Conditions: Gastroparesis
Keywords: gastroparesis early satiety stomach buspirone 5-HT 1a receptor agonist
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
This study evaluates whether the study medication, buspirone, an antianxiety drug, improves the symptoms of gastroparesis in patients with gastroparesis symptoms and at least moderately severe symptoms of fullness and/or inability to eat a full meal. Half the patients will receive buspirone and half the patients will receive a placebo.

Detailed description:
This is a multi-center, randomized, double-masked, placebo-controlled, parallel treatment groups phase 2 trial to determine the effect of buspirone, a 5-hydroxytryptamine (5-HT) 1a receptor agonist, on early satiety and postprandial fullness in participants with symptoms of gastroparesis and with at least moderately severe symptoms of early satiety and/or postprandial fullness. After enrollment, participants aged 18-75 years will be treated with buspirone (10 mg three times per day) or a matching placebo for 4 weeks, followed by a 2-week post-treatment washout period. The primary outcome for the study is 4-week change (week 4 minus baseline) in the 4-item postprandial fullness/early satiety subscore (higher scores indicate worse symptoms) from the Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM) Gastroparesis Cardinal Symptom Index (GCSI). We hypothesize that buspirone treatment will improve symptoms of postprandial fullness/early satiety compared to treatment with placebo, as indicated by a lower (smaller, more negative) 4-week change in the postprandial fullness/early satiety subscore in the buspirone arm compared to the placebo arm; change for a participant will be calculated as subscore at 4-weeks minus subscore at baseline.

Arms:
arm 1: Buspirone HCl 10 mg capsule orally three times daily, 30 minutes before each meal, for 4-weeks arm 2: Placebo capsule orally three times daily, 30 minutes before each meal, for 4-weeks; manufactured to look identical to buspirone capsule

Interventions: intervention 1: Buspirone intervention 2: Placebo
Intervention descriptions: intervention 1: Buspirone tablet intervention 2: "Sugar" pill manufactured to mimic buspirone 10 mg tablet

Protocol document:
Prot_SAP_000.pdf: 
Buspirone for Early Satiety and Symptoms of Gastroparesis:  
A Multicenter, Randomized, Placebo-Controlled, Double-Masked 
Trial (BESST)  
 
Protocol Number: 10 
 
 
National Clinical Trial (NCT) Identified Number:  NCT03587142 
Principal Investigators: Henry P. Parkman, MD and Pankaj Jay Pasricha, MD 
IND Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)   
Funded by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)   
Version Number:  1.3 
13 January 2022 
 
Summary of Changes from Previous Versions, v1.2 (11 Sep 2020): 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
1.1 Synopsis 
Changed Total Study Duration to 137 weeks (31.5 months) 
Changed Recruitment to 131 weeks (30 months) 
Changed: Expected enrollment rate to .6 participants per month per 
clinical center (18 participants each at 6 centers) 
Recruitment has been slower 
than expected. This will extend 
through February 28, 2022. 
5.5.1 Recruitment 
Changed recruitment time to 30 months 
Recruitment has been slower 
than expected. This will extend 
through February 28, 2022. 
10.1.5 
Added new Medical Monitor 
William Hasler, MD 
 Mayo Clinic Arizona 
13400 E. Shea Blvd.,  
Scottsdale, AZ 85259 
480-347-3538 
hasler.william@mayo.edu  
Added new Medical Monitor 
 
 
 


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BESST Protocol Version 13 
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis ............................................................................................................................................... 1 
1.2 
Schema ................................................................................................................................................ 6 
1.3 
Schedule of Activities (SOA) ............................................................................................................. 7 
2 
INTRODUCTION ........................................................................................................................................... 8 
2.1 
Study Rationale ................................................................................................................................... 8 
2.2 
Background .......................................................................................................................................... 9 
2.3 
Risk/Benefit Assessment ................................................................................................................. 11 
2.3.1 
Known Potential Risks .................................................................................................. 11 
2.3.2 
Known Potential Benefits ............................................................................................. 13 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 13 
3 
OBJECTIVES AND OUTCOMES .............................................................................................................. 14 
4 
STUDY DESIGN .......................................................................................................................................... 16 
4.1 
Overall Design ................................................................................................................................... 16 
4.2 
Scientific Rationale for Study Design ............................................................................................. 16 
4.3 
Justification for Dose ........................................................................................................................ 17 
4.4 
End of Study Definition ..................................................................................................................... 17 
5 
STUDY POPULATION ................................................................................................................................ 18 
5.1 
Inclusion Criteria ............................................................................................................................... 18 
5.2 
Exclusion Criteria .............................................................................................................................. 18 
5.3 
Lifestyle Considerations ................................................................................................................... 18 
5.3.1 
Standard treatment recommendations ....................................................................... 19 
5.4 
Screen Failures ................................................................................................................................. 19 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 19 
5.5.1 
Recruitment .................................................................................................................... 19 
6 
STUDY INTERVENTION ............................................................................................................................ 20 
6.1 
Study Intervention(s) Administration .............................................................................................. 20 
6.1.1 
Study Intervention Description From FDA Package INsert ..................................... 20 
6.1.2 
Dosing and Administration ........................................................................................... 21 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................... 22 
6.2.1 
Acquisition and accountability ..................................................................................... 22 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................... 22 
6.2.3 
Product Storage and Stability ...................................................................................... 22 
6.2.4 
Preparation ..................................................................................................................... 22 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 23 
6.4 
Study Intervention Compliance ....................................................................................................... 23 
6.5 
Concomitant Therapy ....................................................................................................................... 24 
6.5.1 
Rescue Medicine ........................................................................................................... 24 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 25 
7.1 
Discontinuation of Study Intervention ............................................................................................ 25 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................................. 25 
7.3 
Lost to Follow-Up .............................................................................................................................. 26 


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STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 26 
8.1 
Efficacy Assessments ...................................................................................................................... 26 
8.1.1 
Visit schedule overview ................................................................................................ 26 
8.1.2 
Screening and baseline data collection ..................................................................... 26 
8.1.3 
Randomization visit ....................................................................................................... 27 
8.1.4 
Follow-up visits .............................................................................................................. 28 
8.1.5 
Standardized questionnaires ....................................................................................... 28 
8.1.6 
Study Procedures .......................................................................................................... 30 
8.2 
Safety and Other Assessments ...................................................................................................... 32 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 33 
8.3.1 
Definition of Adverse Events (AE) .............................................................................. 33 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................. 33 
8.3.3 
Classification of an Adverse Event ............................................................................. 34 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 35 
8.3.5 
Adverse Event Reporting ............................................................................................. 36 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 36 
8.3.7 
Reporting Events to Participants ................................................................................. 37 
8.3.8 
Events of Special Interest ............................................................................................ 37 
8.3.9 
Reporting of Pregnancy ................................................................................................ 37 
8.4 
Unanticipated Problems ................................................................................................................... 37 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................ 37 
8.4.2 
Unanticipated Problem Reporting ............................................................................... 38 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 38 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 38 
9.1 
Statistical Hypotheses ...................................................................................................................... 38 
9.2 
Sample Size Determination ............................................................................................................. 39 
9.3 
Populations for Analyses ................................................................................................................. 40 
9.4 
Statistical Analyses ........................................................................................................................... 40 
9.4.1 
General Approach ......................................................................................................... 40 
9.4.2 
Analysis of the Primary Efficacy OUTCOME(s) ........................................................ 40 
9.4.3 
Analysis of the Secondary OUTCOME(s) ................................................................. 41 
9.4.4 
Safety Analyses ............................................................................................................. 42 
9.4.5 
Baseline Descriptive Statistics .................................................................................... 42 
9.4.6 
Planned Interim Analyses ............................................................................................ 43 
9.4.7 
Sub-Group Analyses ..................................................................................................... 43 
9.4.8 
Tabulation of Individual participant Data .................................................................... 43 
9.4.9 
Exploratory Analyses .................................................................................................... 43 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 44 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 44 
10.1.1 
Informed Consent Process .......................................................................................... 44 
10.1.2 
Study Discontinuation and Closure ............................................................................ 45 
10.1.3 
Confidentiality and Privacy ........................................................................................... 45 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 46 
10.1.5 
Key Roles and Study Governance .............................................................................. 47 
10.1.6 
Safety Oversight: Data and Safety MOnitoring BOard ............................................ 47 
10.1.7 
Clinical Monitoring ......................................................................................................... 48 
10.1.8 
Quality Assurance and Quality Control ...................................................................... 48 
10.1.9 
Data Handling and Record Keeping ........................................................................... 49 


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10.1.10 
Protocol Deviations ....................................................................................................... 49 
10.1.11 
Publication and Data Sharing Policy .......................................................................... 50 
10.1.12 
Conflict of Interest Policy .............................................................................................. 50 
10.2 
Additional Considerations ................................................................................................................ 50 
10.3 
Abbreviations ..................................................................................................................................... 51 
10.4 
Protocol Amendment History........................................................................................................... 53 
11 
REFERENCES ............................................................................................................................................. 54 
12 
APPENDIX .................................................................................................................................................... 56 
12.1 
Participating Centers ........................................................................................................................ 56 
12.2 
Blood collection schedule (amounts in mL) .................................................................................. 58 
 


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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with the International Conference on Harmonisation Guideline for Good 
Clinical Practice (ICH GCP), the United States (US) Code of Federal Regulations (CFR) applicable to clinical studies, and 
the terms and conditions of the award from the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK). The Principal Investigators will assure that no deviation from or changes to the protocol take place without 
prior agreement from the Investigational New Drug (IND) sponsor, prior agreement from the funding agency, and 
documented approval from the Institutional Review Board (IRB) serving as the IRB for the trial, except where necessary 
to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and participant materials will be submitted to the IRB 
for review and approval prior to use. Any amendment to the protocol will first require review and approval by the 
NIDDK, then by the IRB before the changes are implemented. All changes to the consent form will be approved prior to 
implementation; a determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent using a previously approved consent form. Any protocol amendments will be sent 
to the FDA. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Buspirone for Early Satiety and Symptoms of Gastroparesis: A 
Multicenter, Randomized, Placebo-Controlled, Double-masked Trial 
(BESST). 
Study Description: 
 
This is a multi-center, randomized, double-masked, placebo-controlled, 
parallel treatment groups phase 2 trial to determine whether buspirone, a 
5-HT 1a receptor agonist, can improve early satiety and postprandial 
fullness in participants with symptoms of gastroparesis and with at least 
moderately severe symptoms of early satiety and/or postprandial fullness. 
After enrollment, participants aged 18-85 years will be treated with 
buspirone (10 mg three times per day) or a matching placebo for 4 weeks, 
followed by a 2-week post-treatment washout period. The primary 
outcome for the study is the 4-week change (week 4 minus baseline) in the 
4-item postprandial fullness/early satiety subscore (higher scores indicate 
worse symptoms) from the Patient Assessment of Gastrointestinal 
Disorders Symptom Severity Index (PAGI-SYM) questionnaire. We 
hypothesize that 10 mg t.i.d. buspirone treatment will reduce mean 
postprandial fullness/early satiety symptom severity subscores over 4-
weeks compared to treatment with placebo. 
 
Objectives: 
 
Primary Objective: To determine whether 4 weeks of treatment with 
buspirone, a 5-HT 1a receptor agonist, compared to treatment with 
placebo improves symptoms of postprandial fullness and early satiety as 
indicated by the change in the PAGI-SYM questionnaire’s postprandial 
fullness/early satiety subscore (score at 4-weeks minus score at baseline). 


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Secondary Objectives:  To determine whether 4 weeks of treatment with 
buspirone compared to treatment with placebo improves overall and 
other gastroparesis symptoms, and other participant clinical 
characteristics (gastric retention, anxiety, depression, quality of life) and to 
determine the safety and tolerability of buspirone in adult participants 
with gastroparesis symptoms and at least moderate symptoms of 
postprandial fullness and early satiety. 
 
Outcomes: 
Primary Outcome:  The primary outcome is the change in the postprandial 
fullness/early satiety subscore from baseline to 4 weeks; this subscore is 
calculated by averaging the scores for 4 PAGI-SYM questionnaire items: 
stomach fullness, inability to finish a normal-sized meal, feeling excessively 
full after meals, and loss of appetite. 
 
Secondary Outcomes: Changes over 4-weeks (week 4 minus baseline) in: 
1. Gastroparesis Cardinal Symptom Index (GCSI) total score; 
GCSI is comprised of the first 9-items of the PAGI-SYM 
questionnaire. 
2. Four PAGI-SYM questionnaire subscores: nausea/vomiting (3 
items: nausea, retching, vomiting), bloating (2 items: bloating, 
stomach visibly larger), upper abdominal pain (2 items: upper 
abdominal pain, upper abdominal discomfort), GERD (7 items: 
heartburn during the day, heartburn when lying down, feeling of 
discomfort inside chest during the day, feeling of discomfort 
inside chest during sleep, regurgitation or reflux during the day, 
regurgitation when lying down, bitter, acid or sour taste in 
mouth) 
3. Eight single-item PAGI-SYM questionnaire symptom severity 
scores: nausea, vomiting, stomach fullness, inability to finish a 
normal-sized meal, feeling excessively full after meals, loss of 
appetite, bloating, upper abdominal pain 
4. Gastrointestinal Symptom Rating Scale (GSRS) total score 
5. Clinical Patient Grading Assessment Scale (CPGAS) score 
6. Patient Assessment of Upper Gastrointestinal Disorders-Quality of 
Life (PAGI-QOL) questionnaire total score 
7. Hospital Anxiety and Depression Scale (HADS) questionnaire 
anxiety score and depression score 
8. Patient Health Questionnaire 15 Somatic Symptom Severity Scale 
(PHQ-15) questionnaire total somatization score 
9. SF-36v2 Quality of Life questionnaire Physical Component Score 
and Mental Component Score 
10. Percent gastric emptying retention at 2 and 4-hours. 
11. Anthropometric measurements (Body Mass Index (BMI)/ 
weight, waist circumference) (safety) 
12. ECG measures (safety) 
13. Laboratory measures (ALT, creatinine, glucose) (safety) 
14. Frequency of side effects and adverse events, as well as severity 
of adverse events. (safety and tolerability) 
 


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Exploratory/Ancillary Outcomes:  These outcomes either use novel 
techniques (items 1, 2, and 3) or are outcomes that have lower statistical 
power yet might provide insight into paths for future research (items 4,5). 
The outcome measures are changes over 4 weeks (week 4 minus baseline) 
in: 
1. Intragastric meal distribution (IMD) as a measure of 
Fundic Accommodation (FA) using digital analyses of 
the GES test images 
2. Gastric dysrhythmia and volume of water consumed 
until full measured with electrogastrogram (EGG) 
with water load satiety test 
3. GCSI-DD total score and single-item scores on the ANMS 
GCSI-DD questionnaire: nausea, postprandial fullness, 
early satiety, upper abdominal pain, episodes of vomiting, 
episodes of retching, overall symptom severity; this 
instrument is completed daily and the score for an item at 
a time point is the average score for the item over the 
past 7 days, and change in the score from baseline is the 
average for the last 7 days minus the average for the 7- 
days of baseline completion 
4. 12 symptom severity items measured on the PAGI-SYM 
questionnaire and not included in secondary outcomes 
item 3, including retching, lower abdominal pain, lower 
abdominal discomfort, constipation, and diarrhea 
5. 5 subscores of the Gastrointestinal Symptom Rating Scale 
(GSRS) questionnaire 
 
Study Population: 
The study population will be 108 adult men and women aged 18-85 years, 
located in the United States, who have at least moderately severe 
postprandial fullness and/or early satiety and other symptoms of 
gastroparesis.  
 
Phase: 
Phase 2 
Description of 
Sites/Facilities Enrolling 
Participants: 
Participants will be recruited from the six clinical sites of the GpCRC 
located throughout the United States. (see 12.1 for sites) 
 
Description of Study 
Intervention: 
• 
Group 1: Buspirone 10 mg capsule three times daily, 30 minutes 
before each meal, for 4 weeks 
• 
Group 2: Matching oral placebo capsule three times daily, 30 minutes 
before each meal, for 4 weeks 
 
Total Study Duration: 
137 weeks (31.5 months) 
• 
Recruitment: 131 weeks (30 months) 
• 
Participant follow-up: 6 weeks 
• 
Expected enrollment rate: ~1 (.6) participant per month per 
clinical center (18 participants each at 6 centers) 
 


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Participant Duration: 
Up to 14 weeks 
• 
Up to 8 weeks of screening prior to randomization 
• 
4 weeks of treatment starting at randomization 
• 
2 weeks' post-treatment period 
 
Inclusion Criteria: 
 
 
• 
Age 18 to 85 years of age at the initial screening interview 
• 
Symptoms compatible with gastroparesis or other functional 
gastric disorder for at least 3 months (does not have to be 
contiguous) prior to the initial screening interview 
• 
Diagnosis of either diabetic or idiopathic gastroparesis 
• 
Delayed or normal gastric emptying retention on screening 4-hour 
Gastric Emptying Scintigraphy test 
• 
Symptoms of gastroparesis measured by the 9-item PAGI-SYM 
Gastroparesis Cardinal Symptom Index (GCSI) total score > 2.0 at 
enrollment 
• 
Symptomatic with postprandial fullness/early satiety severity 
at enrollment using the PAGI-SYM questionnaire postprandial 
fullness/early satiety subscore ≥ 3 
• 
Upper endoscopy or upper GI series without ulcers or mass 
lesions in the 2 years prior to enrollment 
Exclusion Criteria: 
 
 
• 
Post-surgical gastroparesis, including prior pyloromyotomy, pyloric 
resection, vagotomy, bariatric surgery, or post-Nissen fundoplication 
• 
Another active disorder that could explain symptoms in the 
opinion of the investigator 
• 
Concurrent use of opiate narcotic analgesics more than 3 days per 
week 
• 
Significant hepatic injury as defined by alanine aminotransferase (ALT) 
elevation of greater than 2xULN or a Child-Pugh score of 10 or greater 
• 
History of significant cardiac disorders (prior heart attack, prior 
stroke, unstable angina) or significant cardiac arrhythmias or 
ECG abnormalities defined as history of, or current, arrhythmias 
including ventricular tachycardia, ventricular fibrillation and 
Torsade des Pointes and/or prolonged QTc on ECG (>450 msec 
for men and >470 for women) 
• 
History of chronic kidney disease or on hemodialysis or 
peritoneal dialysis 
• 
Impaired renal function as defined by estimated glomerular filtration 
rate (eGFR) < 60 ml/min/1.732 using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) calculator 
• 
Uncontrolled diabetes defined as HbA1c (%) of 10% or more within 60 
days of enrollment 
• 
Allergy to buspirone 
• 
Concurrent or prior use (within 30 days) of monoamine oxidase (MAO) 
inhibitors 
• 
Concurrent or prior use (within 30 days) of benzodiazepines 


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• 
Concurrent or prior use (within 30 days) of buspirone, warfarin, 
haloperidol, and drugs to treat seizures (e.g., phenytoin and 
carbamazepine) 
• 
For women of child-bearing potential, either pregnancy, planned 
pregnancy, unwillingness to use effective birth control during the trial 
or, breast feeding 
• 
Any other condition, which in the opinion of the investigator would 
impede compliance or hinder completion of the study 
• 
Failure to give informed consent 


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1.2 
SCHEMA 
 
Screening:  
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
↓ 
 
 
Visit 1  
Day 0 
 
 
 
 
↓ 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
↓ 
 
     
  
↓ 
 
Visit 2 
Week 2  
 
 
 
 
 
 
 
 
↓ 
 
Visit 3 
Week 4  
 
 
 
 
 
 
 
 
 
↓ 
 
Visit 4 
Week 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening and Baseline: Obtain informed consent. Screen potential 
participants for eligibility using inclusion/exclusion criteria. Obtain baseline 
assessments: physical exam, anthropometrics, medical history, gastroparesis 
questionnaires, GES, EGG with water load test. Draw blood for plasma, serum, 
metabolic panel, TSH, and banking. Pregnancy test for females.  
(See 1.3 Schedule of Activities) 
Follow-up (primary outcomes): Repeat baseline assessments. Record adverse 
events, symptoms, and medication side effects since last visit. Repeat pregnancy 
test.  
(See 1.3 Schedule of Activities) 
Arm 2 = 
PLACEBO 
(N=54) 
Arm 1 = 
BUSPIRONE 
(N=54) 
Follow-up assessments of study objectives and adverse effects, physical exam, 
symptom side effects, pregnancy test, questionnaires. 
(See 1.3 Schedule of Activities) 
Follow-up (washout/post treatment): Repeat baseline assessments. Record 
adverse events and symptoms since last visit. 
(See 1.3 Schedule of Activities) 
 
Randomize and Dispense buspirone (Arm 1) or placebo (Arm 2) 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Screening 
visits 
Follow-up visits- 
Weeks from Randomization 
Assessment/Procedure 
RZ 
F02 
F04* 
F06 
Consent, HIPAA authorization, demographics 
X 
. 
. 
. 
. 
Baseline medical history 
X 
. 
. 
. 
. 
Follow-up medical history 
. 
. 
X 
X 
X 
Side effects survey 
X 
. 
X 
X 
X 
Review for adverse effects 
. 
. 
X 
X 
X 
Review for concomitant medications 
X 
X 
X 
X 
X 
Hospital anxiety and depression (HADS) 
X 
. 
X 
X 
X 
SF-36v2 Quality of life 
X 
. 
. 
X 
    . 
PAGI-SYM questionnaire (includes the GCSI) 
X 
. 
X 
X 
X 
Gastrointestinal Symptom Rating Scale (GSRS) 
X 
. 
. 
X 
X 
PAGI-QOL questionnaire 
X 
. 
. 
X 
X 
Patient Health Questionnaire (PHQ-15) 
X 
. 
. 
X 
    . 
Clinical Patient Grading Assessment Scale (CPGAS) 
 
. 
X 
X 
X 
Detailed (D) or focused (F) physical exam 
D 
F 
F 
D 
D 
Gastric emptying Scintigraphy (GES) test 
X 
. 
. 
X 
. 
Electrogastrogram (EGG) with water load test* 
X 
. 
. 
X 
. 
Provide supplies of GCSI-DD 
X 
X 
X 
X 
. 
Collection of participant’s completed GCSI-DD 
. 
X 
X 
X 
X 
Standard of care materials provided 
. 
X 
. 
. 
. 
Eligibility confirmation 
X 
X 
. 
. 
. 
Study drug dispensing 
. 
X 
. 
. 
. 
Review of study drug adherence 
. 
. 
X 
X 
. 
Labs: 
Complete blood count (CBC) 
X 
. 
. 
X 
X 
Comprehensive metabolic panel (CMP) 
X 
. 
. 
X 
X 
Thyroid stimulating hormone (TSH) 
X 
. 
. 
. 
. 
Fasting HbA1c 
X 
. 
. 
. 
. 
Pregnancy test 
X 
X 
X 
X 
. 
Banking: Fasting serum and plasma 
X 
. 
. 
X 
X 
Complete Case Report Forms (CRFs) 
X 
X 
X 
X 
X 
Closeout form 
X 
Detailed physical exam (D): anthropometric assessments (body weight [kg], body height [m], waist circumference [cm], 
and hip circumference [cm]); vital signs (temperature, heart rate, respiratory rate, blood pressure), organ systems chest, 
lungs, heart, abdomen, liver and spleen, nervous), resting electrocardiogram (ECG) 
Focused physical exam (F): anthropometric assessments (body weight [kg], body height [m], waist circumference 
[cm], and hip circumference [cm]); vital signs (temperature, heart rate, respiratory rate, blood pressure)  
Complete blood count (CBC): concentration of white blood cells (WBC), red blood cells, hemoglobin, hematocrit, 
platelet count 
Comprehensive metabolic panel (CMP): glucose, calcium, sodium, potassium, CO2 (carbon dioxide/bicarbonate), chloride, 
blood urea nitrogen (BUN), creatinine, total protein, albumin, total bilirubin, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT) 
Thyroid Stimulating Hormone test (TSH) 
*The EGG with water load test is scheduled for a separate day than the GES testing at Screening and F04 week visits. 
 
 


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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Gastroparesis is a chronic symptomatic disorder associated with delayed gastric emptying [1].  Gastroparesis 
predominantly affects young women (females outnumber males by a ratio of 4:1, the average age is 34). The 
symptomatic profile of gastroparesis includes nausea (90% of patients), vomiting (>80%), bloating (75%), early 
satiety (60%), and abdominal pain (approximately 50%) [2]. Symptoms in individual patients can vary in both their 
combination and their severity. Because of its chronic and often intractable nature, the disorder has a tremendous 
impact on both patients and society. 
 
Gastroparesis remains difficult to treat, in large part because of the lack of knowledge of the underlying 
pathophysiology. Several factors in particular have impeded progress in this field, including the paucity of patients 
seen by any one center, the absence of uniform diagnostic criteria, and the lack of generally available and reliable 
methods for physiological testing. Given the complexity of the disorder and its profound degree of morbidity, an 
important need exists to appropriately study new treatments for patients. 
 
A variety of agents have been used for the treatment of gastroparesis [1,3]. These include classic agents such as 
prokinetic metoclopramide, cisapride (restricted use) and domperidone (not available in the U.S.). The track 
record of these drugs is mixed at best, a problem compounded by the paucity of high quality trials. A meta-
analysis has suggested that in double-blind, controlled studies, cisapride produced a mean improvement in 
symptom score of only 8%, whereas metoclopramide produced a mean improvement of 36%. Also, improvement 
in symptoms generally does not correlate well with changes in gastric emptying. This is important as it reinforces 
the concept that symptoms are not necessarily being driven by the gastric emptying abnormalities and redirects 
attention to other aspects of gastric dysmotility and to central mechanisms for symptoms. There is, therefore, a 
need for new and innovative approaches to evaluation and treatment of symptoms of gastroparesis. 
 
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established the Gastroparesis 
Clinical Research Consortium (GpCRC) in 2006 to help address unmet research needs in this condition. The mission 
of the GpCRC is to improve understanding of the pathogenesis and natural history of gastroparesis of all etiologies 
and to advance the diagnosis and therapies of patients affected. The overall objectives of the GpCRC are to 
conduct multicenter observational studies and randomized, controlled treatment trials on well-characterized 
patients with gastroparesis. The GpCRC is a cooperative network of six clinical sites and one Scientific Data 
Research Center (SDRC). The individual clinical centers participate in a cooperative and interactive manner with 
one another and with the SDRC in all aspects of the GpCRC. 
 
In a substantial number of patients who present with symptoms suggestive of gastroparesis (e.g., chronic nausea, 
vomiting, early satiety, postprandial fullness), gastric emptying tests are normal. Although the pathogenesis of 
symptoms in these patients is not known, it is presumed that most have some form of gastric dysfunction. Further, 
they appear to have a demographic and clinical profile that is nearly indistinguishable from classical gastroparesis 
and their treatment remains just as challenging.  The GpCRC uses the term Chronic Unexplained Nausea and 
Vomiting (CUNV) to describe this group of patients. Both groups of patients will be eligible for the GpCRC BESST. 
 
 


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2.2 
BACKGROUND  
 
Normally with food ingestion, the proximal 
stomach relaxes, with an increase in volume, 
allowing the proximal stomach to accommodate 
the ingested meal [4,5]. This is followed by 
progressively tonic contraction to deliver food into 
the distal stomach. Within the antrum, regular 
peristaltic contractions grind down solid food to 
smaller particles that can be passed through the 
pyloric sphincter into the small intestine for 
absorption. This is illustrated in the figure on the 
right [6]. 
 
 
Patients with gastroparesis have symptoms of early satiety, postprandial fullness, nausea, vomiting, and/or 
abdominal pain. It is now better appreciated that symptoms of gastroparesis are not well correlated with current 
standardized gastric emptying results which assess only total gastric emptying [7]. As noted above, some patients 
have symptoms similar to gastroparesis but normal gastric emptying, an entity that the GpCRC has called CUNV 
(defined above) [8]. For this reason, the successful GpCRC APRON trial of aprepitant vs. placebo enrolled patients 
with nausea and vomiting, whether with delayed or normal emptying [9]. 
 
Impaired gastric accommodation to a meal may also cause postprandial symptoms [10]. With impaired 
accommodation, there is increased pressure in the upper stomach which compromises the ability of the upper 
stomach to act as a reservoir for ingested food, resulting in rapid transit of food into the distal stomach. Impaired 
accommodation has been shown to be associated with early satiety and weight loss in both functional dyspepsia 
[11] and idiopathic gastroparesis [12]. Accommodation can be assessed with barostat, gastric mucosal labeling with 
single photon emission computed tomography (SPECT) imaging, and magnetic resonance imaging. Although much 
has been learned with these technologies, they are costly and time consuming and not used routinely in clinical 
evaluation of patients. Gastric emptying scintigraphy (GES) measures overall gastric retention of the ingested meal 
over time; it can also assess, in the same study, intragastric meal distribution (IMD) [13]. With normal fundic 
accommodation (FA), the food initially resides in the proximal portion of the stomach, whereas with impaired 
accommodation, the food is quickly transferred to the antrum [12]. Including assessment of intragastric meal 
distribution as part of a standard GES study will permit improvement in the assessment of the relationship between 
symptoms of gastroparesis with abnormal gastric motility. This additional information may lead to therapy directed 
to improve gastric accommodation. 
 
Use of GES to assess proximal gastric accommodation was originally suggested in observational studies by Troncon, 
et al [12]. Using scintigraphy in patients with functional dyspepsia Piessevaux, Tack et al quantitated the ratio of the 
proximal gastric counts to the distal gastric counts [14]. Forty-five percent of patients had distal redistribution of the 
solid phase of the meal. Early satiety was associated with early distal redistribution, suggesting impaired fundic 
accommodation. 
 
In the GpCRC BESST, images from GES will be analyzed for intragastric meal distribution (IMD) as an assessment 
of transit through the stomach and fundic accommodation. We have previously described proximal retention in 
GERD, distal retention in functional dyspepsia, and global retention in gastroparesis [15]. A recent preliminary 
study performed by us [16] showed that impaired gastric accommodation can be evaluated visually using current 
standardized solid-meal GES images. A simple visual assessment of normal gastric accommodation defined as 


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visualization of the majority of gastric activity (e.g. >50%) being present in the upper portion of the stomach in 
the first set of post-meal ingestion (t=0 minutes) images was used. The upper stomach was defined as the portion 
of the stomach that extends from the fundus to the incisura. Overall, impaired gastric accommodation was 
significantly associated with the severity of early satiety and stomach fullness. Impaired gastric accommodation 
in patients with normal GES was associated with early satiety, whereas impaired gastric accommodation in 
patients with delayed gastric emptying was associated with stomach fullness and postprandial fullness. Thus, this 
study showed that routine visual assessment of gastric accommodation as a part of a GES study may allow for 
better correlation of symptoms to abnormalities of gastric motility. 
 
GpCRC investigators have been assessing regional gastric transit in the GES studies of the patients in the 
Gastroparesis Registry 2. We developed a semi-automated analysis of regional intragastric meal distribution 
during GES. The scintigraphic images were read using a GPCRC-developed application written for MATLAB 
software, which has a freely available runtime environment. We designed the application to construct the 
longitudinal axis of the stomach and subdivide the stomach into two (proximal, distal) regions of interest, 
allowing assessment of the meal distribution during the test. The amount in the proximal region of interest 
provides a measure of fundic accommodation (FA). From our preliminary data, 8 patients with visually impaired 
gastric accommodation had less percent radioactivity in the proximal stomach at time 0 (55.7±9.1%) than the 16 
patients with normal accommodation (83.7±7.7%) and 20 normal subjects (82.6±9.6%). Examples and figure 
below:  
 
Normal intragastric meal 
Rapid proximal 
gastric distribution at time 0. 
transit 
(normal accommodation) 
(impaired accommodation) 
 
 
We have thus achieved the first really semi-automated computer approach to analyzing GES images.  This unique 
analysis offers additional promise to more fully automate analysis of GES. Our studies have shown that fundic 
accommodation can be assessed visually during routine GES with moderate pairwise agreement and high panel 
consistency among nuclear medicine physicians using the semi-automated software quantified IMD with an 
optimum cutoff of IMD<0.568 to define abnormal IMD/impaired FA [17].  Abnormal IMD was significantly 
associated with early satiety, loss of weight, and low BMI and was seen predominantly in nondiabetic patients. 
Assessment of fundic accommodation during GES is associated with several important patient clinical findings 
and symptoms. This approach will be used in this GpCRC BESST trial to help understand the mechanism of action 
of buspirone. 
 
In addition, as a prelude to BESST, we assessed our patients in Gastroparesis Registry 2 (GpR 2), for the relationship 
of early satiety to patient characteristics [18]. We specifically wanted to assess relationships of early satiety with 
etiology of gastroparesis, quality of life, body weight, gastric emptying, and water load testing. 165 patients with 
gastroparesis (111 IG, 54 DG) were assessed. Early satiety was severe or very severe in 83 of 165 (50%) patients. 
Severity scores for early satiety were similar between idiopathic and diabetic gastroparesis. Increasing severity of 
early satiety was associated with increasing gastroparesis severity (p=0.0008), decreasing BMI (p=0.006), decreased 
quality of life from PAGI-QOL (p=0.06) and SF-36v2 physical health summary score (p=0.05). Increasing severity of 
early satiety was associated with increasing gastric retention of a solid meal at 4 hours (p=0.03) and decrease in 


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volume consumed during the water load test (p=0.02). Thus, early satiety is a common symptom in both diabetic and 
idiopathic gastroparesis. Early satiety severity is associated with measures of gastroparesis severity, body weight, 
quality of life, gastric emptying, and water load testing. These relationships make early satiety an important 
symptom characterizing gastroparesis. 
 
In BESST, we will investigate an agent that improves fundic accommodation and determine its impact on 
improving symptoms, specifically early satiety and postprandial fullness.  Buspirone is a 5-HT 1 receptor agonist 
that is approved for the treatment of anxiety. It is an anxiolytic psychotropic drug of the azapirone chemical class, 
used primarily to treat generalized anxiety disorder. Unlike most drugs predominantly used to treat anxiety, 
buspirone's pharmacology is not related to benzodiazepines or barbiturates, and so it does not carry the risk of 
physical dependence and withdrawal symptoms for which those drug classes are known.  
 
The proximal gastric fundus tone is mediated by a balance of excitatory cholinergic and inhibitory non-
adrenergic, none-cholinergic (NANC) neural input. Recently, 5-HT 1a receptor expression has been reported in 
the myenteric plexus of the GI tract including the stomach [19]. Buspirone was effective in relaxing the gastric 
fundus via the 5-HT 1 receptor pathway in both in vitro and in vivo experimental models using guinea pigs. 
Buspirone’s effect on improving gastric accommodation has also been shown in studies in normal subjects [20]. 
In these normal subjects, buspirone slowed solid and liquid gastric emptying at the 20 mg dose, but not at 
lower doses including 10 mg, which is the dose to be used in BESST. In studies of patients with functional 
dyspepsia, buspirone 10 mg three times daily in a 4-week study improved gastric accommodation and 
symptoms of early satiety, postprandial fullness, and bloating [21]. In this study of patients with functional 
dyspepsia, buspirone did not alter the rate of gastric emptying of solids or sensitivity to gastric distension, but 
slightly delayed gastric emptying of liquids. Interestingly, acute anxiety and anxiety disorders have been 
reported to impair gastric accommodation (22). 
  
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
 
Risks of buspirone: Common buspirone side effects may include: headache; dizziness, tiredness, drowsiness, and 
lightheaded feeling; sleep problems (insomnia); nausea, upset stomach; blurred vision; nervousness or 
excitement, nonspecific chest pain; sore throat, nasal congestion, tinnitus; and rarely, tardive dyskinesia. 
Common drug interactions of buspirone include monoamine oxidase (MAO) inhibitors. Thus far, there is no direct 
evidence that buspirone causes physical dependence or drug-seeking behavior. 
 
Interference with cognitive and motor performance:  Studies indicate that buspirone hydrochloride tablets are 
less sedating than other anxiolytics and that it does not produce significant functional impairment. However, its 
central nervous system effects in any individual participant may not be predictable. Therefore, participants 
should be cautioned about operating an automobile or using complex machinery until they are reasonably 
certain that buspirone treatment does not affect them adversely. In general, because the effects of concomitant 
administration of buspirone with most psychotropic (CNS-active) drugs have either not been studied or validated, 
the concomitant use of psychotropic drugs and buspirone should be approached with caution. 
 
While formal studies of the interaction of buspirone hydrochloride with alcohol indicate that buspirone does not 
increase alcohol-induced impairment in motor and mental performance, it is prudent to avoid concomitant use 
of alcohol and buspirone. 
 
 
 


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Potential for Withdrawal Reactions in Sedative/Hypnotic/anxiolytic drug-dependent participants:  
Because buspirone hydrochloride tablets do not exhibit cross-tolerance with benzodiazepines and other common 
sedative/hypnotic drugs, it will not block the withdrawal syndrome often seen with cessation of therapy with 
these drugs. Therefore, before starting therapy with buspirone hydrochloride tablets, it is advisable to withdraw 
participants gradually from their prior treatment, especially participants who have been using a CNS depressant 
drug chronically. Rebound or withdrawal symptoms may occur over varying time periods, depending on the type 
of drug and its effective half-life of elimination. 
 
The syndrome of withdrawal from sedative/hypnotic/anxiolytic drugs can appear as any combination of irritability, 
anxiety, agitation, insomnia, tremor, abdominal cramps, muscle cramps, vomiting, sweating, flu-like symptoms 
without fever, and occasionally, even seizures. 
 
General risks: The condition of the participant may or may not get better or may become worse while in this 
study. During the study, participants will continue to receive clinical care by their primary care physician. 
 
Stopping medications for gastroparesis: Participants may remain on their current treatments for gastroparesis, 
including use of a Gastric Electric Stimulator, if the participant is on a stable drug dose for at least 3-months prior 
to enrollment, and is willing to remain on this stable dose throughout the study (including screening, treatment, 
and post-treatment washout).  The participant will not need to stop these drugs for the testing days for either the 
GES or the EGG with water load procedures.  An exception is that the participant may not take narcotics the 3 
days prior to a GES test. If participants are obtaining symptom relief due to any of the exclusionary medications 
(MAOIs, benzodiazepines, narcotics more than 3 times per week, warfarin, haloperidol, or drugs to treat seizures), 
other choices can be arranged with their Primary Care Provider (PCP) or the potential participant will not be able 
to participate in the trial. This possible medication regimen change may be inconvenient to the participant but is 
judged to not cause any undue hardship on the participant who wants to participate in the trial. 
 
Questionnaires: The questionnaires cover demographics, medical history (comorbidities and medications), 
symptoms of gastroparesis, quality of life, and feelings of anxiety and depression. They will take about 1 hour to 
complete. A subject with significant scores on the Hospital Anxiety and Depression Scale (HADS) questionnaire 
will be referred to a clinical psychologist for follow-up (see section 8.2). 
 
Blood drawing: Blood draw may cause mild discomfort, such as swelling, temporary sensation of pain, burning, or 
a bruise that may develop and last for a few days. Less common risks include a blood clot at the site of puncture, 
swelling of the vein and surrounding tissues, and possible bleeding from the puncture site. Very rarely, fainting, 
blood clots or an infection at the site can occur. During the entire study period (up to 14 weeks), subjects will have 
approximately 6 tablespoons of blood drawn (88 mL) (see section 12.2). 
 
Electrogastrogram (EGG) with water load satiety test: EGG testing involves placement of EGG electrodes on the 
abdominal skin. An EGG will be performed twice: during screening and at 4 weeks. There may be some soreness 
in removing the EGG electrodes. During the water load test, the participant drinks water until they are full. 
Diabetics will have their glucose checked at the beginning and the end of the tests, with appropriate measures 
being taken if hypoglycemia or hyperglycemia is detected.  In addition, each of these two EGG tests will be 
performed on different days than each of the Gastric Emptying Scintigraphy tests, which may cause 
inconvenience to the participant. 
 
Gastric emptying scintigraphy (GES) test: A GES test will be performed twice: during screening and at 4 weeks. 
The total radiation dose for the administration of 0.5-1 microcuries (mCi) 99m-Tc sulfur colloid for one GES test is 
an Effective Dose Equivalent of 37-53 millirem (adult male and adult female, respectively). The internal organ or 
tissue receiving the highest radiation dose is the upper large intestine, which will receive 215 millirad. The total 


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radiation dose for the 0.5-1 mCi administration of 99m-Tc sulfur colloid for the two GES tests included in BESST is 
an Effective Dose Equivalent of 74-106 millirem. The annual average background value that an individual receives 
in the United States is 300 millirem. The internal organ or tissue receiving the highest radiation dose is the upper 
large intestine, which will receive 430 millirad total during BESST. A urine pregnancy test is obtained at study 
screening and at each visit during study treatment to ensure female participants of child-bearing potential are not 
pregnant when exposed to radiation or while taking study drug. 
 
Treatment of side effects: During BESST, if a participant develops non-life threatening side effects that may be 
attributed to the study drug, the study drug will be stopped only if the participant so desires. If the participant 
chooses to no longer receive the study drug, the participant will continue to be followed in the trial, in keeping 
with the intention-to-treat paradigm. In the event of major dermatological reactions such as generalized 
urticaria, bullous rashes, exfoliative dermatitis, or Stevens-Johnson Syndrome, study drug will be discontinued 
immediately. Such skin reactions are expected to be infrequent adverse events. 
 
Study visits: This study requires approximately 8 visits to the study center (up to 3 screening visits, randomization 
visit, and 4 post randomization visits) which may cause some inconvenience to some individuals. 
 
Pregnancy: Since there may be unknown risks to pregnant women and their unborn children, potential participants 
who are breast feeding, pregnant, or planning to become pregnant will not be allowed to participate in BESST. 
Participants need to confirm to the best of their knowledge that they are not pregnant and if they become pregnant 
during the course of the study, they must notify the study investigator immediately and the study drug will be 
stopped. A urine pregnancy test is obtained at study enrollment and at each visit during study treatment for any 
females of child-bearing potential to help assure that the participant is not pregnant. 
 
Safety issues related to participant privacy: For this study, data is being recorded about each participant’s medical 
condition via medical records and case report forms. All data will be kept confidential. Case report forms on which a 
participant’s data or results from specified procedures have been recorded will be stored in locked drawers of file 
cabinets.  Study data are keyed to the GpCRC BESST web-based study database with encrypted (https:) transmission 
of data and via a secure network using an encrypted, password-protected computer accessible only by the study 
coordinator, the site Principal Investigator (PI), and study-certified study personnel. It is the investigator’s 
responsibility to conduct the protocol under the current version of Declaration of Helsinki, Good Clinical Practice, 
and the rules of local IRBs. Each investigator must ensure that the participant’s anonymity is maintained in their data 
submissions to the SDRC. Participants will be identified by an arbitrary unique identification code and not by their 
name, social security number, address, or hospital medical record number. Under no circumstances will any 
identifiable data be transmitted and stored in the BESST study database or be sent in email, scans, or paper-based 
transmissions to the SDRC. Investigators will locally maintain a separate confidential enrollment log, which links 
identification codes with the participants’ names and addresses (i.e., available only to local clinic staff). All study 
material will be maintained in strict confidence. 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Participants may experience short-term relief of the symptoms of anxiety, with low potential of buspirone becoming 
habit-forming.   
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Justification of the risks: All participants will receive standard of care as part of the trial and will potentially 
benefit if they are in the buspirone treatment arm and buspirone improves symptoms relative to placebo. All of 


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the participants in the study have gastroparesis or gastroparesis-like symptoms and are in need of treatment 
beyond lifestyle changes. By conducting the trial and furthering the understanding of buspirone for the treatment 
of gastroparesis, all of the participants in the study stand to benefit in the future if buspirone is proven to be 
effective. 
 
 
3 
OBJECTIVES AND OUTCOMES 
OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR 
OUTCOMES 
Primary 
 
 
To determine whether 4-weeks of 
treatment with buspirone, a 5-HT 
1a receptor agonist, improves 
symptoms of early satiety and 
postprandial fullness in 
participants with symptoms of 
gastroparesis compared to 
placebo. 
 
 The primary outcome is the change in 
the PAGI-SYM postprandial 
fullness/early satiety subscore from 
baseline to 4 weeks; this subscore is 
calculated by averaging the scores for 4 
PAGI-SYM questionnaire items: 
stomach fullness, inability to finish a 
normal-sized meal, feeling excessively 
full after meals, and loss of appetite. 
Buspirone has been shown to be 
effective in relaxing the gastric 
fundus via the 5-HT 1 receptor 
pathway in both in vitro and in vivo 
experimental models using guinea 
pigs, as well as improving gastric 
accommodation in normal subjects 
and symptoms of early satiety and 
postprandial fullness in participants 
with functional dyspepsia. 
(66,67,69). 
Secondary 
 
 
The secondary objectives have 
been selected to provide further 
information on whether 4-weeks of 
treatment with buspirone 
compared to treatment with 
placebo improves overall and other 
gastroparesis symptoms, and other 
participant clinical characteristics 
(gastric retention, anxiety, 
depression, quality of life) and to 
determine the safety and 
tolerability of buspirone in adult 
participants with gastroparesis 
symptoms and with at least 
moderate symptoms of 
postprandial fullness and early 
satiety. 
 
Changes at 4 weeks from baseline in 
the following measures: 
(calculated as score at 4-weeks 
minus score at baseline in:  
1. GCSI total score 
2. Four other PAGI-SYM 
questionnaire subscores: 
nausea/vomiting (3 items: 
nausea, retching, vomiting), 
bloating (2 items: bloating, 
stomach visibly larger), upper 
abdominal pain (2 items: upper 
abdominal pain, upper 
abdominal discomfort), GERD (7 
items: heartburn during the day, 
heartburn when lying down, 
feeling of discomfort inside chest 
during the day, feeling of 
discomfort inside chest during 
sleep, regurgitation or reflux 
during the day, regurgitation 
when lying down, bitter, acid or 
sour taste in mouth) 
3. Eight single-item PAGI-SYM 
symptom severity scores: Nausea, 
vomiting, stomach fullness, inability 
to finish a normal-sized meal, 
These outcomes were selected 
because they measure important 
gastroparesis symptoms or co- 
morbidities of gastroparesis and are 
useful for determining if buspirone 
improves other symptoms 
commonly associated with 
gastroparesis and that buspirone is 
safe to use in adult gastroparesis 
patients. 


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OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR 
OUTCOMES 
feeling excessively full after meals, 
loss of appetite, bloating, upper 
abdominal pain 
4. Gastrointestinal Symptom Rating 
Scale (GSRS) total score 
5. Clinical Patient Grading Assessment 
Scale (CPGAS) score 
6. Patient Assessment of Upper 
Gastrointestinal Disorders-Quality 
of Life (PAGI-QOL) total score 
7. Hospital Anxiety and Depression 
Scale (HADS) anxiety score and 
depression score 
8. Patient Health Questionnaire 15 
Somatic Symptom Severity Scale 
(PHQ-15) total somatization score 
9. SF-36v2 Quality of Life 
questionnaire, Physical 
Component Score and Mental 
Component Score 
10.  Percent gastric emptying retention 
at 2 and 4-hours 
11. Anthropometric 
measurements (Body Mass 
Index (BMI)/weight, waist 
circumference) (safety) 
12.  ECG measures (safety) 
13.  Laboratory measures (ALT, 
creatinine, glucose) (safety) 
14. Frequency of side effects and 
adverse events, as well as severity 
of adverse events. (safety and 
tolerability) 
 
Tertiary/Exploratory  
Changes from screening to 4 weeks: 
 
Tertiary: exploratory/ancillary 
objectives were selected as a basis 
for explaining or supporting 
findings of the primary analysis and 
key secondary outcomes in 
sensitivity analyses and for 
suggesting further hypotheses for 
future research. 
 
Changes at 4-weeks from baseline 
(calculated as score at 4 weeks minus 
score at baseline) in: 
1. Intragastric meal distribution as an 
assessment of Fundic 
Accommodation (FA) using digital 
analyses of the GES test images 
2. Gastric rhythm and water ingestion 
when full measured with EGG with 
water load test. 
3.  ANMS GCSI-DD 7 item scores: 
nausea, postprandial fullness, early 
satiety, upper abdominal pain, 
 
Fundic accommodation (FA) is the 
primary target of the 5-HT 1 
receptor pathway and will provide 
information on the hypothesis of 
action of buspirone on the stomach 
(item 1). 
 
Gastric dysrhythmia outcomes from 
the EGG water load test will help to 
provide insight into the action of 
buspirone on the stomach (item 2). 
 


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OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR 
OUTCOMES 
episodes of vomiting, episodes of 
retching, overall symptom severity; 
each single item score is the 
average of the daily score from the 
last 7 days 
4.  Each of the 15 symptom severity 
items measured on the PAGI-SYM 
questionnaire not included in 
secondary outcomes item 3, 
including retching, lower abdominal 
pain, lower abdominal discomfort, 
constipation, and diarrhea  
5.  Each of the 5 subscores of the 
Gastrointestinal Symptom Rating 
Scale (GSRS). 
The ANMS GCSI-DD uses a Patient-
Reported Outcome (PRO) daily-diary 
to capture symptoms of 
gastroparesis; however, this 
instrument is still being validated 
(item 3). 
 
Improvements in other 
gastroparesis symptoms will be 
explored to study possible other 
effects of buspirone (items 4, 5). 
 
 
 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
• 
The primary hypothesis of the trial is that buspirone treatment improves early satiety and postprandial 
fullness as measured by the PAGI-SYM questionnaire postprandial fullness/early satiety subscore; we 
will test this hypothesis by comparing the mean change from baseline in this subscore over the 4 weeks 
of treatment in the group treated with buspirone to the mean change from baseline in this subscore in 
the group treated with placebo (ANCOVA test for mean between-group differences in differences using 
baseline value as the covariate) 
• 
Phase 2 
• 
A multi-center, randomized, double-masked, placebo-controlled, parallel treatment groups phase 2 trial 
with primary outcome defined as symptomatic improvement in early satiety and postprandial fullness. 
The primary outcome is the change in the postprandial fullness/early satiety subscore from baseline to 4 
weeks; this subscore is calculated by averaging the scores for 4 PAGI-SYM questionnaire items: stomach 
fullness, inability to finish a normal-sized meal, feeling excessively full after meals, and loss of appetite. 
• 
Methods to decrease bias will include placebo control, double masking and randomization. 
• 
Two study arms 
• 
Multisite 
• 
Study intervention is  buspirone 10 mg capsule three times daily, 30 minutes before each meal, for 4 
weeks or matching placebo. 
• 
The randomization design will be stratified by clinical center with participants’ assignments into one of 
two groups (buspirone or placebo) in permuted blocks of random length within each clinic. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The study design is a multi-center, randomized, double-masked, placebo-controlled, parallel treatment groups 
phase 2 trial. 
 
Rationale for a Placebo Group: Currently, there are few effective treatments for symptoms in participants with 
gastroparesis and related syndromes. Studies of various agents have shown placebo effects ranging from 10% and 


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higher. In the NIDDK GpCRC Aprepitant for the Relief of Nausea (APRON) trial, 40% of the participants treated with 
placebo improved on the primary outcome [9]. In the NIDDK GpCRC 48-week Outcomes paper, approximately 28% 
of the participants showed substantial symptomatic improvement at 48 weeks with Standard of Care (SOC) [23]. 
Therefore, it is important to have a placebo group to be able to discriminate a treatment effect over and above 
SOC and the lifestyle advice provided to all of these participants. 
 
In addition, in order to assess the efficacy of an agent in gastroparesis, a placebo group is needed to determine 
the relative efficacy in improving symptoms and physical functions. In order to have the highest quality of 
evidence to test our hypothesis, the BESST trial uses a randomized, double-masked, placebo-controlled study 
design. 
 
The trial is double-masked to prevent bias by investigators and participants. The trial is 4 weeks since the 
Minimum Clinically Important Difference (MCID) in gastroparesis symptoms has been shown in the literature to 
be detected in that timeframe. The trial is powered at 90% to detect a MCID in the PAGI-SYM questionnaire 
postprandial fullness/early satiety subscore primary outcome measure; it is powered at 80% to detect a MCID in 
the GCSI total score, the key secondary outcome. 
 
4.3 
JUSTIFICATION FOR DOSE 
 
Buspirone is a 5-HT 1 receptor agonist that is approved for the treatment of anxiety. It is an anxiolytic 
psychotropic drug of the azapirone chemical class, used primarily to treat generalized anxiety disorder. Unlike 
most drugs predominantly used to treat anxiety, buspirone's pharmacology is not related to benzodiazepines or 
barbiturates, and so does not carry the risk of physical dependence and withdrawal symptoms for which those 
drug classes are known. The proximal gastric fundus tone is mediated by a balance of excitatory cholinergic and 
inhibitory non-adrenergic, none-cholinergic (NANC) neural input. Recently, 5-HT 1a receptor expression has been 
reported in the myenteric plexus of the GI tract including the stomach [19]. 
 
Buspirone was effective in relaxing the gastric fundus via 5-HT 1 receptor pathway in both in vitro and in vivo 
experimental models using guinea pigs.  Buspirone’s effect on improving gastric accommodation has also been 
shown in studies in normal subjects [20]. In these normal subjects, buspirone slowed solid and liquid gastric 
emptying at the 20 mg dose, but not at lower doses, including 10 mg, which is the dose to be used in BESST. 
 
In studies of participants with functional dyspepsia, buspirone 10 mg three times daily in a 4-week study improved 
gastric accommodation and symptoms of early satiety, postprandial fullness, and bloating [21]. In this study of 
participants with functional dyspepsia, buspirone did not alter the rate of gastric emptying of solids or sensitivity to 
gastric distension but slightly delayed gastric emptying of liquids.  Interestingly, acute anxiety and anxiety disorders 
have been reported to impair gastric accommodation [19]. Based on this preliminary data, we will use the same 
dose as used in the functional dyspepsia study. 
 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the study including 
the last visit or the last scheduled procedure (or at the close of the final study visit window) shown in the Schedule 
of Activities (SoA), Section 1.3. 
 
The end of the study globally is defined as completion of the last study visit (or closure of the final study window) 
shown in the SoA for the last randomized participant. 


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5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Aged 18 to 85 years at initial screening interview 
• 
Symptoms compatible with gastroparesis or other functional gastric disorder for at least 3 months (does not 
have to be contiguous) prior to initial screening interview 
• 
Diagnosis of diabetic or idiopathic gastroparesis 
• 
Delayed or normal gastric retention on screening 4-hour Gastric Emptying Scintigraphy test 
• 
Symptoms of gastroparesis measured by the 9-item Gastroparesis Cardinal Symptom Index (GCSI) total score 
> 2.0 at enrollment 
• 
Symptomatic with postprandial fullness/early satiety severity (PAGI-SYM questionnaire subscale > 3) at 
enrollment 
• 
Upper endoscopy or upper GI series without findings of ulcers or mass lesions in the 2 years prior to enrollment 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study:  
 
• 
Post-surgical gastroparesis, including prior pyloromyotomy, pyloric resection, vagotomy, bariatric surgery or post-
Nissen fundoplication 
• 
Another active disorder which could explain symptoms in the opinion of the investigator 
• 
Concurrent use of opiate narcotic analgesics more than 3 days per week 
• 
Significant hepatic injury as defined by alanine aminotransferase (ALT) elevation of greater than 2xULN or a Child-
Pugh score of 10 or greater 
• 
History of significant cardiac disorders (prior heart attack, prior stroke, unstable angina) or significant cardiac 
arrhythmias or ECG abnormalities defined as history of, or current, arrhythmias including ventricular tachycardia, 
ventricular fibrillation and Torsade des Pointes and/or prolonged QTc on ECG (>450 msec for men and >470 for 
women) 
• 
History of chronic kidney disease or on hemodialysis or peritoneal dialysis 
• 
Impaired renal function as defined by estimated glomerular filtration rate (eGFR) < 60 ml/min/1.732 using the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculator 
• 
Uncontrolled diabetes defined as HbA1c (%) of 10% or more within 60 days of enrollment 
• 
Allergy to buspirone 
• 
Concurrent or prior use (within 30 days) of monoamine oxidase (MAO) inhibitors 
• 
Concurrent or prior use (within 30 days) of benzodiazopines 
• 
Concurrent or prior use (within 30 days) of buspirone, warfarin, haloperidol, and drugs to treat seizures (e.g., 
phenytoin and carbamazepine) 
• 
For women of child-bearing potential, either pregnancy, planned pregnancy, unwillingness to use effective birth 
control during the trial or breast feeding   
• 
Any other condition, which in the opinion of the investigator would impede compliance or hinder completion of 
the study 
• 
Failure to give informed consent 
 
5.3 
LIFESTYLE CONSIDERATIONS 


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5.3.1 STANDARD TREATMENT RECOMMENDATIONS  
 
Standard of care (SOC) recommendations prepared by the GpCRC Steering Committee for the management of patients 
with gastroparesis or related disorders cover these broad categories as follows: 
• 
Standardized set of recommendations on following a Gastroparesis diet. 
• 
Recommendations on the use of pain medications and to eliminate drugs that might exacerbate the 
underlying dysmotility disorder or prevent the beneficial actions of a prokinetic. 
These recommendations will be included in the BESST Standard of Care Standard Operating Procedures (SOP) and will 
be provided to each participant. 
 
Also, during the BESST study, participants are asked to: 
• 
Refrain from consumption of alcohol, grapefruit or grapefruit juice, pomelos, exotic citrus fruits, grapefruit 
hybrids, and fruit juices until after the final dose.  
 
These guidelines are given in the investigator’s brochure for buspirone and are included due to possible alteration of 
p450 degradation pathways. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently 
randomly assigned to a study treatment group. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, and to respond to queries from regulatory authorities. Minimal information 
includes demographics, reason for screen failure, and any serious adverse event (SAE). Screening failures also 
include participants who meet medical eligibility criteria but change their mind and do not consent to randomization 
into the trial. We collect all of the above information on each screen failure using a case-report form keyed into the 
BESST database. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a contraindicated 
medication or who is unable to complete all tests within the allotted screening window may be rescreened one 
time. A rescreened participant is assigned the same participant number as for the initial screening. 
 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.5.1 RECRUITMENT 
Approximately 108 participants will be recruited from the six clinical centers of the GpCRC (averaging 18 participants 
per center) over a 30-month period. Participants will be recruited from outpatient clinics and inpatient hospital 
settings. 
 
Potentially eligible participants will be identified and registered for screening at the participating clinical centers 
subject to the inclusion and exclusion criteria listed above. Eligible and consenting participants will be randomized to 
a treatment group after completion of all required screening procedures, keying of all required data elements into 
the data system, and passing eligibility checks for the BESST trial. 
 
Each clinical center will develop a specific recruitment plan. These plans will vary from clinic to clinic depending on 
the available pools of participants and local recruitment resources. Clinics will attempt to recruit sufficient overall 


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numbers of minorities and males since gastroparesis is reported to be rare in African-Americans and infrequent in 
men, so that the study results can be generalized to these sub-groups of the U.S. population. 
 
Participants may be reimbursed for travel expenses for each visit completed depending on each clinic’s resources. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION FROM FDA PACKAGE INSERT 
 
Buspirone hydrochloride tablets, USP is an antianxiety agent that is not chemically or pharmacologically related to 
the benzodiazepines, barbiturates, or other sedative/anxiolytic drugs. Buspirone hydrochloride is a white 
crystalline, water soluble compound with a molecular weight of 422.0. 
 
Chemically, buspirone hydrochloride is 8-[4-[4-(2-pyrimidinyl)-1piperazinyl]butyl]-8-azaspiro[4.5]decane- 7,9-dione 
monohydrochloride. The empirical formula C21H31N5O2 • HCl is represented by the following structural formula: 
 
 
 
The mechanism of action of buspirone is unknown. Buspirone differs from typical benzodiazepine anxiolytics in that 
it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is 
associated with more typical anxiolytics. In vitro preclinical studies have shown that buspirone has a high affinity 
for serotonin (5-HT 1a) receptors. Buspirone has no significant affinity for benzodiazepine receptors and does not 
affect γ-aminobutyric acid (GABA) binding in vitro or in vivo when tested in preclinical models. 
 
Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may 
have indirect effects on other neurotransmitter systems. Buspirone is rapidly absorbed in humans and undergoes 
extensive first-pass metabolism. In a radiolabeled study, unchanged buspirone in the plasma accounted for only 
about 1% of the radioactivity in the plasma. Following oral administration, plasma concentrations of unchanged 
buspirone are very low and variable between subjects. Peak plasma levels of 1 ng/mL to 6 ng/mL have been 
observed 40 to 90 minutes after single oral doses of 20 mg. The single-dose bioavailability of unchanged buspirone 
when taken as a tablet is on the average about 90% of an equivalent dose of solution, but there is large variability. 
 
The effects of food upon the bioavailability of buspirone have been studied in eight subjects. They were given a 20 
mg dose with and without food; the area under the plasma concentration-time curve and peak plasma 
concentration (Cmax) of unchanged buspirone increased by 84% and 116%, respectively, but the total amount of 
buspirone immunoreactive material did not change. This suggests that food may decrease the extent of 
presystemic clearance of buspirone. 
 
Buspirone is a 5-HT 1 receptor agonist that is FDA approved for the treatment of anxiety. It is an anxiolytic 
psychotropic drug of the azapirone chemical class, used primarily to treat generalized anxiety disorder. Unlike most 
drugs predominantly used to treat anxiety, buspirone's pharmacology is not related to benzodiazepines or 


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barbiturates, and so does not carry the risk of physical dependence and withdrawal symptoms for which those drug 
classes are known. The proximal gastric fundus tone is mediated by a balance of excitatory cholinergic and 
inhibitory non-adrenergic, none-cholinergic  neural input. Recently, 5-HT 1a receptor expression has been reported 
in the myenteric plexus of the GI tract including the stomach (66). Buspirone was effective in relaxing the gastric 
fundus via 5-HT 1 receptor pathway in both in vitro and in vivo experimental models using guinea pigs. 
 
6.1.2 DOSING AND ADMINISTRATION 
 
In this trial, a 10 mg buspirone tablet will be over encapsulated in a size 0 gelatin capsule (approximately 2.2 cm) 
with partial filler, the inactive ingredients being: colloidal silicon dioxide, lactose, magnesium stearate, 
microcrystalline cellulose, and sodium starch glycolate. The matching placebo capsule will contain only filler.  Each 
bottle contains 120 capsules.  
 
The random treatment assignment will consist of a numbered study drug bottle; each bottle number will be 
unique and each participant will be assigned a specific bottle number. The bottle number issued by the 
randomization program will correspond to numbered bottles of study drugs which have been sent to the clinical 
center’s research pharmacy by the SDRC’s GMP Research Pharmacy. Upon learning the bottle number to be issued 
to the specific participant, the research pharmacy will issue that bottle to the participant. Each participant’s 
random treatment assignment will be generated for that specific participant and will not be transferable to 
another participant. Once the assignment has been generated, the participant will be issued the study drug and 
instructed about taking the study dug orally 30 minutes before meals every day and monitoring for potential 
adverse effects. The study drug dispensed at the time of randomization will be a bottle containing either over-
encapsulated 10 mg tablets of buspirone or identical looking placebo capsules. 
 
Participants will receive an Information for Patients document with their study medication.  This document will 
instruct the participant as follows: 
 
1. Do not take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not 
sure if you take an MAOI, including the antibiotic linezolid. 
2. Do not take an MAOI within 2 weeks of stopping buspirone unless directed to do so by your physician.  
3. Do not start buspirone if you stopped taking an MAOI in the last 2 weeks unless directed to do so by 
your physician. 
4. Inform your Primary Care Physician that you are participating in a randomized, controlled trial comparing 
buspirone hydrochloride (10 mg 3 times per day) and placebo. 
5. Inform your physician and the study investigator about any prescription or non-prescription medications, 
prescription or non-prescription supplements, alcohol, or drugs that you are now taking or plan to take 
during your participation in BESST. 
6. Inform your physician if you are pregnant or breastfeeding, or if you are planning to become pregnant, or 
if you become pregnant while you are taking buspirone hydrochloride tablets. 
7. Until you experience how this BESST study medication affects you, do not drive a car or operate potentially 
dangerous machinery.  
8. During your treatment with BESST study medication, avoid consumption of grapefruit juice or eating 
grapefruit, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices until after the final dose. 
9. If you miss a dose of this medicine, take it as soon as possible unless it is almost time for your next dose, in 
which case, skip the missed dose and go back to the regular dosing schedule. Do not double doses. 
 
 


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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
An investigator may not administer an investigational new drug to human subjects until the IND goes into effect 
(30 days after IND receipt by FDA) or sooner if notified. After review by the FDA, the use of buspirone in the BESST 
trial was given an IND exempt status. All masked drug and placebo bottles will be distributed to the individual 
GpCRC Clinical Centers’ Investigational Pharmacies or responsible entities by the SDRC’s contracted GMP Drug 
Distribution Center according to the directions of the SDRC. The GMP Drug Distribution Center will purchase the 
study drug (buspirone) and the materials needed for manufacturing the placebo capsules, over-encapsulating the 
buspirone capsule, manufacturing the microcrystalline powder contained in the matching placebo capsule, 
encapsulating the placebo capsule, bottling the active and placebo capsules individually, labeling bottles according 
to the SDRC directions, and shipping the drugs to the clinics. Expired and returned study drug will be disposed of 
by each clinical center after authorization from the SDRC. 
 
The local Investigational Pharmacy will provide the clinic investigator or coordinator with a masked BESST study 
drug bottle upon request after the participant’s randomization. The SDRC provides the bottle number to be 
requested from the local pharmacy after the randomization request by the clinic. Participants will be dispensed a 
bar-coded medication bottle as labeled by the GMP Research pharmacy: “Buspirone 10 mg or placebo. Take one 
capsule orally 3 times per day, 30 minutes prior to meals.” 
 
Participants are instructed to take a single capsule of 10 mg buspirone or placebo three times a day, approximately 
30 minutes prior to meals. 
 
Drug accountability information is maintained by the GMP Research Pharmacy, the local clinic investigational 
pharmacy, and in the study database for adjudication coordinated by the SDRC at the end of the trial or at any 
time during the trial, as needed. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Buspirone hydrochloride is supplied by several pharmaceutical manufacturers and will be purchased by 
the SDRC’s GMP Research Pharmacy, and then over-encapsulated in a gelatin capsule for oral administration.  
Half the capsules will contain 10 mg buspirone hydrochloride, USP (equivalent to 9.1 mg of buspirone free 
base, respectively).  The buspirone tablets contain the following inactive ingredients: colloidal silicon dioxide, 
lactose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The other half of the 
gelatin capsules (placebo) will contain only the filler. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. 
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). 
 
6.2.4 PREPARATION 
 
No preparation is required because capsules will be provided to sites in participant ready packaging. 
 
 
 


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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Randomization: The randomization scheme will assign participants in randomly permuted blocks of assignments 
stratified by clinical center. This scheme will ensure that the two groups will be of nearly equal size and will be 
balanced by calendar time of enrollment to ensure equal numbers of participants by time of enrollment (to 
minimize secular effects) and by clinic (to minimize clinic effects). 
 
The randomization plan will be prepared and administered centrally, using a secure web application, by the SDRC. 
An assignment will be issued only if the trial database shows that the participant is eligible, has signed the consent 
statement, and has had all required baseline data keyed to the data system. 
 
Treatment assignments are double-masked throughout the study until all data collection for the BESST trial has 
been completed, i.e., after completion of the 2-week post-trial follow-up visit for all participants. Every effort will 
be made to maintain the masking throughout the study except in emergency situations. The randomization code 
masking the bottle contents will not be provided by the SDRC without the knowledge of the clinical center’s 
principal investigator. 
 
Unmasking of study medication will occur under the following conditions: 
 
• 
Severe allergic reaction (Stevens-Johnson Syndrome): Study medication is stopped indefinitely. The 
participant, primary care provider (PCP), and the investigator will be unmasked. 
 
• 
Pregnancy during the study: Study medication will be stopped indefinitely, and the coded medication will 
be unmasked. The participant, PCP, and investigator will be notified of the assigned treatment and the 
associated risks of teratogenicity. 
 
In unforeseen situations where the clinical center principal investigator considers unmasking is in the best interest 
of the participant’s health and well-being, unmasking may be done after notifying the Executive Committee. The 
Data and Safety Monitoring Board will review all instances of unmasking that have occurred. 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Assessment of adherence to the assigned study drug will provide clinic staff a means to identify participants 
having problems with adherence. Adherence will be assessed by: 
• Counts of capsules in the participant’s returned medication bottle at the end of the trial 
• Conducting a brief, structured interview, in which the study coordinator will assist the participants to 
identify problems in taking the study drug and to estimate adherence to the prescribed medicine since 
their previous visit during the trial. 
These assessments will guide the consideration of strategies to improve adherence and to assess adherence at the 
end of the trial. 
 
 


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6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. Medications to be reported in the Case Report Forms (CRF) are concomitant 
prescription medications, over-the-counter medications and supplements. 
 
Medication histories are collected at enrollment and at each follow-up visit.  The participant is requested to bring 
all medication and supplement bottles (prescription and non-prescription) or a photo of each bottle to the clinic 
visit.   
 
The drug interaction/contraindication list from the buspirone manufacturer’s drug label (package insert) will be 
the definitive source of identifying which concomitant pharmaceuticals and herbal supplements should be 
considered in determining eligibility for this study and which medications can be safely taken with buspirone 
during the trial.  
 
Medications known to interact with buspirone hydrochloride (buspirone) are excluded from use during the trial. 
These include: 
• 
MAO inhibitors, such as phenelzine, linezolid, isocarboxazid, methylene blue, moclobemide, phenelzine, 
procarbazine, rasagiline, safinamide, selegiline, and tranylcypromine 
• 
The blood thinner warfarin (Coumadin) 
• 
Haloperidol 
• 
Benzodiazepines 
• 
Drugs used to treat seizures, such as phenytoin (Dilantin) and carbamazepine (Tegretol) 
 
In addition, using buspirone with any of the following medicines may cause an increased risk of certain side effects. 
These medications are selective serotonin reuptake inhibitors (SSRIs)(e.g., fluoxetine, nefazodone and trazodone 
(Oleptro)), and tricyclic antidepressants (TCA; e.g., amitriptyline/nortriptyline, trazodone). Some drugs interact with 
buspirone to affect the clearance rate of buspirone, including azole antifungals (e.g., itraconazole, ketoconazole), 
some antibiotics (including erythromycin, rifampin), nefazodone, cimetidine, ritonavir, diltiazem, verapamil, and 
certain anticonvulsants (e.g., phenytoin, phenobarbital).  
 
Drugs with the possibility of a serious adverse event or disruption of the clearance rate have been listed as 
exclusions to the study.  The treating physician will assess each participant’s medication profile both for study 
eligibility at screening and for ongoing safety during the trial, and participants will be excluded from randomization 
or have trial treatment discontinued on a case-by-case basis per local clinical judgment. 
 
Participants will be questioned regarding any new medications at each visit and counseled by the study physician not 
to use drugs on the list of exclusions above, unless they are medically necessary. The study physician will decide 
whether suspension of the study medication is indicated. 
 
 
6.5.1 RESCUE MEDICINE 
 
If symptoms are severe and require further treatment during the trial, participants will be instructed to take rescue 
medications that they would usually take, such as prochlorperazine or ondansetron for nausea and vomiting, and 
acetaminophen, ibuprofen, hyoscamine or tramadol for abdominal pain. 
 


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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
Participants may withdraw voluntarily from the study or the PI may, for cause, discontinue a participant from the 
study. In addition, participants who discontinue the study medication will be encouraged to remain in the study for 
follow-up purposes, especially for safety and efficacy study outcomes. Study medication discontinuations and 
participant discontinuations/withdrawals from the study will be documented on case report forms, which capture the 
dates and the specific underlying reasons for discontinuations of study medications or participant 
discontinuations/withdrawals. 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
If the participant develops a treatment-related CTCAE v5.0-defined adverse event (grade 3 or above) on the 10 mg 
dose, the study medication will be stopped after assessment by the site study investigator, who is a licensed 
physician. If in the view of the study investigator, the participant is intolerant of the medication, the participant 
will be withdrawn from the study medication, but will continue to be followed to the end of the trial. 
 
Discontinuation from buspirone or placebo does not mean discontinuation from the study -- all remaining study 
data should be completed as indicated by the study protocol. If a clinically significant finding is identified after 
enrollment, the investigator or qualified designee will determine if any change in participant management is 
needed. If indicated, adverse event (AE) case report forms will be completed and entered into the study database. 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Labs and anthropometrics at the prior visit or at the AE occurrence 
• 
Study medication bottle numbers and documentation of capsule counts 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon written request. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation 
• 
Participant is unable to receive buspirone for 7 days. 
• 
The sponsor or investigator terminates the study.  
 
 
If, during the trial, a participant develops non-life threatening side-effects, the study medication will be suspended 
if the participant insists, after consultation with a study physician. If the participant decides to stop the study 
medication, the participant will still be followed in the trial according to the protocol, in keeping with the 


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intention-to-treat paradigm. In the event of major dermatological reactions such as generalized urticaria, bullous 
rashes, exfoliative dermatitis, or Stevens-Johnson Syndrome, study drug will be discontinued immediately. 
 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for one scheduled visit and is unable to 
be contacted by the study site staff. 
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 7 days and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter 
to the participant’s last known mailing address or local equivalent methods). These contact attempts will 
be documented in the participant’s medical record or private study  file, but will not be documented in 
the study database. 
• 
If the participant cannot be reached, the participant will be considered to have withdrawn from the study 
with a primary reason of lost to follow-up. All study data collected prior to the lost to follow-up will be 
used. 
 
The occurrence of missing data in this trial is expected to be low and, when present, is expected to be equally 
distributed across the 2 treatment groups. We believe, from past experience, that careful selection and education 
of participants during the screening phase before the consent will result in no more than 10% lost to follow-up 
before completing the full 4-week treatment period and the 2- week post-treatment follow-up.  
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 VISIT SCHEDULE OVERVIEW 
The participant-related activities of the BESST trial can be divided into 4 phases: 
• 
Screening for eligibility for enrollment (up to 3 visits over 8 weeks) 
• 
Randomization to treatment (1 visit) 
• 
Treatment phase (3 visits over 4 weeks: 1 visit at 2 weeks and 2 visits at 4-weeks) 
• 
Post-treatment washout phase (1 visit at 6 weeks) 
 
8.1.2 SCREENING AND BASELINE DATA COLLECTION 
Patients that are likely to meet eligibility requirements after clinic visit or chart review of standard of care tests 
and procedures will be invited to undergo screening. The study will be explained to the potential participant, and 
if interested, the patient will sign the IRB-approved consent form.   
To minimize in-person contact time between the participant and staff during the Covid-19 pandemic and as 
permitted by the site-specific IRBs or sIRB, participants will be offered a telephone or virtual review of the consent 
in place of the in-person review of the consent.  Signature of the consent will take place in person at the study 


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visit and after confirmation that all of the participant’s questions about the study have been answered. Recording 
of screening data on GpCRC BESST forms may not start until the participant has signed the consent statement. 
Screening and baseline data collection procedures will include questionnaires (see 8.1.5) (baseline medical history, 
HADS, SF-36v2, GSRS, PAGI-QOL, PHQ-15, PAGI-SYM, symptoms side effects), physical examination and ECG, 
measurement of fasting complete blood count (CBC), comprehensive metabolic panel (CMP), thyroid stimulating 
hormone (TSH) and HbA1c, a Gastric Emptying Scintigraphy (GES) test, an Electrogastrogram (EGG) with water 
load test (on a separate day), a pregnancy test (if female of child-bearing potential) and fasting blood collection 
for serum and plasma banking.  Prior therapy for gastroparesis and concomitant medications will be reviewed as 
outlined in the inclusion and exclusion criteria. Patient charts will be reviewed for historical medical information 
and procedures. A diagnostic upper endoscopy or an upper GI radiographic series will be scheduled if the 
potential participant has not had this test within the past two years. 
 
Once a potential participant has agreed and consented to participate in BESST, a Gastric Emptying Scintigraphy 
(GES) test will be scheduled. In addition, the preference is to schedule the Electrogastrogram (EGG) with water 
load test within a week of the GES test.  Immediately prior to the GES test, females of childbearing potential must 
have a negative pregnancy test. For the GES test, the participant will arrive at the clinic after an 8-hour fast, that is 
nothing by mouth after midnight except for small sips of water and narcotic free the 3-days prior to the test. The  
PAGI-SYM questionnaire (see section 8.1.5a) will be completed and then the participant will undergo the GES test 
as described in section 8.1.6. Symptoms will be monitored at the beginning and during the GES test. 
 
The potential participant will be given a set of the daily symptom diary (ANMS GCSI-DD) forms to complete each 
night at home. These are returned to the clinic at their second clinic screening visit after 7-days have been 
completed. 
 
For the second screening visit, the participant will arrive at the clinic after an 8-hour fast, that is nothing by mouth 
after midnight, and have the EGG with water load test as described in section 8.1.6. 
   
The GpCRC BESST web-based database management system has an application to check patient eligibility based 
on data forms keyed and verified into the study database. The eligibility check application is used during screening 
a patient to show failed inclusion/exclusion eligibility checks, to show missing required data. Clinic staff can use 
this task to identify the items that still need to be completed, keyed, or verified after data from the screening 
visits are keyed. To avoid inconvenience to potential participants, the randomization application should not be 
attempted until the eligibility check application indicates that the patient is eligible except for the items that can 
only be completed at the randomization visit. 
 
8.1.3 RANDOMIZATION VISIT 
 
The randomization visit is the visit at which randomization takes place and the participant is issued the study 
medication which is randomly assigned to the participant. Randomization is the act of generating the random study 
medication assignment and is the procedure which defines a participant’s enrollment into the trial. Randomization 
can occur after eligibility has been fully checked and all data collected at the screening visits have been keyed to the 
trial database. Since these processes take time, randomization cannot be done at a screening visit, and since study 
medication needs to be issued to the participant, the randomization visit must be completed in person with the 
participant. Therefore, a visit separate from the screening visits is necessary. Since this will be a visit on a different 
calendar day and medication will be started at this visit, good clinical practice requires that a few basic checks of the 
participant’s well-being be completed at the randomization visit. 


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The procedures completed at the randomization visit are: pregnancy test for females of child bearing potential, 
verification that the participant is feeling well, affirmation of consent, review of concomitant drugs and vital signs 
(systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature). All participants will be given 
information on a healthy life style and gastroparesis diet, and instructions on when to take their drug, and 
information to be aware of while taking buspirone (see section 6.1.2). A set of daily-dairy forms will be distributed to 
the participant to complete each day and return to the clinic at their week 2 study visit.  
 
8.1.4 FOLLOW-UP VISITS 
 
Participants will return to the clinical center for follow-up visits at 2 and 4 weeks. A post-treatment washout phase 
visit will occur at week 6. Each visit will have an interval of time surrounding the ideal date for the visit during which 
the visit may be done and the data included in the trial database. The ideal date for the week 2 visit is the 
randomization date plus 2 weeks (14 days); the ideal date for the week 4 visit is the randomization date plus 4 weeks 
(28 days). Visit windows will be constructed to be contiguous, so that at any point in time, some visit window is 
open, subject to a check on the minimum separation of at least one week between consecutive visits. The specific 
assessments and procedures required at each of the follow-up visits are: 
 
• Week 2: pregnancy test for females of child bearing potential, follow-up medical history with review of adverse 
events, concomitant medications and study adherence, assessment of vital signs (systolic and diastolic blood 
pressure, heart rate, respiratory rate, body temperature), and the following surveys: Hospital anxiety and 
depression (HADS), PAGI-SYM, and the Clinical Patient Grading Assessment Scale (CPGAS)(see section 8.1.5) 
and a symptoms side-effect questionnaire (see section 8.2 for details). In addition, the participant will return 
their Daily-Diary forms and receive another set to complete for return at the Week 4 visit. 
 
• Week 4: the week 4 visit will require two fasting visits scheduled as close together as possible, preferably 1 day 
apart. 
o The participant will refrain from taking their buspirone the morning of the GES test, and take it 30 
minutes prior to the GES test. Information to be collected at this visit includes: pregnancy test for 
females of child-bearing potential, a GES test, follow-up medical history with review of adverse events 
and concomitant medications, physical exam and ECG, fasting blood draw for CMP and CBC, review of 
adherence and the following surveys: HADS, SF-36v2 Quality of Life, PAGI-SYM, GSRS, PAGI-QOL, PHQ-
15, symptom side-effects, and the CPGAS.  Fasting blood will be drawn for serum and plasma banking. In 
addition, the participant will return their daily-diary forms and receive one more set of daily-diary forms 
to complete each night to return at their 6-week visit. 
o The EGG test with water load test will be undergone the morning of the following day or as soon as can 
be possibly scheduled within the visit window. The participant will wait and take their buspirone dose 15 
minutes prior to the EGG baseline recording. The participant will return all bottles of the study drug 
dispensed to the clinic staff.  The participant will be instructed to not take any more drug after this visit. 
 
• Week 6:  At this visit, the participant will return their final set of daily-diary forms. Information to be collected 
includes: the follow-up medical history form with review of adverse events and concomitant medications, 
physical exam and fasting blood draw for CMP, CBC, and for banking plasma and serum with the NIDDK 
Biorepository, and the following questionnaires: HADS, PAGI-SYM, GSRS, PAGI-QOL, symptom side-effects, 
CPGAS. A BESST study close-out form will document the participant’s end of participation in BESST. 
8.1.5 STANDARDIZED QUESTIONNAIRES  


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Standardized questionnaires to assess efficacy: 
Several standardized questionnaires will be administered to participants enrolled in the BESST trial. 
Questionnaires will be administered at baseline (prior to randomization) and during follow-up at specified 
intervals (see 1.3 for the Schedule of Activities). The purpose of the questionnaires is to obtain information 
regarding gastroparesis symptoms, side effects, and health-related quality of life. 
 
a. The Patient Assessment of Upper GI Symptoms (PAGI-SYM) assesses the severity of symptoms of 
gastroparesis, functional dyspepsia, and gastroesophageal reflux disease [24]. The scale assesses symptoms over 
the prior two weeks, graded by the participant from none (0) to very severe (5). It includes the nine symptoms of 
the Gastroparesis Cardinal Symptom Index (GCSI), a validated patient-reported outcome (PRO) for gastroparesis 
using a two-week recall period. The nine symptom GCSI (nausea, vomiting, retching, stomach fullness, unable to 
finish a meal, feeling excessively full after meals, loss of appetite, bloating, belly visibly larger) is based on three 
subscales (postprandial fullness/early satiety, nausea/vomiting, and bloating) [25]. The PAGI-SYM also includes 
upper abdominal pain, which will be used for this study. The PAGI-SYM is in the public domain for use by 
investigators and physicians. 
 
b. ANMS GCSI-DD is a daily dairy developed by the American Neurogastroenterology and Motility Society (ANMS) 
for gastroparesis [26]. The ANMS GCSI-DD is undergoing qualification by the FDA for use as a patient-reported 
outcome (PRO) outcome for clinical trials evaluating new treatments for either diabetic or idiopathic gastroparesis 
[27]. The ANMS GCSI-DD consists of five core symptoms (nausea, vomiting, early satiety, postprandial fullness, 
upper abdominal pain). Each night, participants grade the severity of symptoms over the prior 24 hours. The 
ANMS GCSI-DD core symptom composite score (an average of the five core symptoms) is designed to detect 
clinical improvement in symptoms of gastroparesis and to be used as a PRO outcome for clinical trials. 
c. Clinical Patient Grading Assessment Scale (CPGAS) will be used to help assess the therapeutic response of the 
participants. Participants will be asked if their rating of relief of symptoms during the past week compared to the 
way the participant usually feels has improved, stayed the same, or worsened with study treatment. The clinical 
response of their gastroparesis symptoms to study treatment with one point gradations from (+7) = completely 
better; (0) = no change, and (-7) = very considerably worse. Responders are defined as those with score of > 0 and 
non-responders with score of < 0 by CPGAS [28]. 
 
d. Health Survey (SF-36v2) is a 36-item, self-report measure designed to assess quality of life in participants [29]. 
This measure also provides two summary scores (physical and mental health) and eight scale scores. It is reliable 
and internally consistent. A higher summary score indicates better quality of life. 
 
e. Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QOL) is a self-completed 
disease-specific quality of life questionnaire; the respondent scores each of 30 factors from 0 (none of the time) to 
5 (all of the time) [30]. Items cover how often gastrointestinal problems have affected different aspects of their 
quality of life and well-being in the past two weeks.  There are five domains: Daily Activities, Clothing, Diet and 
Food Habits, Relationship, and Psychological Well-Being and Distress. Overall PAGI-QOL scores are calculated by 
taking means of all subscores after reversing item scores; thus a mean PAGI-QOL score of 0 represents poor 
quality of life while 5 reflects the best life quality. 
 
h. The Hospital Anxiety and Depression Scale (HADS) [31] was developed by Zigmond and Snaith (1983) and is 
commonly used to determine the levels of anxiety and depression that a patient is experiencing. The HADS is a 
fourteen-item scale that generates ordinal data. The HADS is comprised of 2 subscores, each scored from 0-21 
points: HADS-A is the anxiety subscore and HADS-D is the depression subscore.  Each subscore includes 7 
questions which are each scored from 0 (not at all) to 3 (most of the time). The items for each subscore are 
summed and the average results in the subscore. 
 


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g. The Gastrointestinal Symptoms Rating Scale (GSRS) is a clinical rating scale for gastrointestinal symptoms in 
participants with irritable bowel syndrome and peptic ulcer disease [32]. There are 15 items on the instrument, 
which are scored on a 7-point Likert scale from 0=no discomfort to 7=very severe. Using the scoring manual, total 
score and 5 scales can be computed (Abdominal pain, Reflux syndrome, Diarrhea syndrome, Indigestion 
syndrome, Constipation syndrome). 
 
h. The Patient Health Questionnaire 15 Somatic Symptom Severity Scale (PHQ-15) [33] is a brief, self-
administered questionnaire that may be useful in screening for somatization and in monitoring somatic symptom 
severity in clinical practice and research.  The total PHQ-15 score ranges from 0 to 30 comprising the sum of 15 
somatic symptoms in the past 4 weeks rated in severity from 0 (not bothered at all) to 2 (bothered a lot). 
 
8.1.6 STUDY PROCEDURES 
Tests to assess efficacy: 
Gastric Emptying Scintigraphy (GES) 
Gastric emptying scintigraphy will be performed using a low-fat, egg white Eggbeaters®meal with imaging at 0, 1, 
2, 4 hours after meal ingestion, as endorsed by the Society of Nuclear Medicine and American 
Neurogastroenterology and Motility Society (ANMS) (34,35). This protocol ensures standardized information 
about gastric emptying across multiple sites. Participants are instructed to come to the Nuclear Medicine Section 
in the morning after an 8-hour overnight fast, that is nothing by mouth after midnight and narcotic free for the 3-
days prior to the scheduled test. The morning of the week-4 GES test, the participant will wait to take their 
buspirone until thirty minutes prior to the start of the GES test. If the participant normally takes insulin, then they 
should take one-half of their normal long-acting insulin dose prior to the visit.  All diabetics will have their glucose 
checked prior to starting the GES test, with appropriate treatment measures being taken if low blood sugar 
(hypoglycemia or glucose < 60 mg/dL) or high blood sugar (hyperglycemia or glucose >270 mg/dl) is detected. GES 
is performed using a standard low-fat, egg-white Eggbeaters®meal to measure solid emptying. The meal consists 
of the equivalent of two large eggs radiolabeled with 0.5-1 mCi Tc-99m sulfur colloid served with two pieces of 
white bread and jelly. Participants are given 120 ml water. Following ingestion of the meal, imaging is performed 
at 0, 1, 2 and 4 hrs with the participant upright for measuring gastric emptying of Tc-labeled solids. In between 
imaging, participants generally sit in the nuclear medicine waiting area. Symptoms (nausea, fullness, pain severity, 
and episodes of vomiting) will be monitored and recorded during the GES test. Gastric emptying is analyzed as 
percent of radioactivity retained in the stomach over time using the geometric center of the decay-corrected 
anterior and posterior counts for each time point. Gastric retention of Tc-99m >60 % at 2-hours and/or >10% at 4-
hours is considered delayed gastric emptying of solids. Delayed gastric emptying is graded according to the gastric 
retention at 4-hours: mild (≤20% gastric retention at 4 hours), moderate (>20 to 35%), and severe (>35%) [35]. 
 
Intragastric meal distribution (IMD), as an assessment of fundic accommodation (FA), during GES.  
Analysis of regional intragastric meal distribution will be performed of the digital archived gastric emptying 
images, both at baseline and at the 4-week visit. We will use a modification of the method reported by Piessevaux, 
Tack, et al to assess intragastric meal distribution [14]. We will use our semi-automated analysis of regional 
intragastric meal distribution during GES. The analysis begins by aligning the images, then drawing regions of 
interest around the stomach using thresholding. The longitudinal axis of the stomach is then constructed. The 
stomach is then divided into two (proximal, distal) regions of interest by finding the midpoint of the longitudinal 
axis. The amount of radioactivity in each gastric region will be expressed as a percent of the total amount of 
radioactivity in the stomach at time 0. This will be assessed over time. The ratio of proximal over distal counts will 
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provides a measure of fundic accommodation. Impaired fundic accommodation using IMD is <0.568 ratio of the 
proximal gastric counts to the total gastric counts. 
 
Electrogastrogram (EGG) with water load satiety test [36]: 
For each EGG and water load test, the clinical center needs to have a one-liter opaque cup for water, 3 EGG leads, 
a dedicated quiet area for the EGG recording, a reclining chair, a blanket and the 3CPM EGG equipment and 
software. In addition, if the participant normally takes insulin, then they should take one-half of their normal long-
acting insulin dose prior to the visit. The morning of the week-4 EGG, the participant will wait to take their 
buspirone dose until 15 minutes before the baseline EGG. 
 
On the morning of the EGG and water load satiety test, the participant will arrive at the center after an 8-hour 
fast, that is nothing by mouth after midnight. Participants may take their usual medications with a small amount 
of water (up to 4 ounces) up to two hours prior to the study, but should refrain from coffee, tea, or juice. After 
arriving at the clinic, diabetic participants’ blood glucose level will be checked to ensure it is less than 270 mg/dL. 
If the participant’s blood glucose level is greater than 270 mg/dL, it is either treated and rechecked before 
proceeding or the EGG and water load satiety test will be rescheduled for another day under better glucose 
control. The participant will take their buspirone dose fifteen minutes prior to the 4-week baseline EGG recording. 
Baseline symptoms prior to EGG recording will be obtained using visual analog scales for stomach fullness, hunger, 
nausea, bloating, and abdominal discomfort. The subject will mark each symptom scale with a vertical line to 
indicate how they currently feel in terms of that symptom’s severity on a score from 0 (no symptoms) to 100 (the 
most severe symptoms). Once the EGG and respiratory signals are stable, the baseline EGG recording period can 
begin. Participants will undergo a 15-minute baseline EGG in a reclining chair with the subject positioned at a 30-
45 degree tilt. Participants will then begin the water load satiety test. For this, participants will sit upright. During 
the test, participants will drink cool water from the 1-liter cup. They will drink for a 5-minute period until they feel 
"completely full." It is important that the research associate at each site gives every participant the same 
instructions as follows: 
 
“I want you to drink water from this container until you feel completely full.  You have up to 
five minutes to reach the feeling of being completely full.  You may stop at any time, up to the 
five-minute time limit, when you feel completely full.  This is not at test to see how much you 
can drink, but to drink until you feel you are completely full in the five-minute period.  Do you 
have any questions about this?”   
 
The total volume of water consumed in mL will be recorded.  
 
A continuous 30-minute EGG recording is then obtained. The participant's symptoms are recorded using a visual 
analog scale at 10, 20, and 30 minutes after ingestion of the water (at the end of the 0-10 minute, 11-20 minute, 
and the 21-30 minute periods after the water load ingestion (post-satiety periods)). The test is completed after 
the 30-minute recording period and the electrodes are removed. 
 
Specimen repositories 
Specimens will be collected and stored in the NIDDK Biosample Repository for use as approved by the Steering 
Committee of the GpCRC and the NIDDK Central Repository after a specified period of time. Specimens include 
serum and plasma. The blood collected during screening, and at the 4 and 6-week follow-up visits will be separated 
into plasma and serum, and divided into 0.5 mL aliquots. Aliquots will be kept in a storage facility at -70 to -80 
degrees Centigrade until they are shipped on dry ice to the NIDDK Biosample Repository at Precision Medicine. 
 


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8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Assessments for Safety 
 
• Physical examination (e.g., height, weight, waist measurements, vital signs (temperature, heart rate, respiratory 
rate, blood pressure, ECG). 
• Laboratory results – All labs including creatinine, ALT, and glucose will be monitored at sites and in the central 
database and all abnormal values will be managed by the site investigator. If the ALT, creatinine, or glucose levels 
are elevated, that measure will be repeated within 5 days. If necessary, the participant will be given management 
advice and information will be provided to the participant’s PCP. 
 
• Standardized Questionnaires: 
a. Symptom side effects: Participants will be asked if they experienced any side effects from the BESST drug 
treatment and to describe any side effects. The baseline and follow-up medical histories will inquire about 
symptoms that may be attributed as side effects of buspirone using a standard set of questions. These 
symptoms include: headache, dizziness, tiredness, drowsiness, sleep problems (insomnia), nausea, upset 
stomach, blurred vision, nervousness or excitement. 
b. Adverse Event Report form: This form will document occurrence of an adverse event that threatens the 
integrity of the BESST trial or the well-being of a study participant during the trial. 
c. Serious Adverse Event/IND Safety Report: This form will document occurrence of any event reported on 
the Adverse Event Report form that satisfies the FDA expedited IND Safety Report requirement. 
 
• Biological specimen collection and laboratory evaluations are included in the Schedule of Activities and section 
in 12.2. Instructions for the preparation, handling, storage, and shipment of specimens are detailed in the BESST 
Standard Operating Procedures manual. 
 
If a participant has scores on the psychological questionnaire indicating significant anxiety or depression (HADS-A 
≥ 15 and/or HADS-D ≥ 15 indicating severe symptoms) or by the clinician’s assessment, the clinical center 
investigator or staff will suggest that they see a clinical psychologist or psychiatrist and information on these 
referrals will be given to the participant [37].  If the clinician is concerned that a participant is actively suicidal or at 
risk of self-harm, the clinical center investigator will help make arrangements for them to be seen that day for 
further assessment. 
 
For assessment of study intervention adherence see Study Intervention Compliance, section 6.4. 
 
Management of Comorbid Conditions 
 
Any participant’s comorbid conditions, including diabetes, will be managed according to the best clinical practice 
or evidence-based practices by the site principal investigator with input from the participant’s primary care 
physician (PCP), and with consideration for medications contraindicated for use with buspirone (listed in section 
6.5).  Most of the comorbid conditions will be treated by continuing the treatments already instituted by the 
participant’s regular physicians; worsening of the condition will be treated by the PI according to best clinical 
practice along with the participant’s regular physicians. If the physician determines that the participant’s safety is 
at risk, the participant’s study drug will be discontinued.  For follow-up care, the physician will refer the 
participant to their PCP or a specialist, if needed, and also continue to follow the participant at the site.  
 
A uniform set of practices to be applied by the GpCRC investigators in the care of these participants will be 
provided in the trial SOP (Standard of Care document), prepared by the GpCRC Steering Committee, including the 


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Study Medical Safety Officer, and in conjunction with the BESST PI. This document is based on accepted best 
clinical practice and guidelines from the American Gastroenterological Association, the American 
Neurogastroenterology and Motility Society, and the American College of Gastroenterology.  
 
If a participant develops diabetes during the participant’s participation in the trial and the physician determines 
the need for antidiabetic medication (e.g., because of lack of response to life style changes), the use of 
medications not contraindicated with buspirone will be recommended for the specialist to consider.  Likewise, for 
other classes of drugs (anti-hypertensives or anti-depressants) that may be prescribed for a worsening comorbid 
condition, careful consideration must be given to whether there is a non-contraindicated treatment with 
buspirone that can be prescribed to the participant, with the ultimate decision being the participant’s safety. 
 
Pregnancy will be managed according to the guidelines and study drug will be discontinued immediately upon 
discovery. For safety, a pregnancy test is done for female participants of child-bearing potential at each follow-up 
visit and before each GES procedure.  In the event of major dermatological reactions such as generalized urticaria, 
bullous rashes, and exfoliative dermatitis, study drug will be discontinued immediately and not restarted. For local 
skin reactions, study drug may be discontinued if the skin reactions are potentially drug related. If the rashes clear, 
the study drug may be restarted. 
 
Monitoring for comorbid conditions is done at each study visit through a follow-up medical history, follow-up 
physical exam, follow-up adverse event reports, and laboratory measures of glucose or other labs, as well as 
assessments of vital signs.  
 
In addition to the medications listed in section 6.5, which are exclusionary for the BESST trial, the 
Buspirone Investigator’s Brochure does not recommend use of the drug in patients with impaired 
hepatic or renal function. Prospective participants with these conditions will be excluded from the 
trial.  Most adverse events reported while taking buspirone are infrequent to rare, and are 
unexpected in the 4-weeks of treatment in the BESST trial. 
  
 
Follow-up of Ongoing Adverse Events 
 
Provisions for follow-up of adverse events (AE) include phone calls by the coordinators to assess 
symptoms, in-person follow up exams when needed to assess vital signs and physical findings and 
referral to local ongoing care by the PCP or hospital when needed. 
 
The participant is queried about the adverse event until there has been a resolution of the AE.  All information is 
recorded on the Adverse Event Report form and reviewed by the DSMB twice a year or at more frequent intervals if 
the DSMB determines the need. In addition, any AE with a severity grade greater than 2 is reviewed by the BESST 
Medical Safety Officer as soon as the event is keyed to the data system. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 


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An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization 
or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be used to 
classify Adverse Events when possible. 
8.3.3.1 SEVERITY OF EVENT 
 
All Adverse Events (AEs) will be assessed by the study clinician and classified and graded for severity using the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 when possible. 
The GpCRC Medical Safety Officer was involved in deciding which grading system to use for the GpCRC. 
 
For AEs not included in the protocol defined grading system, the following guidelines will be used to describe 
severity. 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. Of note, the term 
“severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment.  
 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect. 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or phenomenological 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
after administration of the study intervention, is unlikely to be attributed to concurrent disease or other 


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drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although an 
AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the event 
did not occur within a reasonable time after administration of the study intervention) and in which other 
drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The Study Physician will be responsible for determining whether an AE is expected or unexpected. An AE is 
considered "unexpected" if it is not listed in the Investigator Brochure or is not listed at the specificity or severity 
that has been observed; "unexpected," as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the Investigator Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug 
under investigation. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or serious adverse event (SAE) may come to the attention of study personnel during 
study visits and interviews of a study participant presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate 
case report form. Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study product (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event. All AEs occurring while in the study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as baseline 
and not reported as an AE unless the AE results from a study procedure performed during screening. However, if 
the study participant’s condition deteriorates at any time during the study, it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration 
of each episode. 
 
The Study Physician and Clinical Coordinator will record all reportable events with start dates occurring any time 
after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. 
Events will be followed for outcome information until resolution or stabilization. 


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8.3.5 ADVERSE EVENT REPORTING  
 
The GpCRC BESST Trial will monitor and report adverse events to ensure participant safety. There are two separate 
sets of government regulations that apply to unanticipated or adverse events in research studies: (1) 45 CFR Part 46, 
Subpart A: the Common Rule,42 shared by 17 Departments and Agencies and (2) 21 CFR 312,41: the FDA regulation for 
adverse events. The Common Rule requires written procedures and policies for ensuring reporting of unanticipated 
problems involving risks to participants to IRBs, appropriate institutional officials, and the Department or Agency Head. 
The FDA regulation requires notification of the FDA and participating investigators of any adverse event associated 
with the use of a test article that is both serious and unexpected. Investigators should refer to the 2009 FDA guidance 
Improving Human Subjects Protection,43 for adverse events reportable to their institutional IRB. Since the definitions 
and reporting requirements for unanticipated events differ between the two sets of Federal regulations, the GpCRC 
BESST Trial definitions and procedures for adverse events are designed to satisfy both sets of requirements. 
 
Adverse events will be recorded on the Adverse Event data forms whether or not they are thought to be associated 
with the study or with the study drug. Adverse events may be discovered during regularly scheduled visits or through 
unscheduled participant contacts between visits. Summary data on adverse events will be monitored by the DSMB 
quarterly and at its semi-annual meetings or more frequently, as needed. These summaries will include analyses 
comparing rates of adverse events by treatment group, by clinic, or in other subgroups requested by the DSMB. Where 
applicable, signs and symptoms associated with the adverse event will be graded as to severity by the clinical site staff 
as mild, moderate, or severe using the Common Terminology Criteria for Adverse Events version CTCAE v5.0. 
 
After each meeting, the DSMB will issue a written summary of its review of the study data, including adverse events, 
for transmission to the IRBs at each of the study centers. Analyses or listings of adverse events will not be provided to 
the IRBs; however, adverse events involving unanticipated problems involving risks to participants, or breaches of 
protocol which might entail risk to participants must be reported to local IRBs as soon as possible after they are 
discovered. Each participating center is responsible for ensuring that all local IRB requirements for reporting adverse 
events are met. A summary of adverse events will be reported to the FDA as part of the IND annual report. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
  
Serious adverse events (SAE) must be reported upon discovery at the clinical center per local IRB guidelines. This 
will involve completing an Adverse Event (AE) data form describing the severity and details of the serious adverse 
event. This must be submitted to the SDRC within one business day for review by the Medical Safety Officer. If the 
serious adverse event is judged by the study physician to be unexpected with a reasonable possibility of being 
caused by the buspirone study drug, then the investigator must also submit to the SDRC a SAE/IND Safety Report 
(SR) form, along with a narrative summarizing the circumstances of the event, the current status of the 
participant, and a copy of the IRB report within two working days. The SDRC will submit a preliminary report to 
the NIDDK for review within three calendar days of receiving the SAE/IND Safety Report (SR) form. The 
pharmaceutical manufacturer will be notified within one working day but no longer than three calendar days of all 
fatal/life threatening serious adverse events, regardless of association to study drug, 
 
If NIDDK determines that the SAE requires an expedited IND Safety Report, the NIDDK Program Official or the 
NIDDK Regulatory Affairs Specialist will notify the FDA no more than 15 calendar days from the initial receipt of 
the SAE by the SDRC (no later than 7 calendar days if the SAE is fatal or life threatening). The clinical center 
investigator may also be responsible for completing an FDA MedWatch 3500 form and additional information for 
a follow-up SAE report as information becomes available. If the FDA determines that a change to the Investigators 
Brochure, IND or protocol is needed, the SDRC will send a copy of the IND Safety Report to all clinical centers, with 


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instructions to forward the report to their IRB. NIDDK will determine if the DSMB members should be made aware 
of the event at that time, or it is appropriate to wait until the next DSMB meeting. 
 
The SDRC will maintain a list of all SAEs for reporting and review at Steering Committee meetings and DSMB 
meetings. The DSMB will review all SAE reports, at least twice a year. On a case-by-case basis, the NIDDK program 
staff, in conjunction with the DSMB chairperson, will determine whether the DSMB should review SAE reports 
more efficaciously. The DSMB will review each SAE report and provide comments to the NIDDK Program Official. If 
requested by any member of the DSMB, a teleconference will be scheduled to discuss the SAE and recommend 
any actions to the NIDDK. The clinical center must submit to the NIDDK and to the Scientific Data Research Center 
a follow-up memo within one month of the SAE (and periodic updates if needed) to report the details of the 
disposition of the SAE. 
 
The SDRC will provide to the pharmaceutical manufacturer copies of all SAEs regardless of association to 
buspirone study drug which involve disability, congenital anomaly/birth defects/fetal losses, hospitalizations, and 
important medical events, such as cancers with no prior history within five calendar days of receipt. In addition, 
the SDRC will report any pregnancy occurring in association with the use of study drug to the pharmaceutical 
manufacturer within three calendar days. The SDRC will report overdoses of the buspirone study drug to the 
pharmaceutical manufacturer every six months. An overdose that results in an SAE or is associated with an SAE, 
will follow the normal SAE reporting process and timeframe.  
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
 
Female participants must confirm that they are not pregnant or breastfeeding and if they become pregnant during 
the course of the study, participants must notify the study investigator immediately. A pregnancy test is obtained 
at study enrollment and at each visit to help assure that the participant is not pregnant. If a participant is found to 
be pregnant, study medication will be stopped indefinitely, and the coded medication will be unmasked. The 
participant, PCP, and investigator will be notified of the assigned treatment and the associated risks. 
 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to participants 
or others to include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in 
the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 


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8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing IRB and to the SDRC/principal investigator 
(PI). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• 
UPs that are serious adverse events (SAEs) must be reported to the IRB and to the SDRC/study sponsor 
within one working day from the date the investigator was aware of the event. 
• 
All other UP will be reported to the IRB and to the DCC/study sponsor within 10 days of the investigator 
becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s written 
reporting procedures), the supporting agency head (or designee), and the Office for Human Research 
Protections within 10 days of the IRB’s receipt of the report of the problem from the investigator. 
• Reports should be sent to: IRPT.OS@hhs.gov  
• All timelines related to SAE reporting with details are provided in protocol section 8.3.6. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
These would be reported to participants if they are unexpected, related or possibly related, and suggest a greater risk 
of harm to participants. 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
• 
Primary Efficacy Hypothesis: Buspirone at 10 mg three times daily for 4 weeks is better than placebo in 
improving early satiety and postprandial fullness in adults with symptoms of gastroparesis measured as 
change in the PAGI-SYM postprandial fullness/early satiety subscore. 
 
• 
Secondary Efficacy Hypotheses: Buspirone at 10 mg three times daily for 4 weeks is better than placebo in 
improving the following outcomes: 
1. Changes in GCSI total score 
2. Changes in PAGI-SYM subscores: nausea/vomiting, bloating, upper abdominal pain, GERD 
3. Changes in PAGI-SYM severity scores: Nausea, stomach fullness, inability to finish  a normal-
sized meal, feeling excessively full after meals, loss of appetite, bloating, upper abdominal 
pain 
4. Changes in Gastrointestinal Symptom Rating Scale (GSRS) total score 
5. Changes in Clinical Patient Grading Assessment Scale (CPGAS) score 
6. Changes in PAGI-QOL total score 
7. Changes in the Hospital Anxiety and Depression Scale (HADS) total scores for anxiety and 
depression 


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8. Changes in Patient Health Questionnaire (PHQ-15) total somatization score 
9. Changes in the SF-36v2 Quality of Life questionnaire physical and mental components scores 
10. Changes in percent of gastric emptying retention 
 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
Summary of sample size and computation of primary outcome: 
The primary outcome variable is change in the PAGI-SYM postprandial fullness/early satiety subscore from 
baseline to 4 weeks. This subscore is calculated by averaging the scores for 4 PAGI-SYM items: stomach fullness, 
inability to finish a normal-sized meal, feeling excessively full after meals, and loss of appetite. Each item score 
ranges from 0 (none) to 5 (very severe) on an ordinal scale. The 4-item average is treated as continuous in the 
primary ANCOVA analysis of change and for sample size purposes. 
The planned 108 participants sample size for this trial was derived using the following assumptions and methods: 
• 
2 equal size groups 
• 
Power=90% 
• 
Type 1 error (2-sided) = 0.05 
• 
Two-sided tests 
• 
Sample size increased by 10% to allow for 10% loss in primary outcome measure 
• 
Placebo group assumptions: Based on the APRON RCT placebo data [9], we assumed that: 
o Mean (SD) change in postprandial fullness/early satiety subscore at 4-weeks = 3.7 (0.8) 
o Change from baseline at 4-weeks of fullness/early satiety subscore = -0.7 (1.0) 
o Correlation of postprandial fullness/early satiety subscore at baseline and 4-weeks = 
0.55 
• 
Method of analysis = ANCOVA of the change in the primary outcome score controlling for baseline value 
of the primary outcome score 
• 
Intention-to-Treat Analysis using all randomized participants, corrected for missing outcome data: 
o Multiple imputation of the ANCOVA model using the chained equations method with 50 
imputations using the Stata Software Command:  mi 
• 
Minimal Clinical Important Difference (MCID) = 0.62 SD (0.5 subscore points) 
• 
Sample size software: Stata Software Command: power repeated 
• 
Sample size = 108 total (54 per group) 
 
 
Sample size for the primary outcome varying the MCID 
MCID in SD units 
0.3 SD 
0.50 SD 
0.62 SD* 
1 SD 
MCID subscore units 
0.24 
0.4 
0.5 
0.8 
Total sample size 
460 
168 
108 
42 
Number per group 
230 
84 
54 
21 
* MCID between investigator-related severity and fullness/early satiety subscore range=0.62-0.70 SD [25] 
 
For the key secondary outcome, symptom improvement by 1-point or more in the PAGI-SYM GSCI total score from 
baseline to week 4, we determined that the total sample size of 108 participants (54 per group) gives 80% power 
to detect an MCID for a relative improvement ratio=1.8 (60% buspirone vs. 32% (placebo based on APRON 


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placebo data)). We used a nominal Type 1 error of 5%, with no corrections of the Type 1 error for the multiplicity 
of secondary outcomes. 
 
The investigators conducting this trial have previously recruited for two trials for the GpCRC and along with their 
experiences in their clinic research were confident that the estimated number of 18 participants per site at a rate 
of one participant per month per site was a recruitment target that could be met. 
 
9.3 
POPULATIONS FOR ANALYSES 
Analysis datasets will include:  
a. Intention-to-Treat – all randomized participants 
b. Safety Analysis Dataset – participants who took at least one dose of treatment 
c. Other Datasets for Sensitivity analyses on a per-protocol basis (as needed: by etiology, sex, race, narcotic 
use, etc.) 
i. 
Complete-Case Analysis Dataset – subset of participants with 4-week outcome data 
ii. 
Adherence Analysis Dataset – subset of participants who took at least 80% of treatment 
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
 
The primary analysis is an intention-to-treat analysis of the change in the PAGI-SYM questionnaire  
postprandial fullness/early satiety subscore over 4-weeks of treatment. This subscore is calculated as the 
average of four items on the PAGI-SYM questionnaire: stomach fullness, inability to finish a normal-sized 
meal, feeling excessively full after meals, and loss of appetite. The subscore average and each item score 
ranges from 0 (none) to 5 (very severe) on an ordinal scale and is treated as a continuous measure. The 
statistical model for change in postprandial fullness/early satiety at 4-weeks will be an ANCOVA model with an 
indicator variable for treatment group adjusted for the baseline value of the postprandial fullness/early satiety 
subscore. If a participant has missing 4-week outcome data, then multiple imputation modeling for missing 
data will be used. 
 
Secondary, sensitivity analyses on a per-protocol basis will also be carried out, excluding participants from 
both groups who do not have the 4-week outcome data, but conclusions about the primary objective will be 
based on the intention-to-treat analysis. In addition, sensitivity analysis may be done using the subset of 
participants with adherence (defined as taking their treatment at least 80% of the time). 
 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY OUTCOME(S) 
• 
Intention-to-Treat (ITT) Analysis Dataset  
 
The primary outcome will be change in the PAGI-SYM questionnaire postprandial fullness/early satiety subscore 
from baseline to 4 weeks; this subscore is calculated by averaging the scores for 4 PAGI-SYM items: stomach 
fullness, inability to finish a normal-sized meal, feeling excessively full after meals, and loss of appetite. The 
subscore average and each item score ranges from 0 (none) to 5 (very severe) on an ordinal scale and is treated as 
a continuous measure. The treatment effect will be estimated using an intention-to-treat (ITT) analysis of 
covariance (ANCOVA) model, regressing the change from baseline in postprandial fullness/early satiety subscore 
at 4-weeks on an indicator variable for treatment group and the baseline value of the outcome. The treatment 
group difference in adjusted mean change will be presented, along with a two-sided 95% confidence interval, and 
a P-value. 


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The confidence limits and P-value will come from the Intention-to-Treat multiple imputation ANCOVA model 
using all randomized participants, corrected for missing data, as described in Section 9.2 above. 
  
Descriptive analyses will address the assumption of normality of the outcomes using distributional tests (Shapiro-
Wilks) and plots (lowess smoothed histograms, boxplots). Tests of normality of the residuals post-ANCOVA 
regression will be done. If the normality assumptions are not met, then sensitivity analyses using bootstrapped 
ANCOVA regression will be used to assess validity of the confidence limits and P-values. 
 
Secondary, sensitivity analyses of the primary outcome will use the ITT Dataset and include: 
• 
Complete case ANCOVA, excluding participants with missing data 
• 
The same analysis as above comparing subsets of participants with high  vs. not high adherence 
• 
Repeat the Intention-to-Treat analysis adjusting for potential confounders not balanced by the 
randomization, such as use of narcotics, gastroparesis etiology, percent gastric retention, sex, and age. 
• 
Other secondary, sensitivity analysis conducted will be to model each of the four individual symptom 
scores of the PAGI-SYM questionnaire postprandial fullness/early satiety subscore using the same 
methods as above. 
• 
Graphs plotting the time course of mean change scores of the outcome and two-sided 95% confidence 
intervals by treatment group across visit (screening, 2, 4, 6 weeks) will be done. The significance of the 
overall treatment effect of change over time will be computed from generalized estimating equations 
(GEE) linear regression, modeling change as a function of treatment group, visit code indicator, baseline 
value of the outcome, and a treatment group by visit code interaction term. 
• 
Using the PRO GCSI-DD, the two items, “not able to finish a normal-sized meal” and “feeling excessively 
full after meals” will be averaged to measure postprandial fullness/early satiety.  The same method as 
above will be used; however, the baseline value is the average of the 7-day screening period daily-diary 
responses, and the 4-week measure is the average of the last 7-days of treatment. The change in each 
outcome is computed as the baseline average value subtracted from the 4-week average measure. A 
sensitivity analysis using a repeated measures method to account for within participant correlation will 
also be used. 
 
 
9.4.3 ANALYSIS OF THE SECONDARY OUTCOME(S) 
 
• 
Analysis of secondary outcomes are not dependent on findings of the primary endpoint  
• 
Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants)  
• 
Complete-Case Dataset 
 
The analyses of secondary and exploratory outcomes are not dependent on findings of the primary outcome. The 
ITT Analysis Dataset will be used for any binary efficacy outcomes, and for continuous efficacy outcomes with 10% 
or more of the participants having missing data for the 4-week outcome. In that case, the ITT Analysis Dataset 
using multiple imputation with chained equations method modeling missing data on treatment group and 
baseline value of the outcome using 50 datasets will be done. Otherwise, the Complete-Case dataset may be used 
to analyze the continuous secondary efficacy outcomes and all safety outcomes. Except for improvement in GCSI 
total score defined as being 1 or more points less at 4-weeks than at baseline, and some safety measures (adverse 
event counts), the other secondary outcomes are continuous changes from baseline at 4-weeks. 
 
Secondary outcomes are listed in section 9.1. Assumptions will be checked and models checked post-estimation of 
the regressions as stated in section 9.4.3. 


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The “main” secondary outcome is the change in the total GCSI score. This will be analyzed as both a continuous 
change variable, and also as the binary improvement variable using a logistic regression model regressing 
improvement on treatment group and the baseline value of the total GCSI. Relative Odds, two-sided 95% 
confidence intervals and a significance level computed using a likelihood ratio test will be reported. 
 
The analysis of secondary outcomes will use complete-case analysis of covariance (ANCOVA) models for 
continuous outcomes, regressing the change from baseline in outcome at 4-weeks on an indicator variable for 
treatment group and the baseline value of the outcome. The treatment group difference in adjusted mean change 
will be presented, along with a two-sided 95% confidence interval, and P-value for each secondary outcome from 
the ANCOVA model for the between-groups difference in the means. P-values will be nominal, and not be 
adjusted for the multiplicity of secondary outcomes. 
 
 
9.4.4 SAFETY ANALYSES 
 
Safety data will be presented by treatment group to the Data and Safety Monitoring Board during the course of 
the trial. Each adverse event will be displayed showing AE name per the CTCAE v5.0 when applicable, class, 
severity grade, random patient ID, clinic, treatment group, time since randomization, resolution status and 
physician’s assessment of relatedness to treatment. Participant-specific summary tables including any adverse 
event (yes vs no), frequency of multiple adverse events (i.e., 0, 1, 2, 3+) and highest severity grade of adverse 
event (none, mild, moderate, severe, life-threatening) will be displayed by treatment group along with p-values 
from Fisher’s exact tests. 
 
In addition, rates of adverse events and hospitalizations will be reported between treatment groups, both by 
number of events and by participant. Count data will be analyzed using a negative binomial model accounting for 
over-dispersion of the count data. 
 
Other safety data to be monitored include baseline levels and changes in laboratory measures, weight, and ECG 
results. These will be compared between treatment groups using ANCOVA models for change in measures or 
Fisher’s Exact Tests for categorical outcomes. 
 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline data will be presented by treatment group and total. Data include demographics, complete metabolic 
panel, complete blood count, HbA1c, TSH, concomitant medications, comorbidities, physical exam measures and 
baseline values of the outcome measures including the GCSI total score, PAGI-SYM questionnaire subscores and 
individual severity item scores, GSRS total score, other questionnaires, percent gastric retention at 4-hours, and 
EGG and satiety results. Means and standard deviations (continuous), medians and inter-quartile range (skewed 
continuous) or number and percent (binary, categorical) will be reported. P-values will be presented in the 
footnotes as descriptive statistics only if reaching ≤ 0.05 level and noting that any treatment group differences are 
due to chance. 
 
Binary and categorical variables will be analyzed using chi-square tests, and continuous variables using t- tests. If a 
continuous variable is highly skewed, then a nonparametric test (Wilcoxon rank sum tests for comparison of the 
distribution of changes in each group) will be used to determine significance. 
 
 


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9.4.6 PLANNED INTERIM ANALYSES  
 
There are no planned interim analyses for efficacy or safety. This is a trial with a very short duration of treatment 
of 4-weeks, that is using a drug that has a history of safety and is non-habit forming. Safety will be monitored by 
the DSMB throughout the trial. 
 
9.4.7 SUB-GROUP ANALYSES 
 
Post-hoc subgroup analysis of the primary outcome will be done by possible confounders including clinic, etiology 
(diabetic or idiopathic), gastric retention (delay or not delayed), sex, age (< 50, ≥50 yrs), adherence (80% or more 
of dose vs <80%), narcotic use at baseline and during trial (vs no use), symptoms at baseline (severe/very severe 
vs none to moderate), BMI group (normal/underweight vs overweight/obese). If available at the time of the 
primary paper analyses, then fundic accommodation at baseline (impaired vs normal) will also be included in the 
subgroup analyses. 
 
Subgroup analyses will use the same models as used for the Intention-To-Treat ANCOVA models for the complete 
data, as described above. Difference in effects between subgroups will be assessed using the same ANCOVA models 
augmented with an interaction term for the difference in treatment effects between the subgroups; a P-value less 
than 0.01 for the interaction term from the augmented ANCOVA will be required for statistical significance of the 
subgroup difference. If subgroup differences are found, these will be reported and used to provide additional 
information about the effectiveness of the drug in subgroups of this participant population; however, the primary 
result of the trial will stand regardless of any subgroup differences that may be found. 
 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
For monitoring of adverse effects, individual data may be presented to the Data and Safety Monitoring Board. In that 
case, study participants will be identified only by study IDs. Names and other unique individual identifiers such as Social Security 
Number are not collected by the study and therefore will not be presented to the DSMB. Individual data including ID will not be 
presented in a manuscript. 
 
 
9.4.9 EXPLORATORY ANALYSES 
   
Outcomes for exploratory or ancillary analysis, depending on the timeframe of additional work required to 
interpret and quality control data from the gastric emptying scintigraphy tests and the electrogastrogram test 
digital scans at the GpCRC central resource centers, are listed below: 
 
The first and second outcomes are ancillary: 
 
1. Changes at 4-weeks in Fundic Accommodation (FA) using digital analyses of the GES test images 
2. Changes and mean changes, respectively, at 4-weeks in EGG test gastric rhythm measures and water 
satiety:  a) clinical EGG diagnosis (normal, tachygastria, bradygastria, mixed gastric dysrhythmias; b) 
percentage time and distribution of power in normal 3 cpm EGG activity before and after the water load 
satiety test and c) total volume of water ingested. 
 
This following outcome is exploratory since it is using the PRO daily-diary version of the ANMS GCSI questionnaire 
that is not currently validated; however, these outcomes may provide sensitivity analyses on several secondary 
outcomes. 


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3. Mean changes at 4-weeks in each of the 7 items on the ANMS GCSI-DD questionnaire: nausea, 
postprandial fullness, early satiety, upper abdominal pain, episodes of vomiting, episodes of retching, 
overall symptom severity, as well as the total core symptom composite score. The average severity scores 
from the last 7-days of treatment are subtracted from the 7-day average baseline severity scores for each 
of the items. 
 
These two outcomes listed below are ancillary since they are not necessarily powered to detect a change between 
treatment groups; however, they may provide information on buspirone to develop further hypotheses in the 
future. 
 
4. Changes at 4-weeks in each of the 15 symptom severity items measured on the PAGI-SYM instrument not 
included in secondary outcomes item 3, including retching, lower abdominal pain, lower abdominal 
discomfort, constipation, and diarrhea 
5. Changes at 4-weeks in each of the 5 subscores of the Gastrointestinal Symptom Rating Scale (GSRS). 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
 
Template consents will be prepared for the GpCRC BESST Trial by the SDRC. Individual clinical centers may add 
material, but may not delete material thought to be necessary for informed consent. Clinical centers may 
reformat and reword information to conform to their local IRB requirements. A consent form must be signed by 
each participant. The consent form will describe the purpose of the study, the procedures to be followed, and the 
risks and benefits of participation. A copy of the consent form will be given to the participant and this fact will be 
documented in the subject’s study files. 
 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to starting intervention and administration of 
the study intervention and procedures. The following consent materials, BESST Combined Consent – HIPPA Adult, 
are submitted to IRBs with this BESST protocol. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation. Consent forms will be Institutional Review Board (IRB)-
approved and the participant will be asked to read and review the document. The investigator will first explain the 
research study to the participant and answer any questions that may arise. A verbal explanation will be provided 
in terms suited to the participant’s comprehension of the purposes, procedures, and potential risks of the study 
and of their rights as research participants. 
 
Participants will have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their family or surrogates or think 
about it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the BESST study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the informed 


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consent document will be given to the participants for their records. The informed consent process will be 
conducted and documented in the source documents (including the date) for the participant, and the form signed 
before the participant undergoes any study-specific procedures. The rights and welfare of the potential 
participants will be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
To minimize in-person contact time between the participant and staff during the Covid-19 pandemic and as 
permitted by the site-specific IRB and/or the sIRB, participants will be offered a telephone or virtual review of the 
consent in place of the in-person review of the consent.  Signature of the consent will take place in person at the 
study visit and after confirmation that all of the participant’s questions about the study have been answered. 
 
10.1.2  
STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigators, funding agency, the Investigational New Drug 
(IND) sponsor (N/A) and regulatory authorities. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and 
be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy 
the DSMB, sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological samples in 
addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence. No information concerning the study or the 
data will be released to any unauthorized third party without prior written approval of the sponsor. 
 
All laboratory specimens, study forms, reports, and other records that are part of the study data collection 
materials will be identified by coded number to maintain participant confidentiality. All records will be kept in 
locked file cabinets. All electronic records of study data will be identified by the coded number. Clinical 
information will not be released without written permission of the participant, except as necessary for monitoring 
by the IRB. Consent procedures and forms, and the communication, transmission and storage of participant data 
will comply with individual site IRB and NIH requirements for compliance with The Health Insurance Portability 
and Accountability Act (HIPAA). 
 
All research activities will be conducted in as private a setting as possible. 
 


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The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review 
Board (IRB), regulatory agencies or pharmaceutical company supplying the study product may inspect all 
documents and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site 
will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the GpCRC SDRC. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique identification 
number and letter code. The study data entry and study management systems used by clinical sites and by GpCRC 
SDRC research staff will be secured, password-protected and are encrypted. At the end of the study, all study 
databases will be de-identified and archived at the NIDDK Data Repository. 
 
Consent procedures and forms, and the communication, transmission and storage of participant data will comply 
with individual site IRB and NIH requirements for compliance with The Health Insurance Portability and 
Accountability Act (HIPAA). 
 
Per NIH Notice NOT-OD-17-109 (Notice of Changes to NIH Policy for Issuing Certificates of Confidentiality 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-109.html), this research is deemed to be issued a 
Certificate through this Policy and is therefore required to protect the privacy of individuals who are subjects of 
such research in accordance with subsection 301(d) of the Public Health Service Act. 
 
This certificate protects identifiable research information from forced disclosure. It allows the investigator and 
others who have access to research records to refuse to disclose identifying information on research participation 
in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. 
By protecting researchers and institutions from being compelled to disclose information that would identify 
research participants, Certificates of Confidentiality help achieve the research objectives and promote 
participation in studies by helping assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Biological specimens will be collected and stored for use as approved by the Steering Committee of the GpCRC 
(see Appendix 12.2 for blood collection schedule). Specimens to be stored include plasma and serum. Twenty mL 
of blood will be collected at the screening visit and at the week 4 and 6 follow-up visits. The blood will be drawn in 
the morning during the study visit while the participant is still fasting. The blood will be separated into plasma and 
serum and then divided into 0.5 mL aliquots. Plasma and serum aliquots will be kept in a freezer at -70 or -80 
degrees Centigrade and will be sent to the NIDDK Biosample Repository for banking. 
 
 


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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
BESST Principal Investigator 
BESST Principal Investigator 
Medical Monitor 
Henry P. Parkman, MD 
Pankaj Jay Pasricha, MD 
William Hasler, MD 
Temple University Hospital 
Johns Hopkins University School 
of Medicine 
 Mayo Clinic Arizona 
3401 North Broad St., 8th Floor 
Philadelphia, PA 19140 
720 Rutland Ave., Room 958 
Baltimore, MD 21287 
13400 E. Shea Blvd.,  
Scottsdale, AZ 85259 
215-707-7579 
410-955-8612 
480-347-3538 
henry.parkman@temple.edu 
ppasric1@jhmi.edu  
hasler.william@mayo.edu  
 
GpCRC Executive Committee (EC) - Consists of GpCRC co-chairpersons, SC representatives, principal 
investigator of the SDRC, NIDDK program official, and NIDDK project scientist. The GpCRC EC discusses 
directions and strategic issues related to the scientific aims of the GpCRC; organizes and sets agenda for 
Steering Committee meetings and provides oversight of study. 
 
GpCRC Steering Committee (SC) – Consists of the principal investigators of each of the clinical centers, the principal 
investigator of the SDRC, and the NIDDK project scientist, each of whom has one vote in any decision requiring a 
formal vote. The GpCRC SC is the major decision-making body for GpCRC, which provides oversight in the planning and 
conduct of studies. The SC votes on all important decisions and approves the final database and protocol and any 
amendments or modifications of the protocol. 
 
10.1.6 SAFETY OVERSIGHT: DATA AND SAFETY MONITORING BOARD 
 
• 
Each participating clinical center is responsible for ensuring that local IRB requirements for 
reporting adverse events are met. 
• 
The SDRC staff at the Johns Hopkins Bloomberg School of Public Health follows the 
JHSPH IRB guidelines and reports the unanticipated problems or adverse events to the 
NIDDK and the DSMB. 
• 
The NIDDK appointed DSMB will monitor the data for safety and efficacy for outcomes such 
as toxicity and any other outcomes or events identified as safety-related. 
 
Safety oversight will be under the direction of an independent Data and Safety Monitoring Board 
(DSMB) composed of individuals with the appropriate expertise, including gastroenterology, internal 
medicine, and statistics. Members of the DSMB are independent from the study conduct and free of 
conflict of interest. 
 
The DSMB is appointed by the NIDDK and will review the protocol for the BESST trial and monitor 
the safety data as the trial progresses to ensure participant safety. The DSMB is a multidisciplinary 
group with a written charge provided by the NIDDK. The DSMB reports to the NIDDK, which will 
communicate DSMB recommendations to the investigators, as appropriate. The DSMB will hold a 
meeting to approve the protocol. The DSMB will review performance and safety data. The DSMB 
may request more frequent meetings if necessary to fulfill its charge. It may also request additional 
safety reports on a more frequent basis. All serious adverse events are reported to the DSMB for 
their consideration and recommendations as they occur. 
 
The DSMB also reviews the overall progress of the trial in terms of recruitment and data quality and 
makes a formal recommendation to the NIDDK at the end of each scheduled meeting as to whether 
the trial should continue unmodified, continue with protocol modifications, or be stopped. 


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10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial complies with the currently approved protocol/amendment(s), with 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable 
regulatory requirement(s). 
• 
Monitoring for this study will be performed by the SDRC of the GpCRC. 
• 
To ensure data quality and reduce data entry error, double-data entry of all data collection forms is 
required. The SDRC will incorporate into the data entry programs a series of edit checks, including range 
checks, logic checks (e.g., skip patterns), and consistency checks, both within a data form and across 
forms. These integral checks are designed to detect deficiencies in the data before they are entered into 
the study database, so that the deficiencies may be easily and accurately corrected. In addition, the SDRC 
will perform frequent computerized edit checks on entered data. The SDRC will also perform ongoing 
comparisons of copies of entered data forms with the databases to ensure that data entered into the data 
system reflect those recorded on the forms. Such audits will help to pinpoint problems that cannot be 
detected by computer editing and may be used to guide increased scrutiny when needed. Any data 
queries identified will be flagged for action by the clinical site until resolved. 
• 
The data system will maintain a clear and complete audit trail of all changes to the study databases. All 
changes to data forms will be documented appropriately on the paper form and entered into GpCRC 
BESST data system. All forms entered and/or edited in the data system will be identified by the unique 
Personal Identification Number (PIN) of the operator, the network address (the “IP” address) of the 
computer being used, and the date and time of the operation. Records will not be deleted but rather 
marked as having been superseded. The SDRC will implement various procedures to ensure the quality of 
its internal operations. These will include the development and maintenance of documentation regarding 
procedures for receiving, processing, and analyzing data, and duplicated programming for selected 
procedures to check for errors in software database and analysis systems. 
• 
Performance monitoring: The web-based data system will allow for real-time reporting of most 
recruitment and data management activities. However, additional performance reports will be generated 
and circulated monthly and typically reviewed at each Steering Committee (SC) meeting. These reports 
include several key indicators of study performance, including counts of participants screened and 
randomized, of completed visits and of missing key data, of missed visits, and statistics summarizing 
performance with respect to timeliness of data entry and response to data queries. 
• 
The SC and the DSMB will conduct a formal review of the study by conference call or in-person meeting 
twice a year and will address quality assurance as part of their agenda. These Committees will have 
responsibility for recommending corrective actions based on the performance data. It is anticipated that the 
primary responsibility for formulating and implementing these actions will reside in the SC. Potential actions 
might include specific recommendations for training, redistribution of study resources, or possibly 
termination of support for a center. 
• 
Independent audits outside the SDRC will not be conducted. 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
   
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion. 


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Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks 
that are run on the database. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the GpCRC monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and reported 
in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for 
the purpose of monitoring and auditing by the GpCRC, and inspection by local and regulatory authorities. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site Principal 
Investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. 
 
Hard copies of the study visit worksheets will be provided for use as source document worksheets for recording 
data for each participant enrolled in the study. Data recorded in the electronic case report form derived from 
source documents should be consistent with the data recorded on the source documents. 
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse  reactions data and 
clinical laboratory data) will be entered into the GpCRC database, a 21 CFR Part 11-compliant data capture system 
provided by the SDRC. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents (case report forms).  
 
10.1.9.2 STUDY RECORDS RETENTION  
 
The NIDDK records retention policy is to maintain clinical trial records for 3 years after the granting period ends or 
the trial ends, whichever is later. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Standard Operating Procedures (SOP) requirements. The 
noncompliance may be on the part of either the participant, the investigator, or the study site staff.  Because of 
deviations, corrective actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH GCP: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 


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It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations within 5 
working days of identification of the protocol deviation, or within 10 working days of the scheduled protocol-
required activity. All deviations must be addressed in study source documents, reported to NIDDK Program Official 
and the SDRC. Protocol deviations must be sent to the reviewing IRB per local site policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. Further details about the handling of 
protocol deviations will be included in the SOP. 
 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy ensures that the public has access to the published results 
of NIH-funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from 
NIH funds to the digital archive PubMed Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical 
Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will 
be registered at ClinicalTrials.gov, and results and information from this trial will be submitted to ClinicalTrials.gov. 
In addition, every attempt will be made to publish results in peer- reviewed journals. 
 
Data from this study may be requested from the NIDDK Central Repository 
(https://www.niddkrepository.org/search/study/) two years after the completion of the primary outcome. 
 
This study will not be collecting DNA specimens from participants, so there will be no genomic data or genomic 
sequencing data from DNA to deposit in in the NIH Genomic Repository.  
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation 
in the design and conduct of this trial. The GpCRC study leadership in conjunction with the NIDDK has established 
policies and procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
None 
 
 


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10.3 ABBREVIATIONS 
 
5-HT 
5-hydroxytryptamine 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANMS 
American Neurogastroenterology and Motility Society 
APRON 
Aprepitant for the Relief of Nausea in Patients with Chronic Nausea and Vomiting of 
Presumed Gastric Origin Trial 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index (kg/m2) 
BUN 
Blood Urea Nitrogen 
CO2 
Carbon Dioxide/bicarbonate 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CMP 
Complete Metabolic Panel 
CNS 
Central Nervous System 
CPGAS 
Clinical Patient Grading Assessment Scale 
CPM 
Cycles Per Minute 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CUNV 
Chronic Unexplained Nausea and Vomiting 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EGG 
Electrogastrogram 
FA 
Fundic Accommodation 
FDA 
Food and Drug Administration 
GES 
Gastric Emptying Scintigraphy  
GCSI 
Gastroparesis Cardinal Symptom Index 
GCSI-DD 
Gastroparesis Cardinal Symptom Index – Daily Diary 
GERD 
Gastroesophageal reflux disease 
GpCRC 
Gastroparesis Clinical Research Consortium 
GpR 
Gastroparesis Registry (study) 
GSRS 
Gastrointestinal Symptoms Rating Scale 
HADS 
Hospital Anxiety Depression Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
IMD 
Intragastric Meal Distribution 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
MAOI 
Monoamine oxidase inhibitor 
MCID 
Minimal Clinical Important Difference 
N/A 
Not applicable 
NIDDK 
National Institute of Diabetes and Digestive Kidney Diseases 
OHRP 
Office of Human Research Protections 
PAGI-QOL 
Patient Assessment of Upper Gastrointestinal Disorders-AGI Life 
PAGI-SYM 
Patient Assessment of Upper Gastrointestinal Disorders Symptom Severity Index 
PCP 
Primary Care Provider 
PHQ-15 
Patient Health Questionnaire 15 Somatic Symptom Severity Scale 


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PI 
Principal Investigator 
PIN 
Personal Identification Number 
PRO 
Patient-Reported Outcome 
RCT 
Randomized Control Trial 
SAE 
Serious Adverse Event 
SDRC 
Scientific Data and Research Center 
SoA 
Schedule of Activities 
SOP 
Standard Operating Procedures 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problems 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a description of the 
change and rationale. A Summary of Changes table for the current amendment is located in the Protocol Title Page.  
 
 
Version 1.2; 11 Sep 2020 
Description of Change 
Brief Rationale 
 
1.1 Synopsis  
Changed age range from 18-75 to 18-85  
Changed Total Study Duration to 96 weeks (24 months) 
Changed Recruitment to 90 weeks (22.5 months) 
Changed: Expected enrollment rate to .8 participant per month per 
clinical center (18 participants each at 6 centers) 
Compliance with Inclusion across 
the Lifespan policy. 
Recruitment has been slower 
than expected. This will extend 
through May 31, 2021. 
1.3 Schedule of Activities  
Removed x at screening for Clinical Patient Grading Assessment 
Scale (CPGAS) 
This is only done during follow-up 
5.1 Inclusion Criteria  
Changed Aged 18 to 75 years at initial screening interview to 
Aged 18 to 85 years at initial screening interview 
 
Compliance with Inclusion across 
the Lifespan policy. 
5.5.1 Recruitment  
Changed recruitment time to 22.5 months 
Recruitment has been slower 
than expected. This will extend 
through May 31, 2021. 
8.1.6 Study Procedures  
Deleted: This analysis reads the scintigraphic images in an 
application written for MATLAB software [17]. 
Remove reference to software 
used as this may change. 
8.1.2, 10.1.1.2 
Added: To minimize in-person contact time between the participant 
and staff during the Covid-19 pandemic and as permitted by the 
site-specific IRB and or sIRB, participants will be offered a telephone 
or virtual review of the consent in place of the in-person review of 
the consent.  Signature of the consent will take place in person at 
the study visit and after confirmation that all of the participant’s 
questions about the study have been answered. 
COVID19 
7.2 Participant Discontinuation/Withdrawal from the Study  
Added: The sponsor or investigator terminates the study.  
 
COVID19 
 
10.3 Abbreviations 
Bicarbonate; accommodation 
 
Corrected spelling 
11. References  
Added PMID to References 
NIH format 
 
 
 


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24. Rentz AM, Kahrilas P, Stanghellini V et al. 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 2004;13(10):1737-49. 
25. Revicki DA, Rentz AM, Dubois D, Kahrilas P, Stanghellini V, Talley NJ, Tack J.  Gastroparesis Cardinal Symptom 
Index (GCSI): Development and validation of a patient reported assessment of severity of gastroparesis 
symptoms.  Qual Life Research 2004;13:833-844. PMID: 15651544 
26.  Revicki DA, Camilleri M, Kuo B, Szarka LA, McCormack J, Parkman HP. Evaluating symptom outcomes in 
gastroparesis clinical trials: validity and responsiveness of the Gastroparesis Cardinal Symptom Index-Daily 
Diary (GCSI-DD). Neurogastroenterol Motil 2012;24(5):456-63. PMID: 15129893 
27. Hui R. Gastroparesis: Clinical evaluation of drugs for treatment: Guidance for industry. Food and Drug 
Administration Center for Drug Evaluation and Research (CDER). July 2015. 
28. Simmons K, Parkman HP. Granisetron Transdermal System Improves Refractory Nausea and Vomiting in 
Gastroparesis. Dig Dis Sci. 2014;59:1231-1234. PMID: 24615549 
29. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and 
item selection. Med Care 1992; 30: 473-483. PMID: 1593914 
 


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30. De La Loge C, Trudeau E, Marquis P, Kahrilas P, Stanghellini V, Talley NJ, Tack J, Revicki DA, Rentz AM, Dubois 
D. Cross cultural development and validation of a patient self-administered questionnaire to access quality of 
life in upper gastrointestinal disorders: the PAGI-QOL. Qual Life Res 2004; 13: 1751-1762. PMID: 16283929.  
PMCID: PMC1325267 
31.  Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361-370. 
PMID: 6880820 
32. Svedlund J, Sjodin I, Dotevall G. GSRS--a clinical rating scale for gastrointestinal symptoms in patients with 
irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci 1988;33:129-34. PMID: 3123181 
33. Kroenke K, Spitzer RL, Williams JB. The PHQ-15: validity of a new measure for evaluating the severity of 
somatic symptoms. Psychosom Med 2002; 64: 258-266. PMID: 11914441 
34. Tougas G, Eaker EY, Abell TL, et al.  Assessment of gastric emptying using a low fat meal: Establishment of 
international control values.  Am J Gastroenterol 2000;95:1456-1462. PMID: 10894578 
35. Abell TL, Camilleri M, Donohoe K, et al.  Consensus recommendations for gastric emptying scintigraphy: a 
joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear 
Medicine.  Am J Gastroenterol 2008;103:753-763. PMID: 18028513 
36. Koch KL, Hong SP, Xu L. Reproducibility of gastric myoelectrical activity and the water load test in patients 
with dysmotility-like dyspepsia symptoms and in control subjects. J Clin Gastro 2000;31:125-9. PMID: 
10993427 
37. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An 
updated literature review. J Psychosom Res 2002;52:69–77. PMID: 11832252 
 
12  APPENDIX  
12.1 PARTICIPATING CENTERS 
Clinical Centers 
Johns Hopkins Hospital, Baltimore, MD 
Massachusetts General Hospital, Boston, MA 
Temple University, Philadelphia, PA 
Texas Tech University Health Science Center, El Paso, TX 
University of Louisville, Louisville, KY 
Wake Forest University Health Sciences, Winston-Salem, NC 
Scientific Data Research Center 
 
Johns Hopkins University, Baltimore, MD 
National Institutes of Health 
 
National Institute of Diabetes and Digestive and Kidney Diseases 
EGG Reading Center 
 
Wake Forest University Health Sciences, Winston-Salem, NC 


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GES Reading Center for Fundic Accommodation 
 
Temple University, Philadelphia, PA 
NIDDK Central Repository 
 
 
 
 
 


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12.2 BLOOD COLLECTION SCHEDULE (amounts in mL) 
 
 
Screening 
visits 
Follow-up visits 
Weeks from Randomization 
mL 
Labs 
RZ 
f2 
f4 
f6 
Total mL 
Complete blood count (CBC) 
5 
. 
5 
5 
15 
Comprehensive metabolic panel (CMP) 
2 
. 
. 
2 
2 
6 
Thyroid Stimulating Hormone (TSH) 
2 
. 
. 
. 
. 
2 
Fasting HbA1c 
5 
. 
. 
. 
. 
5 
Banking: 
 
Fasting plasma 
10 
. 
. 
10 
10 
30 
Fasting serum 
10 
. 
. 
10 
10 
30 
Total 
34 
0 
0 
27 
27 
88 
All BESST study visits with blood collection are fasting visits and need to be scheduled for early morning. Fasting is 
defined as nothing by mouth after midnight, except for a small amount of water to take medications.  
 
 

ICF_001.pdf: 
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BESST-Combined-Consent_HIPAA_15sep21.docx 
 
National Institutes of Health (NIH) 
Gastroparesis Clinical Research Consortium (GpCRC) 
 
  
ADULT INFORMED CONSENT/HIPAA AUTHORIZATION 
 
 
 
 
What is the purpose of this consent form? 
 
This form is called a consent form. The purpose of this form is to let you know about a research study 
being done here at insert institution name. It tells you about the purpose, risks and benefits, and 
describes what is involved in the study. It also tells you what other choices you have. 
 
What you should know about this study 
 
This study is funded by a grant from the National Institute of Diabetes and Digestive and Kidney 
Diseases (NIDDK). 
 
You are being asked to join a research study. 
 
This consent form explains the research study and your part in the study. 
 
Please read it carefully and take as much time as you need. 
 
You are a volunteer. You may choose not to take part in the study at all, and if you join, you may 
quit at any time.  There will be no penalty if you decide to quit the study. 
 
During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to be in the study. 
 
Purpose of research project 
This study is to find out if the study medication, buspirone, improves the symptoms of gastroparesis (or 
slow emptying of the stomach). The purpose of the BESST Trial is to find out whether taking the drug 
buspirone improves symptoms of gastroparesis (such as fullness and inability to finish a meal) compared 
to taking a placebo (an inactive study drug like a sugar pill). The placebo capsule looks just like the 
buspirone capsule, but has no active ingredients. Half the participants in this trial will receive the 
placebo, and the other half will receive buspirone. The United States Food and Drug Administration 
(FDA) has approved buspirone to treat anxiety. It is not FDA-approved for symptoms related to 
gastroparesis; however, some doctors use it to reduce the feeling of early fullness when eating. This is a 
nationwide study funded by the National Institutes of Health (NIH) and the National Institute of Diabetes 
and Digestive and Kidney Diseases (NIDDK). Your participation could last up to 14 weeks. 
 
We intend to learn more about how buspirone affects other gastroparesis symptoms like nausea, 
hunger, bloating, abdominal pain, how rapidly the stomach empties the food, and if there are any 
significant side effects. There will be an NIH database to store medical information collected during this 
study, and blood will be collected for serum and plasma analysis and storage (banking) in a NIH- 
Study Title: Buspirone for Early Satiety and Symptoms of Gastroparesis: A Multicenter, Randomized, 
Placebo-Controlled, Double-masked Trial (BESST). 
 
NCT Number: NCT03587142 
Principal Investigator: 
PI Version Date: 15 September 2021 
IRB No.: Pro000054803 


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sponsored biorepository. 


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Why we are asking you to participate 
We are asking you to take part in this research study because you have a condition suggesting 
gastroparesis (delayed stomach emptying) that causes long-term (chronic) symptoms including feeling 
full early when you eat, fullness after eating, nausea, and abdominal discomfort. People with diabetes, 
prior stomach surgery, or those who have had certain viral infections seem to be at greater risk of 
developing this condition. If you are eligible for this study and you agree to join the study, then you will 
be one of about 108 adults nationwide enrolled in this study. 
 
Procedures 
Adults that will be participating in this study will be randomly put into one of two groups by using a 
chance mechanism, similar to flipping a coin: (1) those taking buspirone or (2) those taking placebo only. 
Neither you nor the study staff will know which drug you are taking. This “masking” of study drug is 
done so that the study gives fair and unbiased results. The type of study drug you are taking will be 
unmasked if needed in an emergency. 
 
If you agree to participate in this study, the following will happen: 
 
Visit #1 - Screening for Eligibility ~ 2.0 hours 
The first visit will focus on seeing if you are eligible for this study. In addition to the information 
collected at this visit, there will be two additional screening visits: one to have a Gastric Emptying 
Scintigraphy Test (GES) and the other to have an Electrogastrogram (EGG) with a water load test. 
 
You will be asked to sign this consent and HIPAA authorization form allowing us to look at your medical 
records and begin screening tests. We cannot begin qualifying you to participate in the BESST study until 
this form is signed. 
 
The study doctor will conduct a detailed physical exam and review your medical history. The study 
doctor will listen to your heart and lungs, record your blood pressure, check your eyes, limbs and 
abdomen, chest and nervous system. You will also have an Electrocardiogram (ECG) to measure the 
electrical activity of your heart to show whether it is working normally. You will also be interviewed 
about any medications that you are taking now or in the past. The doctor will also review your medical 
history to see if you have had an upper endoscopy (EGD) or an upper GI radiographic series in the past 
two years, and if not, one will be scheduled for you as part of your gastroparesis diagnosis. You will be 
given several questionnaires to complete about your gastroparesis symptoms, quality of life, and mood. 
 
You may not enroll in this study if you are pregnant or breastfeeding an infant, because it is not known 
whether buspirone will harm the baby. If you become pregnant during the study, your study doctor will 
have you immediately stop the study drug, and just return to the clinic for follow-up. If you are able to 
become pregnant, we will perform a urine pregnancy test at every visit to ensure your and the baby’s 
safety. If you are able to become pregnant and are sexually active, you must use two effective forms of 
birth control during the study. Examples of birth control are: no sexual intercourse, hormonal 
contraceptives (oral, implant, transdermal patch, or injection) at a stable dose for at least 1 month prior 
to screening, an IUD (intrauterine device), and barrier (condom with spermicide, diaphragm with 
spermicide). 


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We will give you symptom diaries for you to fill out each night (daily diaries). You will record how severe 
your symptoms were during the day. We will schedule your next visit when you will have a gastric 
emptying scintigraphy test. 
 
Visit #2 – Screening Test 1 ~ 4.5 hours 
You will come to this visit in a fasting state, which is nothing by mouth after midnight the night before 
the visit. You should not use any narcotics for 3-days before the GES test. You can take your normal 
morning medications at home with sips of water. However, if you have diabetes and normally take 
insulin, you will be asked to take one-half the dose of your normal long-acting insulin and to bring in 
your regular short acting insulin if you take this with meals. Your fasting blood glucose level will be 
checked prior to the gastric emptying test to ensure it is above 60 and less than 270 mg/dL. If your blood 
glucose is not in control, then the GES will be rescheduled. 
 
If you are a female and able to become pregnant, you will have a urine pregnancy test prior to the test. 
If you are pregnant, the GES test will not be done. You will not be able to enroll in this study. 
 
You will complete a symptom questionnaire immediately before the gastric emptying test and also 
during the test. 
 
To confirm a diagnosis of gastroparesis, you will have a 4-hour gastric emptying test with solids using a 
standardized low fat egg meal with toast and strawberry jam. 
 
Visit #3 – Screening Test 2 ~ 1.5 hours 
You will come to this visit in a fasting state, which is nothing by mouth after midnight the night before 
the visit except sips of water, and wear clothes that permit access to your chest and abdomen. You will 
bring your normal morning medications with you and once you have had your blood drawn, you can 
take them with a few sips of water. If you have diabetes and normally take insulin, you will be asked to 
take one-half the dose of your normal long-acting insulin and to bring in your regular short acting insulin 
if you take this with meals. Your fasting blood glucose level will be checked prior to the 
electrogastrogram test to ensure it is above 60 and less than 270 mg/dL. If your blood glucose is not in 
control, then the EGG will be rescheduled. You are asked to bring the symptom daily diaries that you 
were given after the first screening visit with you and give them to the clinical center staff. 
 
If you are a female and able to become pregnant, you will have a urine pregnancy test prior to the EGG. 
If you are pregnant, the test will not be done. You will not be able to enroll in this study. 
 
You will have about 3 teaspoons (14 mL) blood drawn for laboratory tests and 4 teaspoons (20 mL) for 
banking (storage for future studies). 
 
You will undergo a study test called an electrogastrogram (or EGG) with a water load satiety test. For 
this test, electrodes will be placed on the skin of your stomach to record the movements of your 
stomach. The electrodes are like those used when you have a heart tracing ECG. First, you will mark your 
nausea and other symptoms on a paper scale. Next, your stomach movements are recorded for 15 
minutes. Then you will drink water for up to 5 minutes or until you feel completely full. Your stomach is 
recorded for 30 minutes after drinking the water. You will mark your nausea and other symptoms on a 
paper scale at 10, 20, and 30 minutes after you finish drinking the water and then the test is finished. 


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Visit #4 - Randomization (Treatment Assignment) ~ 30 minutes 
The randomization visit occurs after the screening evaluations are complete. We will review that 
eligibility criteria continue to be met, by conducting a brief physical exam and asking about any changes 
in medication use and any symptoms. If you are a female and able to become pregnant, you will have a 
urine pregnancy test to confirm you are not pregnant. You will also affirm that you still consent to 
participate in the study. 
 
If you are still eligible for the study, we will use a computer to choose the study drug you will be given 
for the study. This is done randomly, like a flip of a coin. Neither you nor the study team will know 
whether you are receiving buspirone or placebo. Once we have your drug assignment, the study staff 
will provide the assigned study drug (in person) and give you verbal instructions for taking the drug, 
along with written instructions. You will take one capsule three times a day, about 30 minutes before 
each meal. You will also be given an Information for Patients document with your study medication. 
Important directions are that you cannot take a monoamine oxidase inhibitor (MAOI) and should avoid 
drinking alcohol and eating grapefruit or drinking grapefruit juice while you are taking the study drug. 
 
The Study Coordinator will provide educational material regarding diet and healthy lifestyle for adults 
with gastroparesis. Before you leave the clinic, you will be given more symptom daily dairies that you 
will complete each night before bed. These will be returned in around two-weeks at your first follow-up 
visit. 
 
Four Follow-up visits: You will need to return to the clinic every 2 weeks to see how the study 
medication is working and if it is causing any side effects. You will return for follow-up visits at 2, 4, and 
6 weeks after enrollment. The specific procedures to be completed at each of the follow-up visits are 
detailed below. 
 
Visit #5 - Week 2 Follow-Up Visit ~ 1 hour 
Bring your study medication bottle and your daily diaries to the clinic and give to the Study Coordinator. 
You will come to the clinic in a fasting state, which is nothing by mouth after midnight the night before. 
If you are a female able to become pregnant, you will have a urine pregnancy test. 
 
The study doctor will ask about your health, conduct a brief physical exam and check for any side 
effects. You will be interviewed about any new medications, medical issues or illnesses since the 
randomization visit or any adverse effects you have experienced. You will be given several 
questionnaires to complete about your gastroparesis symptoms and mood. We will also collect your 
daily diaries. 
 
You will be given more daily diaries to fill out each night about the severity of your symptoms during the 
day to bring completed to your next visit in 2-weeks. You will continue to take your study medication 
three times a day, 30 minutes before meals. 
 
 
Visit #6 - Week 4 Follow-Up Visit 1 ~ 4.5 hours 
You should bring your completed daily diaries, your study medication bottle, and your regular 
medications with you to this visit. You will come to the clinic in a fasting state, which is nothing by 
mouth after midnight the night before. You should not use any narcotics during the 3-days prior to the 
GES test. You will have 1.5 teaspoons (7 mL) of blood drawn for laboratory tests and 4 teaspoons (20 


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mL) for banking (storage for future studies). Once you have had your fasting blood drawn, you can take 
your regular medications, except for your study drug. If you have diabetes and normally take insulin, you 
will be asked to take one-half dose of your normal long-acting insulin and bring in your regular short 
acting insulin if you take this with meals. You can take your normal morning medications at home with 
sips of water, but do not take your study drug. If you are a female and can become pregnant, you will 
have a urine pregnancy test. If you are pregnant, you will not have the gastric emptying test nor will you 
take your study medication for the rest of the follow-up visits. Otherwise, you will wait and take your 
study drug about 30 minutes before the gastric emptying test. If you are diabetic, your fasting blood 
glucose level will be checked prior to the gastric emptying test to ensure it is above 60 and less than 270 
mg/dL to continue with the testing done at this visit. If the blood glucose is not in control, then the test 
must be rescheduled. Otherwise, you will have a 4-hour gastric emptying scintigraphy test (GES) using 
the Egg Beaters® with toast and jam, which will be started 30 minutes after taking your study 
medication. 
 
The study doctor will ask about your health, any adverse effects you have experienced, and check for 
side effects. The study doctor will ask you whether you have taken any new medications or have had 
any illnesses or medical conditions diagnosed since the last visit. The study doctor will conduct a 
detailed physical exam similar to the screening visit and you will have another Electrocardiogram (ECG) 
to measure the electrical activity of your heart. You will be given several questionnaires to complete 
about your gastroparesis symptoms, quality of life, and mood. 
 
If you do not agree to complete the Week 4 follow-up Visit 2 to complete the EGG and water load 
satiety test in the next 7 days, you will turn in your daily diaries and study drug bottle to the study staff. 
You will be given another set of daily diaries to complete until the next study visit. You will no longer be 
taking your study medications. 
 
If you agree to complete the optional week 4 EGG and water load satiety test like you did at screening, 
you will return within 1-7 days to undergo the EGG and water load test. You will continue to take your 
study drug and complete your daily diaries and bring them to the next visit. 
 
Visit #7 - Week 4 Follow-Up Visit 2 ~ 1.5 hours- OPTIONAL 
You should bring your completed daily diaries, your study medication bottle, and your regular 
medications with you to the clinic. You should come to the clinic in a fasting state, which is nothing by 
mouth after midnight the night before, except for small sips of water, and wear comfortable clothes 
providing easy access to your chest and stomach. If you are a female able to become pregnant, you will 
have a urine pregnancy test. If you are pregnant, you will not take your morning study drug. 
 
If you have diabetes and normally take insulin, you will be asked to take one-half dose of your normal 
long-acting insulin and bring in your regular short acting insulin if you take this with meals. 
 
If you are diabetic, your fasting blood glucose level will be checked to ensure it is above 60 and less than 
270 mg/dL to continue with the testing done at this visit. You will undergo a repeat EGG with a water 
load satiety test. You will take your study drug 15 minutes prior to the start of the EGG. Electrodes will 
be placed on the skin of your stomach to record the movements of your stomach. First, you will mark 
your nausea and other symptoms on a paper scale. Next, your stomach movements are recorded for 15 
minutes. Then you will drink water for up to 5 minutes or until you feel completely full. Your stomach 


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will be recorded for 30 minutes after drinking the water. You will mark your nausea and other symptoms 
on a paper scale at 10, 20, and 30 minutes after you finish drinking and then the test is finished. 
 
After the test, you will return your daily diaries and study drug bottle to the study staff if you have not 
already done so. You will be given another set of daily diaries to complete until the next study visit. You 
will no longer be taking your study medications. 
 
Visit #8 - Week 6 Follow-Up Visit ~ 1.5 hours 
(Completion of the study) 
You will come to the clinic in a fasting state. You should bring back your study medication bottle if you 
did not bring it to the last visit and your completed daily diaries. You will have 1.5 teaspoons (7 mL) of 
blood drawn for laboratory tests and 4 teaspoons (20 mL) of blood will be drawn for banking (storage 
for future studies). The study doctor will ask about your health and any adverse effects and check for 
side effects. You will be asked about any new medications or illnesses since your last visit. You will have 
a detailed physical exam similar and complete several questionnaires about your symptoms, quality of 
life and mood. At this time, you will have completed the study and will receive further care as needed. 
 
 
Risks/discomforts 
Buspirone: 
Buspirone is an approved drug used to treat certain anxiety disorders or to relieve the symptoms of 
anxiety. It is not known exactly how buspirone works to relieve the symptoms of anxiety. Buspirone is 
thought to work by decreasing the amount and actions of a chemical known as serotonin in certain parts 
of the brain. 
 
Risk of buspirone: The most common buspirone side effects may include: headache; dizziness, tiredness, 
drowsiness; sleep problems (insomnia); nausea, upset stomach, blurred vision; nervousness or 
excitement, and rarely, tardive dyskinesia (a disorder that results in involuntary, repetitive body 
movements). Common drug interactions of buspirone include monoamine oxidase (MAO) inhibitors 
since the taking both drugs may increase your blood pressure. It is important to tell both the study 
physician and your primary care doctor that you will be taking buspirone before beginning any new 
medications, to ensure there are no drug interactions. Thus far, there is no direct evidence that 
buspirone causes physical dependence or drug-seeking behavior. 
 
Interference with Cognitive and Motor Performance: 
Studies indicate that buspirone may make you tired. Because you will not know if you are taking 
buspirone or a placebo, you should be careful operating an automobile or using complex machinery 
until you are reasonably certain that the study medication treatment does not make you feel tired or 
less alert. 
You should avoid use of alcohol while taking the study medication. 
Contact the study doctor if you have any of the following symptoms: 
• Dizziness or lightheadedness especially when getting up from a sitting or lying position suddenly 
• Drowsiness (severe) 
• Loss of consciousness 
• Nausea or vomiting 


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• Stomach upset 
• Very small pupils of the eyes 
 Any allergic reaction, including swelling, rash, difficulty breathing 
 Any illness that you feel is caused by the study drug 
 
Blood drawing: Blood drawing may cause mild discomfort and bruising. Very rarely, fainting, blood clots 
or an infection at the site can occur. You will have approximately 2 tablespoons (38 mL) of blood drawn 
during screening. During the entire study period, you will have approximately 6 tablespoons (88 mL) of 
blood drawn from you. 
 
Are there risks if I get pregnant? There may be unknown risks to an unborn baby if you become 
pregnant during the BESST Trial. We do not know how buspirone, the study medication being tested, 
will affect an unborn baby. The use of buspirone in pregnancy has not been studied in humans. If you 
decide to take part in this study, and have periods, you must be as sure as possible that you are not 
pregnant. It is important that you contact the study doctor right away, if you think you may be pregnant, 
if you missed a period or it is late, or if you have had a change such as heavier bleeding than usual or 
bleeding between periods. If you become pregnant during the study, you will stop taking the study 
medication immediately and you will not have the follow-up gastric emptying scintigraphy. You will still 
continue to be followed during the study. 
 
Questionnaires: The questionnaires ask about your symptoms, quality of life, levels of stress and 
anxieties. You are also asked about your medical history and medications you take. They will take about 
1 hour to fill out. If you have certain scores on the psychological questionnaires such as severe 
depression, you may be referred to see a clinical psychologist or psychiatrist. The questionnaires can be 
long, and at times, seem repetitive, which can be tedious. 
 
Electrogastrography (EGG) with water load satiety test: There is a small risk of an allergic reaction to the 
adhesive used to attach the electrodes to your skin. If you have a reaction, the electrodes will be 
removed and the test will be stopped. In addition, fasting or adjusting your insulin in preparation of the 
EGG could drastically reduce your blood glucose. During the water load satiety tests, you will drink water 
until you feel completely full. If you have diabetes, you will have your glucose checked at the beginning 
and the end of the tests, with appropriate measures being taken if low blood sugar (hypoglycemia) or 
high blood sugar (hyperglycemia) is detected. 
 
Radiation risk -Gastric emptying scintigraphy tests: If you take part in this research, you will undergo two 
gastric emptying scintigraphy tests (GES). The GES is a type of medical imaging study that exposes you to 
radiation. In this study, you will be exposed to radiation called "ionizing radiation," which is like x-rays. A 
millirem (mrem) is how we measure radiation doses. The effective dose to a patient per test from the 
0.5 -1 microcurie (mCi) Tc-99m egg meal that is used for this test is estimated to be 37-53 millirem (adult 
male and adult female, respectively), assuming normal transit times. The total radiation dose for the 0.5 
– 1 mCi administration of 99m-Tc sulfur mixture in the meal for two gastric emptying studies included in 
this trial would be an Effective Dose Equivalent of 74-106 millirem. This is below the total average 
annual dose a person in the United States receives from natural background radiation that we are 
exposed to all the time – like from the sun. This exposure averages 300 millirem (3 millisievert (mSv)). 
Although no immediate harmful effects are expected, there is a very small, theoretical (that means not 
proven) long-term health risk from this small amount of radiation exposure. The amount of radiation to 
which participants may be exposed could be higher or lower than this value depending on their body 


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weight or size. Neither chest x-rays nor background radiation have been found to harm most healthy 
adults. The radiation dose we have discussed is what you will receive from this study only and does not 
include any exposure you may have received or will receive from other tests or treatments. 
 
In addition, fasting or adjusting your insulin in preparation for the scintigraphy test, could lower your 
blood glucose. If you have diabetes, you will have your glucose checked at the beginning and the end of 
the test, with appropriate measures being taken if low or high blood sugar is detected. 
 
General risks: Your condition may not get better or may become worse while you are in the study. 
During the study, you will still be getting clinical care by your physician and will be able to remain on 
your regular medications if you have been on a stable dose for at least 3-months prior to study 
enrollment. 
 
Benefits 
You may or may not receive a direct personal benefit from being in the study. The study drug may help 
your gastric symptoms and it may not. We will not know until we complete this study. You may help 
future patients by providing important information about whether the study drug helps your symptoms 
of gastroparesis. If you ask us, we will provide the results of any procedures done to screen you for this 
study to other doctors involved in your care. 
 
Payment 
<<insert your clinic policy guided by your institution’s policies, if different >> 
You will be given a $50 reimbursement for time and travel for each of the study visits completed. This 
stipend can be up to $150 for the screening study visits and $50 for each of the four follow-up visits. 
You will receive up to $350 if you complete all aspects of the study. 
 
Protecting data confidentiality 
Every effort will be made to maintain your privacy. Your health and medical information will be labeled 
with only an identifying number and a random three-letter code that cannot be linked to your name or 
other personal identifiers, except at the clinical center where you complete your visits. All study material 
will be kept in strict confidence in locked cabinets and on computers that have password-protection and 
use security measures such as encryption.  Only study-certified, trained and certified study personnel 
are able to access the clinic computers or your information. Your health and medical information will be 
sent over a password-protected, encrypted transmission to the Scientific Data Research Center currently 
located at The Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. At the end of 
the study, a dataset is sent to the NIDDK Central Repository; however, it does not include any personal 
identifiers, your date of birth, and a random patient identifier. Therefore, the Repository will not be able 
to give out your name or other information that identifies you to any researchers approved to use your 
study data.  A Data and Safety Monitoring Board will have access to research records including your 
health information, but not your personal identifiers. 
 
All research projects carry some risk that information about a participant may become known to people 
outside of a study, if a person with the right skills would determine how to get access to your research 
record, and then work hard to connect the report with other information about you. If that happened, 
you could experience stress, anxiety, or embarrassment. Your participation in this study will be kept 
confidential and will not be made known to anyone other than the study staff at your clinic. When 


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PI Name: 
IRB No. 
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Leave blank for IRB Office Use. 
 
 
 
results from this study are published in the medical literature, you will not be identified by name or any 
personal identifiers. 
 
Your study information is protected by an NIH Certificate of Confidentiality. This Certificate allows us, in 
some cases, to refuse to give out your information even if requested using legal means. It does not 
protect information that we have to report by law, such as some infectious diseases.  The Certificate 
does not prevent us from disclosing your information if we learn of possible harm to you or others. 
 
Disclosures that you consent to in this document are not protected under HIPAA. This includes putting 
research data in the medical record or sharing research data for this study for future 
research. Disclosures that you make yourself are also not protected. 
 
Protecting subject privacy during data collection 
Researchers have an obligation to respect and protect your right to privacy. Any discussions with you 
and a study staff member concerning private health information or sensitive subjects are done in a 
private setting and are kept confidential. Your information will not be shared with anyone outside the 
certified study personnel at your clinic, including your family members, unless you give permission, or 
there is a strong, compelling medical reason for the need to share information. 
 
Alternatives to procedures or treatments 
You may choose not to participate in this study without any penalty by the study physician. There are no 
proven drug treatments for gastroparesis. You can continue to see a gastroenterologist and discuss 
other alternatives with your doctors. 
 
Biological specimens 
The blood and data collected from you during the study are important to science. The blood is separated 
into two parts: plasma and sera. You will not own the plasma, sera, or data after you give it to the study. 
You will not receive any financial benefit from any product or idea created by the investigators using the 
data or materials collected from you.  Neither the NIDDK, the sponsor of this study, nor the NIDDK 
Central Repository will benefit financially from such ventures. Your biospecimens are identified only 
with an identifying number that can be linked to the 4-digit identifier used with your other data. 
Therefore, your name and personal identifiers are not linked to your specimen. 
 
The sera and plasma samples collected as part of this study will be sent to the NIDDK Biosample 
Repository as they are collected during the study. At the end of the study, the data collected on you will 
be sent to the NIDDK Data Repository. The  NIDDK Central Repository is a research resource supported 
by the NIH. The Repositories store and  distribute samples and study data from people with many kinds 
of disorders, from unaffected family members, and from other healthy people. The purpose is to make 
samples and data available for use in health research. Your samples and data will be used by the 
researchers carrying out the BESST Trial, but they also may be used by other researchers and/or 
commercial companies after the study ends. Your samples and data may be stored indefinitely. 
 
We will remove direct identifiers (such as your name, date of birth) and instead code your information 
before sending your samples and data to the NIDDK Central Repository. NIH will never get the identifiers 
we have removed. The repository is a controlled-access repository. Controlled-access data are only 
available to researchers and companies who apply to the NIH. The NIH will review data requests for 
scientific merit and for methods to protect data and methods to ensure data will be used for the 


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approved purpose. We will not know what types of health-related research will be done with the data 
and samples that are sent to the repository. 
 
How will your data and/or biospecimens be shared now and in the future? 
Sharing data and/or biospecimens is part of research and may increase what we can learn from this 
study. 
 
Often, data/biospecimen sharing is required as a condition of funding or for publishing study results. It 
also is needed to allow other researchers to validate study findings and to come up with new ideas. 
 
Your data and/or biospecimens may be shared: 
 
directly with research collaborators, other researchers, sponsors, government agencies, 
publishers of papers and other research partners, including commercial companies 
 
through government or other databases/repositories 
 
Data/biospecimen sharing could change over time, and may continue after the study ends. 
 
We will do our best to protect and maintain your data/biospecimens in a safe way. Generally, if we 
share your data/biospecimens without identifiers (such as your name, address, date of birth) further 
review and approval by an IRB is not needed. However, when we share data/biospecimens, we limit the 
uses of the information and whether these data/biospecimens can be shared with another research 
team. If data/biospecimens are shared with identifiers, further IRB review and approval may be needed 
and the IRB will determine whether additional consent is required. 
 
If you do not agree to have your samples and data sent to the NIDDK Central Repository, you may not 
participate in the BESST trial. If you agree to have your samples and data sent to the NIDDK Central 
Repository, you can change your mind up until the end of the BESST trial. When study researchers 
receive written instructions from you, they will destroy your unused samples and all information that 
identifies them. No additional samples will be sent to the NIDDK Central Repository and no further data 
will be collected on you, but samples and data already collected and used will continue to be used. After 
the BESST study ends, you will not be able to withdraw your samples or data because the Repository will 
not know which are yours. The samples will stay in the NIDDK Central Repository indefinitely. 
 
Because researchers will not have access to your identity, you will not get the results of any studies that 
might be performed on your samples. Sometimes research leads to findings or inventions that have 
value if they are made or sold. These findings or inventions may be patented or licensed, which could 
give a company the sole right to make and sell products or offer testing based on the discovery. Some of 
the profits may be paid back to the researchers and the organizations doing this study, but you will not 
receive any financial benefits. 
 
Cost of participation in the study 
There are no costs to you regarding this study. 
 
What happens if you leave the study early? 
Participation in this study is entirely voluntary. You may refuse to participate or decide to stop 
participating at any time without jeopardy to the medical care you receive. 


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If you are found to be ineligible to continue with the study, or had to stop taking the study medication, 
we ask that you still come to all study visits. We will keep your data in the database. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay in this 
study. Your decision will not result in any penalty or loss of benefits to which you are entitled. If you 
have questions about your rights, or to report research related problems, please contact: << insert 
contact info>> 
 
Payment of treatment costs for injury or illness from study participation 
<< Insert local institutional language here if required or use language below >> 
If you are injured as a direct result of participation in this research, the <<insert your Institution>> will 
provide any medical care needed to treat those injuries. The <<insert your Institution>>> will not 
provide any other form of compensation to you if you are injured. You may call the <<insert your 
Institution>> Human Research Protections Program office to inquire about your rights as a research 
subject or to report research-related problems at (xxx) xxx-xxxx. 
 
Clinical Trial Registration 
A description of this trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time. 
Authorization for Disclosure of Protected Health Information for Research 
What information is being collected, used, or shared? 
To do this research, we will need to collect, use, and share your private health information. By signing 
this document, you agree that your health care providers (<<insert your institutions>>, ) may release 
your private health information to us, and that we may use any and all of your information that the 
study team believes it needs to conduct the study. Your private information may include things learned 
from the procedures described in this consent form, as well as information from your medical record 
(which may include information such as HIV status, drug, alcohol or STD treatment, genetic test results, 
or mental health treatment). 
 
Who will see, use or share the information? 
The people who may receive or use your private health information include the researchers and their 
staff. Additionally, we may share your information with other people at <<your institution>>, for 
example if needed for your clinical care or study oversight. By signing this form, you give permission to 
the research team to share your information with others inside of <<your institution>>.  Also, some 
other people may see your private health information (but nothing that can identify you) outside of the 
research team or <<your institution>>.  They may include the sponsor of the study, study safety 
monitors, government regulators, legal compliance staff, data managers and other agents and 
contractors used by the study team. We try to make sure that everyone who sees your information 
keeps it confidential, and if possible, that it is de-identified, but we cannot guarantee that your 
information will not be shared with others.  If your information is disclosed by your health care 
providers or the research team to others, federal and state confidentiality laws may no longer protect it. 
 
All these people must also keep your information confidential. 


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Do you have to sign this Authorization? 
You do not have to sign this Authorization, but if you do not, you may not join the study. It is your 
choice. 
 
How long will your information be used or shared? 
Your Authorization for the collection, use, and sharing of your information does not expire. Additionally, 
you agree that your information may be used for similar or related future research studies. 
 
What if you change your mind? 
You may change your mind and cancel this Authorization at any time. If you cancel, you must contact 
the Principal Investigator in writing to let them know by using the contact information provided in this 
consent form. Your cancellation will not affect information already collected in the study, or 
information that has already been shared with others before you cancelled your authorization. 
 
Ending Consent 
You may end your consent at any time. Information obtained and used before you end your permission 
will continue to be used for research. If you wish to end your permission to participate, let us know, 
preferably in writing. 
 
Who do I call if I have questions or problems? 
• Call the principal investigator [use the name of the local PI], <<insert name>>, at <<telephone 
number>> if you have questions, complaints, or get sick or injured as a result of being in this study. 
 
• Call or contact the [insert local IRB Office] if you have questions about your rights as a study 
participant. Contact the IRB if you feel you have not been treated fairly or if you have other concerns. 
The IRB contact information is: 
 
By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
 
or call toll free: 877-992-4724 
 
or by email: adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: Pro00054803 
 
Keep the questions below on the same page as the signature lines. 
What does your signature (or thumbprint/mark) on this consent form mean? 
Your signature on this form means: 
 You have read the above information about the study and have been informed about this 
study’s purpose, procedures, possible benefits and risks. 
 You have been told that you can change your mind about participating later if you want. 
 You have been given the chance to ask questions to help you understand what you will do in the 
study and any risks. 
 You have voluntarily agreed to participate in this study. 
You will be given a copy of this consent form to keep. 


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Print name of Adult Participant 
Signature of Adult Participant 
Date 
 
 
 
Print name of Person Obtaining 
Signature of Person Obtaining Consent 
Date 
Consent 
 
 
 
Print name of Witness 
Signature of Witness 
Date 
 
 
Give one copy to the participant and keep one copy in your study records