical laboratory assessments (HbA1C, hematology, chemistry, thyroid stimulating 
hormone (TSH), thyroxine (T4), urinalysis, and urine drug screen)  
• ECG 
• Semi-supine routine vital signs (weight, body temperature, respiratory rate, blood 
pressure, and pulse) 
• Full PE (excluding pelvic, rectal and breast examinations unless clinically indicated) 
• Since last visit C-SSRS 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• Modified PAGI-SYM (mPAGI-SYM) 
• Clinical Global Impression of Severity (CGI-S) 
• Patient Assessment of Upper Gastrointestinal Disorder Quality of Life (PAGI-QOL) 
• Study medication dispensation 
 
20.1.10.2. Visit 5 (Study Day 56 +/- 3 days) 
• Adverse event query 
• Review of concomitant medication 
• Urine pregnancy test and collection of menstrual cycle information (for females of 
child-bearing potential) 
• Clinical laboratory assessments (HbA1C, hematology, chemistry, thyroid stimulating 
hormone (TSH), thyroxine (T4), urinalysis, and urine drug screen)  
• ECG 
• Semi-supine routine vital signs (weight, body temperature, respiratory rate, blood 
pressure, and pulse)  
• Since last visit C-SSRS  
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• Modified PAGI-SYM (mPAGI-SYM) 
• Clinical Global Impression of Severity (CGI-S) 
• Patient Global Impression of Change (PGI-C) 
• Diary review 
• Study medication collection and review  
• Study medication dispensation 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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20.1.10.3. Visit 6 (Day 84/EOS ± 3 days or ET) 
• Adverse event query 
• Review of concomitant medication 
• Serum pregnancy test and collection of menstrual cycle information (for females of 
child-bearing potential) 
• Clinical laboratory assessments (HbA1C, hematology, chemistry (including eCLcr; 
based on the Cockcroft-Gault equation), urinalysis, thyroid stimulating hormone 
(TSH), thyroxine (T4), and urine drug screen)  
• ECG 
• Semi-supine routine vital signs (weight, body temperature, respiratory rate, blood 
pressure, and pulse)  
• Full PE (excluding pelvic, rectal and breast examinations unless clinically indicated) 
• Gastric Emptying Breath Test (GEBT) 
• Since last visit C-SSRS 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• Modified PAGI-SYM (mPAGI-SYM) 
• Clinical Global Impression of Severity (CGI-S) 
• Patient Global Impression of Change (PGI-C) 
• Patient Assessment of Upper Gastrointestinal Disorder Quality of Life (PAGI-QOL) 
• Diary review 
• Study medication collection and review  
20.1.11. 
Efficacy Assessments 
The efficacy assessments should be conducted as specified in the Schedule of Evaluations for 
OLE (Table 8).  These assessments include: the Gastroparesis Core Symptom Daily Diary 
(GCSDD), Modified Gastroparesis Cardinal Symptom Index (mGCSI), Modified PAGI-SYM 
(mPAGI-SYM), Patient Global Impression of Change (PGI-C), and the Patient Assessment of 
Upper Gastrointestinal Disorders-QOL (PAGI-QOL) (see Section 10.1.1 for a description of the 
patient reported outcomes) and the Clinician Global Impression – Severity (CGI-S) (see 
Section 10.2 for a description of the assessment). 
20.1.12. 
Safety Assessments 
The safety assessments should be conducted as specified in the Schedule of Evaluations for OLE 
(Table 8).  These assessments include: the regular monitoring and recording of all adverse events 
and serious adverse events (SAEs); the regular monitoring of hematology, blood biochemistry and 
urinalysis values; the regular monitoring of vital signs; the regular monitoring of suicidal ideation 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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and behavior, and the performance of physical examinations, and electrocardiograms. Refer to 
Section 11 for additional details relating to the collection of safety assessments. 
 
20.1.13. 
Statistical Methods 
Statistical analysis for the OLE phase will be based on data summaries, using similar layouts as 
for the randomization phase, and will be exploratory in nature. 
 
 
 
 
 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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20.2. 
Continued Open Label Extension Phase 
20.2.1. 
Phase Objectives 
20.2.1.1. Primary 
• To evaluate long term dosing of tradipitant on standard measures of subject safety by 
assessing adverse events (AEs) including suicidal ideation or behavior, changes in vital 
signs, clinical laboratory evaluations, electrocardiograms (ECGs) and physical exam 
findings during treatment 
 
20.2.1.2. Secondary 
• To evaluate the efficacy of tradipitant in reducing individual symptoms associated 
with gastroparesis  
• To evaluate the efficacy of tradipitant in global improvement and quality of life 
measures 
 
20.2.2. 
Phase Rationale 
20.2.2.1. Study Rationale 
The underlying pathophysiology of gastroparesis is complex and remains largely unknown.  
Prokinetic therapy has been the traditional mainstay of gastroparesis treatments, but studies 
continue to demonstrate a lack of correlation between reduction in gastric emptying delays and 
relief of gastroparesis symptoms [5]. 
 
Two case reports have documented the efficacy of open-label NK-1 antagonist therapy in 
severe, refractory gastroparesis cases [13][14].  Since the treatment of gastroparesis symptoms 
requires chronic administration of tradipitant 85mg, this study evaluates the long-term safety 
and tolerability of 85 mg tradipitant administered twice daily for 12 months. 
 
20.2.2.2. Rationale for Dose and Study Design 
In a multiple-dose PET clinical study, frontal cortex receptor occupancy was recorded at 93% 
following 7 days of 100 mg daily dosing.  Based on the PET study findings, it is estimated that a 
dose of approximately 85 mg daily would achieve 90% brain receptor occupancy 24-hours post 
steady-state dosing.  A target brain NK-1 receptor occupancy of 90% is based on a published 
study comparing the efficacy of two different doses in aprepitant, an NK-1 antagonist approved 
for CINV and PONV, in which a greater antiemetic effect was observed at a dosing regimen 
which reached 90% receptor occupancy than a dosing regimen reaching 80% receptor 
occupancy [12].   


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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While it is hypothesized that a daily dose of 85 mg will provide adequate central receptor 
occupancy coverage to centrally mediate nausea and vomiting, there is some evidence to suggest 
that the antiemetic effects of NK-1 antagonism may also have a peripherally-mediated 
component involving modulation of abdominal vagal afferent activity [15].   Additionally, the 
pharmacokinetic profile of tradipitant administered to individuals with delayed gastric emptying 
has not been fully characterized and therefore it is not known if delayed gastric emptying will 
significantly impact the dose-exposure relationship seen in healthy volunteers.  These two 
factors lead to the possibility that a higher daily dose of tradipitant might be necessary to 
achieve maximal efficacy and importantly, a more frequent dosing regimen may be warranted.  
As 85 mg BID was well tolerated in previous studies, this current safety study will test 85 mg 
BID.  Because gastroparesis requires long term chronic treatment, a long term dosing up to 12 
months is being assessed. 
 
The completed nonclinical and clinical safety studies with tradipitant showed a favorable safety 
profile. Clinical laboratory tests, vital signs, 12-lead ECG, and physical examination (PE) data 
showed no clinically significant alterations due to administration of tradipitant.  Additionally, 
preclinical studies showed no evidence of a drug-related QT prolongation. 
 
20.2.2.3. Risk Benefit 
The potential benefit for subjects on continued open label tradipitant is the possibility of 
experiencing decreased symptoms of gastroparesis while participating in this study. Nonclinical 
and clinical data to date have not indicated any likely toxicity at doses to be used in this study, 
and the drug has been well-tolerated in previous clinical studies.  The most commonly reported 
adverse events (≥ 2% and 1.25x placebo) in previous clinical studies were somnolence, 
dizziness, fatigue, and dry mouth.  Nonetheless, as tradipitant is an experimental compound, 
there may be unforeseen risks associated with its use. 
 
20.2.3. 
Investigational Plan 
 
20.2.3.1. Overall Phase Design and Plan: Description 
This is a continued open label extension phase. Approximately one hundred fifty (150) patients 
diagnosed with gastroparesis of either diabetic or idiopathic origin that have previously enrolled 
in VLY-VP-686-2301 randomized and open label phases will be asked to take 85mg tradipitant 
twice daily at 12 hour intervals for 12 months in an open-label fashion. Patient participation will 
include: 
• Day 0, COLE Screening Visit 1 (A/B) 
• Week 4, COLE Visit 2 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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• Week 8, Health Assessment Call 1 
• Week 12, COLE Visit 3 
• Week 16, Health Assessment Call 2 
• Week 20, COLE Visit 4 
• Week 24, Health Assessment Call 3 
• Week 28, COLE Visit 5 
• Week 32, Health Assessment Call 4 
• Week 36, Health Assessment Call 5 
• Week 40, COLE Visit 6 
• Week 44, Health Assessment Call 6 
• Week 48, Health Assessment Call 7 
• Week 52, COLE Visit 7  
 
20.2.3.2. Screening Visit COLE-Visit 1-A (Day 0) 
 For patients currently enrolled in VP-VLY-686-2301, this visit should correspond to the Visit 6 
visit such that there is no interruption of participation between phases if possible.   
During this visit, patients will sign the informed consent. Eligibility will be assessed based on 
their current medication use, physical examination (PE), vital signs, ECG, C-SSRS result, urine 
drug screen, urine and serum pregnancy test, if applicable, and clinical laboratory results from 
VP-VLY-686-2301 Visit 6.   
Patients that meet all of the study requirements will be enrolled into the phase. The study staff 
will provide instructions to patients detailing the instructions on how to take tradipitant. Study 
drug will be dispensed to the patient.  
 
20.2.3.3. Screening Visit COLE-Visit 1-B (Day 0) 
For patients who completed VP-VLY-686-2301 through Visit 6 and would like to enroll in the 
continued open label phase (COLE) after being off study drug for a period of time.   
During this visit, patients will sign the informed consent. Eligibility will be assessed based on 
their gastroparesis diagnosis, their current medication use, medical history, a physical 
examination (PE), vital signs, ECG, C-SSRS, urine drug screen, urine and serum pregnancy test, 
if applicable, and clinical laboratory results.  Patients will complete the since last visit C-SSRS, 
Modified Gastroparesis Cardinal Symptom Index (mGCSI), Modified PAGI-SYM (mPAGI-
SYM), Clinical Global Impression of Severity (CGI-S), Patient Assessment of Upper 
Gastrointestinal Disorder Quality of Life (PAGI-QOL). 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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Patients that meet all of the study requirements will be enrolled into the COLE. The study staff 
will confirm the patient’s demographic information and provide instructions to patients detailing 
the instructions on how to take tradipitant.  Study drug will be dispensed to the patient. 
 
20.2.3.4. COLE Visit 2-Visit 6 (Day 28, Day 84, Day 140, Day 196, Day 280  ± 5 days) 
On COLE Visit 2, COLE Visit 3, COLE Visit 4, COLE Visit 5 and COLE Visit 6, patients will 
return to the site to be queried for any adverse events and updates to their current medication 
use. Patients will undergo a physical examination (PE), vital signs, ECG, C-SSRS, urine drug 
screen, urine and serum pregnancy test, if applicable, and clinical laboratory results. Patients 
will complete the since last visit C-SSRS, Modified Gastroparesis Cardinal Symptom Index 
(mGCSI), Modified PAGI-SYM (mPAGI-SYM), Clinical Global Impression of Severity (CGI-
S), Patient Assessment of Upper Gastrointestinal Disorder Quality of Life (PAGI-QOL). Daily 
diary compliance will be reviewed, study medication will be collected and reviewed, and new 
study drug will be dispensed. 
 
20.2.3.5. Monthly Call to Subjects to Assess Health (Day 56, Day 112, Day 224, Day 252, 
Day 308, Day 336,  ± 3 days) 
A member of the study team will call patients to assess overall health and query for any adverse 
events or updates to their current medication. Note: An unscheduled visit will be performed if 
medically warranted  in the opinion of the Investigator. 
 
20.2.3.6. End of Study or Early Termination COLE Visit 7 (Day 364 ± 7 days) 
At the End of Study COLE Visit 7 Day 364 ± 7 days or at the time of early termination, subjects 
will return to the clinic for safety and efficacy assessments.  Diary and medication compliance 
will be reviewed. Patients will undergo a physical examination (PE), vital signs, ECG, urine 
drug screen, urine and serum pregnancy test, if applicable, and clinical laboratory results. 
Patients will complete the since last visit C-SSRS, Modified Gastroparesis Cardinal Symptom 
Index (mGCSI), Modified PAGI-SYM (mPAGI-SYM), Clinical Global Impression of Severity 
(CGI-S), Patient Assessment of Upper Gastrointestinal Disorder Quality of Life (PAGI-QOL). 
Daily diary compliance will be reviewed, study medication will be collected and reviewed. 
 
Table 9: 
Schedule of Evaluations for COLE 
COLE Visits 
V1-A 
Screening 
V1-B 
Screening 
V2 
 
V3-V6 
 
V7 
EOS/ET 
COLE Study Day 
Day 0 
Day 0 
Day 281 
Day 84, 140, 
196, 2801  
Day 3652 
VP-VLY-686-2301 EOS Procedures 
X 
 
 
 
 
Informed Consent Form (ICF)3 
X 
X 
 
 
 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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COLE Visits 
V1-A 
Screening 
V1-B 
Screening 
V2 
 
V3-V6 
 
V7 
EOS/ET 
COLE Study Day 
Day 0 
Day 0 
Day 281 
Day 84, 140, 
196, 2801  
Day 3652 
VP-VLY-686-2301 EOS Procedures 
X 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
Subject demography and medical 
history  
X 
X 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
Adverse Event (AE) Query4 
X 
X 
X 
X 
X 
Serum β-HCG (for WOCBP) 
 
X 
 
 
X 
Urine pregnancy test (for WOCBP) 
 
 
X 
X 
 
TSH, T4 
 
X 
X 
X 
X 
Urine Drug Screen 
 
X 
X 
X 
X 
HbA1c, hematology, chemistry, and 
urinalysis 
 
X 
X 
X 
X 
12-lead resting ECG 
 
X 
X 
X 
X 
Vital Signs and Body Measurements5 
 
X 
X 
X 
X 
Physical Examination (PE) 
 
X 
X 
X 
X 
C-SSRS6 
 
X 
X 
X 
X 
mGCSI 7 
 
X 
X 
X 
X 
mPAGI-SYM 
 
X 
X 
X 
X 
PAGI-QOL  
 
X 
X 
X 
X 
Patient Global Impression of Change 
(PGI-C)  
 
 
X 
X 
X 
Clinical Global Impression of 
Severity (CGI-S)  
 
X 
X 
X 
X 
Study medication dispensation  
X 
X 
X 
X 
 
Study medication collection & 
compliance 
 
 
X 
X 
X 
Subject diary instruction  
X 
X 
 
 
 
Subject diary review 
 
 
X 
X 
X 
Schedule Monthly Call 
 
 
X 
X 
 
EOS 
 
 
 
 
X 
Gastroparesis Core Symptom Daily 
Diary (GCSDD)  
            
 
 
 
 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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COLE Visits 
V1-A 
Screening 
V1-B 
Screening 
V2 
 
V3-V6 
 
V7 
EOS/ET 
COLE Study Day 
Day 0 
Day 0 
Day 281 
Day 84, 140, 
196, 2801  
Day 3652 
VP-VLY-686-2301 EOS Procedures 
X 
 
 
 
 
Health Assessment Call between 
Visits (every 4 weeks) 
 
 
X 
X 
 
EOS= End of Study; WOCBP = Women of Child-bearing Potential; ECG = electrocardiogram; C-SSRS = 
Columbia Suicide Severity Rating Scale; mGCSI = modified Gastroparesis Cardinal Symptom Index; PAGI-QOL = 
Patient Assessment of Upper Gastrointestinal Symptoms – Quality of Life 
1 within ± 5 days 
2 within ± 7 days 
3 Informed consent will be obtained prior to the performance of any study procedure(s) 
4 Adverse event collection will begin at the time the ICF is signed.  
5 Vital sign collection at all visits. Height collection at V1. Body weight collection at V1-V7. 
6 The Screening/Baseline C-SSRS will occur at V1-B.  The Since Last Visit C-SSRS will occur at all other visits.  
7mGCSI questions on symptom changes  (Part II) will only be administered at V2- V7.  
 
20.2.4. 
Selection and Withdrawal Criteria of Subjects for the OLE Phase 
 
20.2.4.1. Inclusion Criteria 
A subject is eligible for enrollment into the COLE phase of this study if he/she meets the following 
criteria: 
• Has completed the randomization phase and open label phase through Visit 6 (Study 
Day 84);  
• Is willing to provide an additional written informed consent for the COLE phase if 
enrolled in study prior to COLE becoming available. 
 
See Section 6.1 for complete study Inclusion Criteria and Section 6.2 for complete study 
Exclusion Criteria. 
 
20.2.4.2. Early Withdrawal of Subjects 
The term “discontinuation” refers to the subject’s premature withdrawal from the study before 
completing all scheduled evaluations. 
 
Subjects may voluntarily withdraw from the COLE at any time for any reason. Subjects may 
also be discontinued from the study for any of the following reasons: 


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• If in the Investigator’s judgment, continuation in the study may prove harmful to the 
subject.  Such a decision may be precipitated by adverse events, including changes in 
vital signs, physical examination, ECG, or laboratory tests.  The Investigator will 
maintain autonomy in making medical/safety decisions regarding the subject’s 
continued participation in the trial.  Clinically notable abnormalities in vital signs or 
laboratory tests are provided in Appendices 20.4  and 20.3, respectively, to guide 
clinical focus regarding a subject’s continued participation; 
• Noncompliance; 
 
For subjects withdrawing from the study prematurely, all efforts will be made to perform the 
COLEVisit 7 Early Termination procedures.  
 
Documented reason:   
It will be documented whether or not each subject completed the clinical study.  If, for any subject, 
study treatment or observations were discontinued, the reason will be recorded (only 1 choice is 
acceptable) on the electronic case report form (electronic CRF).  Acceptable reasons for a subject 
discontinuing participation in this clinical study are as follows: 
9. Protocol deviation (including noncompliance to study requirements) 
10. Adverse event(s) (including abnormal laboratory values, and abnormal test procedures) 
11. Pregnancy 
12. Lost to follow-up 
13. Death 
14. Subject withdrew consent 
15. Unsatisfactory therapeutic effect 
16. Other (specify). 
20.2.5. 
Treatment of Subjects 
20.2.5.1. Dosing 
Subjects will be dispensed study medication under open-label conditions at the study visits 
indicated in the Schedule of Evaluations for COLE (Table 9).  Subjects will be instructed to take 
one capsule of study medication every day in the morning, and one capsule of study medication 
every day in the evening approximately 12 hours later. Each capsule will contain either 85 mg of 
tradipitant. 
 
20.2.5.2. Guidance for Taking Study Medication 
Subjects should be instructed to take study medication approximately every 12 hours at the same 
times each day. The morning dose of study medication should be taken at least 30 minutes 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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before breakfast and the evening dose of study medication should be taken at least 30 minutes 
prior to dinner or bedtime. Study medication should be taken on an empty stomach whenever 
possible. 
In the event that a patient vomits within 15 minutes of taking study medication and an intact 
capsule can be identified in the emesis, a second capsule should be administered. 
 
20.2.6. 
 Concomitant Medication During the COLE Phase 
The administration of concomitant medication (including OTC medication) will be clearly 
documented on the concomitant medication CRF page. 
In general, concomitant medications that may interfere with the assessment of the efficacy and 
safety of tradipitant are not allowed in this protocol or are allowed with specific provisions. 
 
20.2.6.1. Prohibited Medication 
Prohibited medications and treatments are prohibited from the screening visit (or 4 weeks prior to 
the Randomization Visit when a washout is required) through the end of study participation. 
Questions regarding the use of concomitant medications not listed should be directed to the 
Medical Monitor. 
All medications prohibited during the randomization phases (Section 7.2.1) will also be prohibited 
during this phase. 
 
20.2.6.2. Rescue Medication 
Anti-nausea or antiemetic medication that is not administered on a stable daily dosing regimen 
is considered rescue medication. Patients may use rescue medication per the Rescue Medication 
Guidelines (Section 7.2.2.1). 
 
20.2.7. 
Treatment Compliance 
Compliance in this study will be assessed by the Investigator. The Investigator will consider 
patient interviews as well as returned capsules when assessing compliance. Subjects who were 
not fully compliant will be re-educated by the Investigator or study staff on the importance of 
taking the study medication daily at the scheduled time.  
Any overdose that occurs during study participation must be recorded on the overdose CRF. An 
overdose (intentional or accidental) is defined as the following: >3 capsules of open label study 
medication taken within a 24-hour period (except when re-administered within the guidance of 
Section 7.1.2). 
 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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20.2.8. 
Treatment Assignment 
At COLE Visits 1-6, (Table 9), study personnel will dispense enough COLE medication to the 
subject to last until the next scheduled visit.  
 
20.2.9. 
Study Drug, Packaging, and Labeling 
Tradipitant capsules are white opaque, hard gelatin capsules provided as a strength of 85 mg. The 
85 mg capsule formulation also contains spray-dried lactose monohydrate, microcrystalline 
cellulose (Avicel PH102 and PH200), povidone, croscarmellose sodium, sodium lauryl sulfate, 
and magnesium stearate as excipients. 
 
Study medication capsules will be provided in high-density polyethylene (HDPE) bottles with a 
child-resistant cap containing desiccant. Each bottle will contain 36 capsules. Each bottle will 
have a two-part label. The second part of the label will be attached to the subject’s source 
documents before the bottle is dispensed to the subject. 
 
Study medication should be stored at 20-25 °C with excursions permitted to 15-30 °C. Capsules 
should not be crushed or broken, but should be swallowed whole. Study medication will be 
dispensed to only randomized subjects at the study site. 
 
20.2.10. 
Study Medication Materials and Management 
See Section 8 for information on study medication packaging, storage and accountability.  
 
20.2.11. 
Study Assessments per Visit 
20.2.11.1. COLE Screening Visit A or B (Visit 1, COLE Day 0) 
The following will be performed after the subject signs the informed consent form: 
• Review of inclusion/exclusion criteria 
• Collection of demographic information, medical history, and prior and concurrent 
medications;   
• Vital sign and body measurements 
• Patients who are coming directly from VP-VLY-686-2301 Visit 6 can coordinate this 
visit with VP-VLY-686-2301 Visit 6. 
• Patients who are returning after a gap (Vist 1-B) will  perform the following additional 
procedures: 
− Physical examination (PE) (excluding pelvic, rectal and breast examinations 
unless clinically indicated) 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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−  ECG 
− Screening C-SSRS questionnaire 
− Clinical laboratory assessments: hematology, chemistry (including estimated 
creatinine clearance (eCLcr; based on the Cockcroft-Gault equation), urinalysis, 
HbA1c, thyroid stimulating hormone (TSH), thyroxine (T4), urine drug screen,  
− Serum pregnancy test and collection of menstrual cycle information (for females 
of child-bearing potential) 
− Modified Gastroparesis Cardinal Symptom Index (mGCSI) Part I 
− Modified PAGI-SYM (mPAGI-SYM) 
− Gastroparesis Treatment Benefit Survey (GTBS) 
• Study medication instruction and dispensation 
Collection of adverse event information will begin at the time the ICF is signed.  Subjects will 
be set up on phone diary and instructed to begin completing their diary daily (Section 10.1.1). 
 
20.2.11.2. COLE Visit 2-Visit 6 (COLE Day 28, Day 84, Day 140, Day 196, Day 280, ± 5 
days) 
On COLE Visit 2 through Visit 6, the following assessments will be performed to assess the 
subject’s continued eligibility:  
• Adverse Event query 
• Concomitant medication review 
• Urine pregnancy test (for females of child-bearing potential)  
• Semi-supine routine vital signs (body temperature, respiratory rate, blood pressure, 
and pulse)  
• ECG 
• Physical examination (PE) (excluding pelvic, rectal and breast examinations unless 
clinically indicated) 
• Clinical laboratory assessments (HbA1C, hematology, chemistry (including eCLcr; 
based on the Cockcroft-Gault equation), urinalysis, thyroid stimulating hormone 
(TSH), thyroxine (T4), and urine drug screen) 
• Since last visit C-SSRS 
• Diary review 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• Modified PAGI-SYM (mPAGI-SYM) 
• Patient Global Impression of Change (PGI-C) 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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• Clinical Global Impression of Severity (CGI-S) 
• Study medication collection and review 
• Study medication dispensation 
• Schedule Monthly Calls 
 
20.2.11.3. COLE Visit 7/End of Study/Early Termination (COLE Day 365, ± 7 days)  
• Adverse Event query 
• Concomitant medication review 
• Full PE (excluding pelvic, rectal and breast examinations unless clinically indicated) 
• Laboratory evaluations (HbA1C, hematology, chemistry (including eCLcr; based on 
the Cockcroft-Gault equation), urinalysis, thyroid stimulating hormone (TSH), 
thyroxine (T4), and urine drug screen) 
• Serum pregnancy test and collection of menstrual cycle information (for females of 
child-bearing potential)  
• ECG 
• Semi-supine routine vital signs (body temperature, respiratory rate, blood pressure, 
and pulse) and weight  
• Since last visit C-SSRS 
• Diary review 
• Modified Gastroparesis Cardinal Symptom Index (mGCSI) 
• Modified PAGI-SYM (mPAGI-SYM) 
• Patient Global Impression of Change (PGI-C) 
• Patient Assessment of Upper Gastrointestinal Disorder  Quality of Life (PAGI-QOL) 
• Clinical Global Impression of Severity (CGI-S) 
• Study medication collection and review  
• Record EOS 
 
20.2.11.4. Unscheduled Visits 
Unscheduled visits may be performed at any time at the discretion of the Investigator. 
 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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20.2.11.5. Monthly Calls to Patients (COLE Day 56, Day 112, Day 224, Day 252, Day 308, 
Day 336, ± 3 days) 
Members of the study team will call patients between visits to assess overall health and query 
for any adverse events or updates to their current medication.  An unscheduled visit will be 
performed if medically warranted  in the opinion of the Investigator. 
 
20.2.12. 
Efficacy Assessments 
The efficacy assessments should be conducted as specified in the Schedule of Evaluations for 
COLE (Table 9).  These assessments include: the Gastroparesis Core Symptom Daily Diary 
(GCSDD), Modified Gastroparesis Cardinal Symptom Index (mGCSI), Modified PAGI-SYM 
(mPAGI-SYM), Patient Global Impression of Change (PGI-C), and the Patient Assessment of 
Upper Gastrointestinal Disorders-QOL (PAGI-QOL) (see Section 10.1.1 for a description of the 
patient reported outcomes) and the Clinician Global Impression – Severity (CGI-S) (see 
Section 10  for complete descriptions of the assessments). 
20.2.13. 
Safety Assessments 
The safety assessments should be conducted as specified in the Schedule of Evaluations for COLE 
(Table 9).  These assessments include: the regular monitoring and recording of all adverse events 
and serious adverse events (SAEs); the regular monitoring of hematology, blood biochemistry and 
urinalysis values; the regular monitoring of vital signs; the regular monitoring of suicidal ideation 
and behavior, and the performance of physical examinations, and electrocardiograms.  
 
Refer to Section 11 for additional details relating to the collection of safety assessments and 
adverse event reporting. 
 
20.2.14. 
Statistical Methods 
Statistical analysis for the COLE phase will be based on data summaries, using similar layouts as 
for the randomization phase, and will be exploratory in nature (See Section 13 for further details). 
 
 
20.3. 
Laboratory Ranges Used to Identify Clinically Notable Abnormal 
Laboratory Values 
Criteria for identifying laboratory values as Potentially Clinically Notable Abnormalities are 
based on the Guidelines for the Division of Neuropharmacological Drug Products, US Food and 
Drug Administration (revised on April 2, 1987). 
 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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Variable 
Criterion Values 
 
Standard Units 
SI Units 
Chemistry 
 
 
SGOT 
 3 x Upper Limit Normal 
 
SGPT 
 3 x Upper Limit Normal 
 
Alkaline Phosphatase 
 3 x Upper Limit Normal 
  
LDH 
 3 x Upper Limit Normal 
 
BUN 
 30 mg/dL 
 10.7 M 
Creatinine 
 2.0 mg/dL 
 176.8 M 
Uric Acid                         Male 
 10.5 mg/dL 
 624.6 M 
                                       Female 
 8.5 mg/dL 
 505.6 M 
Bilirubin (Total) 
 2.0 mg/dL 
 34.2 M 
Hematology 
 
 
Hematocrit                      Male 
 37% 
 
                                       Female 
 32% 
 
Hemoglobin                    Male 
 11.5 g/dL 
 
                                       Female 
 9.5 g/dL 
 
Platelets 
 75,000/mm3 or  700,000/mm3 
 75 x 109/L or  700 x 109/L 
Leukocytes 
 2,800/mm3 or  16,000/mm3 
 2.8 x 109/L or  16 x 109/L 
Eosinophils 
 10% 
 
Neutrophils 
 15% 
 
Urinalysis 
 
 
Protein 
Increase of  2 units 
 
Glucose 
Increase of  2 units 
 
Casts 
Increase of  2 units 
 
 
20.4. 
Vital Signs Values 
Criteria for identifying vital signs values as Potentially Clinically Notable Abnormalities are based 
on the Guidelines for the Division of Neuropharmacological Drug Products, US Food and Drug 
Administration (revised on April 2, 1987). 
 
Variable 
 
 
 
Criteria 
 
 
 
 
 
 
Change Relative to Baseline 
Heart Rate  
 
 
≥ 120 bpm      
and an  
 
increased of ≥ 15 bpm 
 
 
 
 
 
 
≤ 50 bpm  
 
and a  
 
decrease of ≥ 15 bpm 


VP-VLY-686-2301                                                                              Vanda Pharmaceuticals Inc. 
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Systolic 
Blood Pressure 
 
≥ 180 mmHg      and an  
 
increase of ≥ 20 mmHg 
 
 
 
 
 
 
≤ 90 mmHg 
     and a  
 
decrease of ≥ 20 mmHg 
 
Diastolic 
Blood Pressure 
 
≥ 105 mmHg      and an   
 
increase of ≥ 15 mmHg 
 
 
 
 
 
 
≤ 50 mmHg 
     and a 
 
 
decrease of ≥ 15 mmHg 
 
Temperature  
 
≥ 38.3 oC        
and a  
 
change of ≥ 1.1 oC 
 
 
 
 
 
 
≥ 101 oF           
and a   
 
change of ≥ 2 oF         
         
Weight  
 
 
 
--  
 
 
 
 
 
 
 
change of ≥ 7% body weight