Clinical trial NCT04849559
Conditions: Healthy Volunteer
Keywords: tradipitant NK-1 antagonist neurokinin 1 receptor
Sponsor: Vanda Pharmaceuticals
Start date: 2021-02-01; Completion date: 2021-09-24
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the effects of tradipitant relative to placebo on satiation, gastric volume, gastric accommodation, and gastric emptying in healthy volunteers.

Detailed description:

Arms: arm 1: Oral Capsule arm 2: Oral Capsule
Interventions: intervention 1: Tradipitant intervention 2: Placebo
Intervention descriptions: intervention 1: Tradipitant Capsule intervention 2: Placebo Capsule

Protocol documents:
Prot_000.pdf: 
VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
Amendment No. 2 to the Clinical Study Protocol                                10 May 2021       
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CONFIDENTIAL 
 
 
TRADIPITANT  
AMENDMENT NO. 2 TO PROTOCOL VP-VLY-686-1301 
 
A SINGLE CENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
EFFECTS OF TRADIPITANT ON SATIATION, GASTRIC 
VOLUME, GASTRIC ACCOMODATION AND GASTRIC 
EMPTYING IN HEALTHY VOLUNTEERS  
 
Author: 
Michael Camilleri, M.D. 
Jesse L. Carlin, Ph.D  
Document Type:  
 
 
 
 
Clinical Study Protocol 
Sponsor:  
 
 
 
 
 
 
Vanda Pharmaceuticals Inc. 
 
 
 
 
 
 
 
 
 
 
2200 Pennsylvania Ave. NW 
 
 
 
 
 
 
 
 
 
 
Suite 300E 
 
 
 
 
 
 
 
 
 
 
Washington, DC 20037 
USA 
 
 
Principle Investigator:  
 
 
Michael Camilleri, M.D. 
Co Investigators:  
 
 
 
 
Dan Maselli M.D., Jessica Atieh M.D. 
Study Product:  
 
 
 
 
tradipitant (VLY-686) 
Protocol Number: 
 
 
 
 
VP-VLY-686-1301 
Study Phase:  
 
 
 
 
 
I 
IND Number: 
 
 
 
 
 
131545 
 
 
Date:  10 May, 2021 
Status: Final 
Number of Pages: 68 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
Amendment No. 2 to the Clinical Study Protocol                                10 May 2021       
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CONFIDENTIAL 
SIGNATURE PAGE FOR VANDA PHARMACEUTICALS INC. 
 
Amendment No. 2 to VP-VLY-686-1303
 
Approved by the following: 
 
Program Lead: 
 
  
 
Jesse L. Carlin, Ph.D.  
 Date 
 
Clinical Project Lead 
 
 
  
 
 
  
Medical Director: 
 
  
 
Christos Polymeropoulos, M.D. 
 Date 
 
Medical Director 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
Amendment No. 2 to the Clinical Study Protocol                                10 May 2021       
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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: VP-VLY-686-1301: A Single-Center, Placebo-Controlled, Double-Blind Study to 
Evaluate the Effects of Tradipitant on Satiation, Gastric Volume, Gastric Accommodation and Gastric 
Emptying in Healthy Volunteers 
Study center(s): Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo 
Clinic,  Rochester, MN  
Indication:  Healthy Volunteers 
Phase of development: I 
Number of subjects (planned):  Approximately 36 patients will be screened in order to fully complete 
the testing of 24 healthy subjects.  
Inclusion Criteria: 
1. Male and female subjects aged 18  65 years (inclusive); 
2. No medical problems or chronic diseases, specifically, no type 2 diabetes mellitus. 
3. 
35 kg/m2 (BMI = weight (kg)/ [height (m)]2);  
4. Subjects must agree to the following study restrictions:   
5. 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;  
6. 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;  
7. Ability and acceptance to provide written informed consent;  
8. Willing to participate in the pharmacogenomics sample collection; 
9. Willing and able to comply with all study requirements and restrictions 
10. Willing to not participate in any other interventional trial for the duration of their participation. 
Exclusion Criteria: 
11. Unable or unwilling to provide informed consent or to comply with study procedures. 
12. Unwilling to agree to provide pharmacogenomics sample
13. Diagnosis of gastrointestinal diseases. 
14. Structural or metabolic diseases that affect the GI system. 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
Amendment No. 2 to the Clinical Study Protocol                                10 May 2021       
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15. Unable to avoid the following over-the-counter medications 48 hours prior to the receipt 
of study medication and throughout the study: 
16. Medications that alter GI transit including laxatives, magnesium and aluminum 
containing antacids, prokinetics, erythromycin;  
17. Analgesic drugs including NSAIDs and COX-2 inhibitors 
NOTE:  Stable doses of thyroid replacement, estrogen replacement, low-dose aspirin for 
cardioprotection, and birth control are permissible.   
18. History of recent surgery (within 60 days of screening). 
19. Pregnant or nursing;  
20. History of intolerance and/or hypersensitivity to medications similar to tradipitant and its 
accompanying excipients; 
21. History (including family history) or current evidence of congenital long QT syndrome or 
known acquired QT interval prolongation (including QTcF > 450 in males or > 470 in females 
at screening); 
22. 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 visits, in the opinion of the investigator;  
23. Recent history (within six months of screening) of Alcohol Use Disorder or Substance Use 
Disorder which may include a positive drug screen at the Screening visit; 
24. Acute or chronic illness or history of illness, which in the opinion of the investigator could pose 
a threat or harm to the subject or obscure interpretation of laboratory test results or interpretation 
of study data such as frequent angina, Class III or IV congestive heart failure, any impairment of 
renal or hepatic function, poorly controlled diabetes, etc; 
25. Indication of impaired liver function (including values for AST, ALT, or bilirubin > 2 times the 
Upper Limit of Normal, unless isolated bilirubin > 2 
 
26. Has a creatinine level > 2x ULN; 
27. Anyone affiliated as a member of the investigative team or sponsor and/or anyone who may 
consent under duress;  
28. 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 from Mayo 
Research Pharmacy. Subjects will be randomized to one of two treatment arms to receive 85 
mg tradipitant BID or placebo. 
Duration of treatment:  Up to 9 days 
Objectives:  
Primary:  


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
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To evaluate the effects of tradipitant relative to placebo in healthy volunteers in the 
following: 
 Difference in fasting GV 
 Difference in postprandial GV and in accommodation volume (that is, postprandial 
minus fasting gastric volumes) 
 Difference in gastric emptying (T1/2, emptying at 2h and emptying at 4h) 
 Volume to fullness (sensation of usual postprandial fullness) and maximum feeling 
of fullness (MTV). 
 
Secondary: 
 Absolute postprandial gastric volume 
 Gastric volume (GV) ratio (postprandial/fasting GV) 
 
 Gastric emptying of solids at 2h 
 Gastric emptying of solids at 4h 
Intragastric meal distribution at time zero, (IMD0) following ingestion of test meal
 Maximum tolerated volume (MTV) during satiation test 
 Aggregate symptoms score 30 min after MTV on satiation test  
 Individual symptom scores (nausea, bloating, fullness, pain) on satiation test 
  
Overall Design: 
This is a randomized, double-blind, placebo-controlled, single center study during which 
healthy volunteers will be recruited, enrolled, and randomized to one of 2 treatment groups.  
Subjects meeting all inclusion/exclusion criteria will be randomized to either placebo or 
tradipitant, two 85mg tablet daily (b.i.d.) for 9 consecutive days. Subjects may be involved in 
study activity for up to five weeks from screening date to completion of all studies. The actual 
study related testing will be conducted on three days. 
 
Enrollment of subjects will continue until N=24 of those that have been randomized to study 
medication and have completed all study testing through Day 9.  Subjects who withdraw 
consent after being randomized will be included in an intent-to-treat analysis with missing data 
imputed based on data of completed subjects.  Subjects that withdraw from participation before 
receipt of medication will be replaced. Subjects who have started their assigned study 
medication, but do not complete all the study testing  through Day 9 will be replaced. 
Primary Endpoint:  
The primary objectives of this study are: 
 Comparison of fasting gastric volume induced by tradipitant vs. placebo studied by 
single photon emission computed tomography (SPECT) 
 Comparison of accommodation volume induced by tradipitant vs. placebo studied by 
SPECT 
 Comparison of volume to fullness (VTF,mL) on satiation test for tradipitant vs. 
placebo 
 Comparison of gastric emptying T1/2 of solids on scintigraphy for tradipitant vs. 
placebo 
 Comparison of gastric emptying values at 2 and 4 hours 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
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Criteria for evaluation: 
Efficacy:  
 Single photon emission computed tomography (SPECT) to calculate fasting gastric 
volume and postprandial gastric accommodation  
 Measurement of volume to fullness (mL) on satiation test  
 Gastric emptying by scintigraphy 
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:  
Sample size is based on the results of primary endpoints in the Mayo Clinic lab. Expected  
23.6% in the gastric accommodation volume and 29.2% in gastric emptying T1/2, based 
on the coefficients of variation observed from the Mayo Clinic laboratory in prior studies.  
 
 
 
 
 
 

SAP_001.pdf: 
VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
Amendment No. 2 to the Clinical Study Protocol                                10 May 2021       
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11. 
STATISTICS 
11.1. 
Sample Size and Accrual 
 
Sample size assessment is based on the results of primary endpoints in the Mayo Clinic lab [data 
compared to placebo is 23.6% in the gastric accommodation volume and 29.2% in gastric 
emptying T1/2, based on the coefficients of variation observed from the Mayo Clinic laboratory 
in prior studies, as shown in the table below. [23] [24]  
 
Table 7: 
Sample size and effect size estimates 
Response 
Mean 
SD 
Effect size detect-able,  
n=12/ group 
Gastric accommodation, 
mL  
507 
100 
119.7 
GE solids t1/2 min  
122 
29.8 
35.6 
 
It is anticipated that all primary and secondary endpoints will be normally distributed.   
-test to compare study parameters between the  
placebo and Tradipitant groups. Covariate analysis may be conducted using gender and BMI as 
covariates, since these may  significantly affect gastric functions such as satiation maximum 
tolerated volume. 
 
11.2. 
Statistical Methods and Analysis Plan 
This section describes the planned statistical analyses in general terms.   
 
11.2.1. 
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 (GE, NDT, GA) will be included in the per protocol analysis. Unless otherwise 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
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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. A per protocol analysis of 
efficacy will be conducted using data actually collected and without any imputed data . 
 
Categorical variables will be analyzed using the Cochran-Mantel-Haenszel (CMH) test blocking 
on sites, and 
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. 
 
11.2.2. 
Subject Populations for Analysis 
A subject will be defined as screened after the signature of the informed consent, regardless of the 
completion of all the screening procedures. 
A subject will be defined as eligible if he/she meets all the inclusion/exclusion criteria. Otherwise 
he/she will be defined as a screen failure.  
A subject will be defined as enrolled in the study if he/she is included into the evaluation phase of 
the study. 
An eligible but not enrolled subject will be defined as a reserve. 
 
The following analysis populations will be defined for this study: 
Per protocol: 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; 
Intent to Treat: 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. 
 
11.2.3. 
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. 
 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
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11.2.4. 
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. 
 
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 enrolling (Visit 1) and resolved 
(not on-going) as of Visit 1.  Current medical conditions, defined as an onset date on or after the 
date of enrolling (Visit 1) or an onset date prior to enrolling (Visit 1) and unresolved (on-going) 
as of Visit 1, 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. 
 
11.2.5. 
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 phase 
will be summarized by treatment groups. 
 
11.2.6. 
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. 
 
11.3. 
Efficacy Data Analysis
11.3.1. 
Primary Outcome and Methodology 
 
The primary objectives of this study are: 
 Comparison of fasting gastric volume induced by tradipitant vs. placebo studied by single 
photon emission computed tomography (SPECT) 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
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 Comparison of accommodation volume induced by tradipitant vs. placebo studied by 
SPECT 
 Comparison of volume to fullness (VTF, mL) on satiation test for tradipitant vs. placebo 
 Comparison of gastric emptying T1/2 of solids on scintigraphy for tradipitant vs. placebo 
 Comparison of gastric emptying at 2 and 4 hours 
  
11.3.2. 
Secondary Efficacy Analysis 
The secondary efficacy outcomes include: 
 Absolute postprandial gastric volume 
 Gastric volume (GV) ratio (postprandial/fasting GV) 
 
 Gastric emptying of solids at 2h 
 Gastric emptying of solids at 4h 
 Intragastric meal distribution at time zero, (IMD0) following ingestion of test meal 
 Maximum tolerated volume (MTV) during satiation test 
 Aggregate symptoms score 30 min after MTV on satiation test  
 Individual symptom scores (nausea, bloating, fullness, pain) on satiation test 
 
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. 
 
11.4. 
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. 
 
11.4.1. 
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, 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
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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.  
 
11.4.2. 
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 18). 
 
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. 
 
11.4.3. 
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.  
 


VP-VLY-686-1301                                                                              Vanda Pharmaceuticals Inc. 
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11.4.4. 
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. 
 
11.4.5. 
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. 
 
11.5. 
Subgroup Analysis 
The subgroup analysis (such as, gender, age, etiology, etc.) for efficacy variables and safety 
variables may be conducted as described in the SAP. 
 
11.6. 
Interim Analysis
No interim analyses are planned. 
 
11.7. 
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.