Clinical Management With SmartPill Motility Monitoring System and Validation of the SmartPill Five Hour Cutoff in Patients With Symptoms of Gastroparesis
Phase: NA
Conditions: Gastroparesis
Sponsor: Medtronic - MITG

 
 
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Clinical Trial Protocol 
MA-501 
Clinical Management with SmartPill Motility 
Monitoring System and Validation of the SmartPill 
Five Hour Cutoff in Patients with Symptoms of 
Gastroparesis 
 
 
 

 
 
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Principal Investigator: 
 
 
Dr. Braden Kuo 
  
 
 
  
 
Test Product: 
Given SmartPill Motility Monitoring Capsule 
Sponsor Name: 
Given Imaging Inc. 
Sponsor Address: 
Given Imaging Corporation 
3950 Shackleford Road 
Suite 500 
Duluth, GA 30096 
Sponsor Telephone: 
 
Study Number: 
MA-501 
Version Number and date: 
Version 3- March 15 2015  
 

 
 
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The undersigned confirm that they agree to conduct the study under the conditions 
described in this protocol: 
 
Investigator 
 
Signature: 
_________________ 
Date: 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPONSOR  
VP Medical and Regulatory Affairs 
 
Tim Thomas  
Signature: 
_________________ 
Date: 
      
 

 
 
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Table of Contents 
Study Summary .......................................................................................................................... 8 
1. Introduction ........................................................................................................................... 9 
2. Tested Device ....................................................................................................................... 16 
.2.1 
Intended purpose ....................................................................................................... 16 
.2.2 
Device Description ..................................................................................................... 16 
.2.3 
Packaging, distribution, labeling and caution statements ........................................... 18 
.2.4 
Inventory Control ...................................................................................................... 20 
.2.5 
Findings from non-clinical and clinical trials ............................................................. 20 
.2.6 
Manufacturer of investigational device ...................................................................... 21 
.2.7 
Description of & justification for route of administration & treatment period(s) ....... 21 
.2.8 
Training and experience needed to use the investigational device ............................... 22 
.2.9 
Risk Anlysis ............................................................................................................... 22 
3. Objectives ............................................................................................................................ 23 
.3.1 
Primary objective ...................................................................................................... 23 
.3.2 
Secondary objectives ................................................................................................. 23 
4. Study Endpoints ................................................................................................................... 24 
.4.1 
Primary Endpoint...................................................................................................... 24 
.4.2 
Secondary Endpoint .................................................................................................. 24 
5. Study Design ........................................................................................................................ 26 
.5.1 
Overall design ............................................................................................................ 26 
6. Subject Eligibility ................................................................................................................. 27 
.6.1 
Inclusion criteria ....................................................................................................... 28 
.6.2 
Exclusion criteria....................................................................................................... 28 
.6.3 
Withdrawal criteria ................................................................................................... 31 
7. Study  Plan ........................................................................................................................... 32 
7.1 
Enrollment of participants ......................................................................................... 32 
7.2 
Informed Consent Process ......................................................................................... 32 

 
 
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7.3 
Survey Instruments ................................................................................................... 33 
7.4 
Screening- Assessment of eligibility (Visit 1) .............................................................. 35 
7.5 
SmartPill Testing and Gastric Scintigraphy (Visit 2) ................................................. 37 
7.6 
Follow up visit (Visit 3) .............................................................................................. 40 
7.7 
Follow up visit (Visit 4) .............................................................................................. 40 
7.8 
3 month follow-up (visit 5) ......................................................................................... 42 
7.9 
6 Month Follow UP (Visit 6) ...................................................................................... 42 
7.10 
Data organization and shipment ................................................................................ 43 
8. Assesments of the SPM and Gastric Scintigraphy systems .................................................... 44 
8.1 
Assessment of efficay ................................................................................................. 44 
8.2 
Assessment of Saftey .................................................................................................. 46 
8.3 
Adverse Events Definitions and Reporting Requirements .......................................... 46 
8.4 
Anticipated adverse events reactions associated with SPM ans Gastric Scintigraphy . 49 
8.5 
Device Deficiency ....................................................................................................... 53 
9. Statistical consideration ....................................................................................................... 54 
9.1    Determination of Sample size ........................................................................................ 54 
9.2 
Interim Analysis ........................................................................................................ 55 
9.3 
Description of statistical methods ............................................................................... 55 
9.4 
Adverse Events .......................................................................................................... 58 
10. Suspension or premature termination .................................................................................. 58 
11. Data collection and quality control ....................................................................................... 59 
11.1 
Data collection ........................................................................................................... 59 
11.2 
Archiving .................................................................................................................. 59 
11.3 
Monitoring Plan ........................................................................................................ 60 
12. Ethical and legal aspectes ..................................................................................................... 60 
12.1 
Independent Ethics Committee (IEC)/ Institutional Review Board (IRB) ................... 60 
12.2 
Ethical conduct of the study ....................................................................................... 60 
12.3 
Amendments and Deviations from clinical investiagtion plan ..................................... 61 
12.4 
Subject Information and Consent .............................................................................. 62 
12.5 
Insurance .................................................................................................................. 62 
12.6 
Confidentiality ........................................................................................................... 62 
12.7 
Use of Data and Publications ..................................................................................... 63 

 
 
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13. References ............................................................................................................................ 65 
14. Appendices ........................................................................................................................... 71 
 

 
 
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Glossary 
SPM- SmartPill Motility Monitoring System  
GET- Gastric Emptying Time 
GES-  Gastric Emptying Scintigraphy 
UM - User Manual 
CRA - Clinical Research Associate 
IEC - Independent Ethics Committee 
IRB- Institutional Review Board  
eCRF - electronic Case Report Form 
AE - Adverse Event 
SAE - Serious Adverse Event 
ADE- Adverse Device Effect 
USADE - Unanticipated serious Adverse Device Effect 
SQA - Software Quality Assurance 
GCP - Good Clinical Practice 
PI - Principal Investigator 
 
 
 
 
 
 
 

 
 
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Study Summary 
Purpose of study 
To evaluate the agreement between gastric emptying scintigraphy 
tests and SmartPill Motility Monitoring System (SPM) study and to 
assess both impact on patient management and diagnostic gain 
associated with the SPM test.       
Study design 
Comparative study  
Number of 
subjects 
275 
Subject 
population 
Patients with symptoms of Gastroparesis 
No of centers 
Up to 12 
Duration of 
enrollment 
Up to 24 months from IRB approval to enroll study subjects 
Procedure 
Duration 
Two to five weeks (including medication wash) + 6 months follow 
up 
Primary 
objectives 
To evaluate device agreement in the diagnosis of delayed gastric 
emptying between SmartPill Motility Monitoring System (SPM) 
gastric emptying time (GET >5 hours) and the non-reference 
standard gastric scintigraphy test (>10% retention of a solid meal at 
4 hours) in patients with symptoms of gastroparesis 

 
 
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1. Introduction 
Gastroparesis—Clinical Manifestations and Management 
 
Gastroparesis presents with a range of gastrointestinal manifestations including 
nausea, vomiting, bloating, postprandial fullness, early satiety, and abdominal 
discomfort in association with demonstrable delays in gastric emptying (1).  In the 
largest accumulated series to date, approximately two thirds of patients exhibited 
gastroparesis of an idiopathic nature while approximately 25% developed the 
disease as a consequence of long-standing diabetes mellitus (2).  Even in smaller 
single center series, the predominant etiology of disease appears to be idiopathic 
(3).  Gastroparesis has profound impact on the lives of affected patients, impairing 
quality of life, and produces a significant health care burden, leading to extensive 
emergency department visits and inpatient stays. 
 
A range of therapies has been proposed for use in gastroparesis to reduce 
symptoms and promote adequate nutrient intake (1, 4, 5, 6, 7, 8).  Determination of 
the rate of gastric emptying is commonly employed to facilitate the decision to 
prescribe one of these therapies for a gastroparesis patient with significant 
symptoms.   
Gastroparesis - Survey Tools 
Patient Assessment of Gastrointestinal Disorders—Symptoms (PAGI-SYM) -  The 
PAGI-SYM survey consists of 22 questions which encompass a broad range of 
symptoms pertinent to organic and functional disorders of the gut (22).  Contained 
within the PAGI-SYM is the Gastroparesis Cardinal Symptom Index (GCSI).  The 
GCSI is comprised on 9 symptoms relevant to gastroparesis and has been stratified 

 
 
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into three subscales—nausea/vomiting (3 questions), postprandial fullness/early 
satiety (4 questions), and bloating (2 questions) (23).  The GCSI has been validated 
in seven university-based clinical practices in the United States which correlates 
well with patient and physician ratings of gastric symptom severity with an internal 
consistency reliability score of 0.84.  GCSI scores are responsive to changes in 
overall gastroparesis symptoms reported by both clinicians and affected patients.    
Patient Assessment of Gastrointestinal Disorders—Quality of Life (PAGI-QOL)- The 
PAGI-QOL has been validated in two large longitudinal, multicenter, multinational 
trials to reliably assess quality of life in upper gastrointestinal disorders (24).  The 
survey exhibits a high sensitivity to change with therapy in eight week observation 
studies.  The PAGI-QOL consists of 30 options, which each are answered on a 
scale ranging from 0=lowest to 5=highest.  Items are grouped into:  daily activities 
(10 items), clothing (2 items), diet and food habits (7 items), relationship (3 items), 
and psychological well-being and distress (8 items). 
Short Form-36 version 2 (SF-36v2) - The SF-36v2 is a validated survey consisting 
of 36 questions which rates quality of life in 4 mental and 4 physical health scores 
(25).  In contrast to the PAGI-QOL, it is a generic measure, which relates quality of 
life in this population to that of patients with unrelated conditions to provide 
perspective on the degree of impact conferred by gastroparesis.     
Rome III Modules -  The Rome III modules for (1) nausea, vomiting, and belching 
and (2) functional dyspepsia to assess upper functional symptoms and (3) all 
functional bowel disorders to assess lower functional symptoms are validated 
measures developed by the Rome Foundation to quantify symptoms and to suggest 

 
 
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the presence of functional disorders involving the upper and lower gastrointestinal 
tracts, respectively (26, 27).   
Visual Analog Scales (VAS):  VAS will be completed for 8 symptoms which are 
quantifiable in a continuous fashion before scintigraphic meal ingestion and after 
each hour of scanning.  The VAS form will also provide 3 options for assessing the 
severity of retching and vomiting.  The VAS is a non-validated measure specifically 
designed for this protocol.   
Bristol Stool Form Scale: The Bristol Stool Form Scale provides a measure of stool 
hardness based on a scale of 1- 7 to describe hardest to loosest stool form.  The 
scale provides a visual image along with descriptive text for each successively 
looser stool type (38).   
 
Status of Diagnostic Testing in Gastroparesis—Emerging Role of SmartPill 
Wireless Motility Capsule 
 
For many years, the standard of clinical practice mandated performance of 
gastric scintigraphy for diagnosis of gastroparesis.  However, it has been apparent 
that this method has a number of serious drawbacks which call into question its 
validity to discriminate those with versus those without disease.  Firstly, there are 
significant variations in methodology between centers which raise the possibility 
that what might be delayed emptying in one institution would be normal at another.  
One source of variability has been the choice of meal; many hospitals employ 
scrambled eggs while others use oatmeal, chicken liver, beef stew, pancakes, or 
water (9, 10, 11).  A second factor in the variability of scintigraphy results has been 

 
 
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the timing of image acquisition.  The majority of centers measure gastric emptying 
early in the postprandial period (90-120 minutes after eating), when emptying is 
incomplete even in healthy individuals.  A commonly reported measure, the half 
time of emptying, in many instances is an extrapolated value that is calculated from 
the very little emptying that occurs in the early postcibal phase and is likely fraught 
with inaccuracy.  Because of these variabilities in meal- and image timing-related 
factors, it has been difficult for many institutions to define their range for normal 
gastric emptying.  In a recent survey, 40% of academic and non-academic centers 
did not have experimental data to support the diagnostic cutoff for delayed gastric 
emptying at their hospitals (12).  As a consequence, a standardized protocol has 
been advocated that employs a standard test meal (Egg Beaters®, bread, jam) with 
measurement of emptying in the late postprandial time period (4 hours) when most 
emptying is complete in healthy controls (13).  Guidelines published by both the 
American Neurogastroenterology and Motility Society and the Society of Nuclear 
Medicine recommended this method in an effort to standardize diagnosis of the 
disease across all centers (14, 15).  However to date, a small minority of medical 
centers in the United States have adopted this protocol.  Additional drawbacks of 
gastric scintigraphy include the requirements to have access to a qualified nuclear 
medicine department and the potential for radiation exposure to individuals who 
may already have undergone extensive radiographic testing. 
 
Because of the well-documented deficiencies of gastric scintigraphy, other 
methods for determination of gastric emptying have been proposed e.g. Breath 
testing after consumption of different meals labeled with a non-radioactive isotope 

 
 
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(13C) (16, 17).  Such measures can be influenced by small bowel and pancreatic 
diseases that impair digestion and by pulmonary conditions that disrupt gas 
exchange.  Furthermore, most studies of gastric emptying breath tests to date have 
been validated against non-standardized scintigraphic measures of gastric 
emptying such as the half time of emptying or emptying rates in the early 
postprandial period (90-150 minutes). 
 
The SmartPill Motility Monitoring System (SPM) employs an ingested capsule 
that measures pH and pressure activity within the gastrointestinal lumen.  The SPM 
gastric emptying time (GET) is determined when the capsule pH increases at least 
2 units from the acidic environment of the stomach to the more neutral proximal 
duodenum.  In an initial published comparison trial versus gastric scintigraphy in 87 
healthy subjects and 61 patients with a previously established scintigraphic 
diagnosis of gastroparesis, correlation of the percent retention of an Egg Beaters® 
meal at 4 hours by scintigraphy and the GET of the SPM capsule at 4 hours was 
0.73 (18).  The diagnostic accuracy of the SPM GET (0.83) was comparable to that 
of the standardized 4 hour scintigraphy method (0.82).  Using a cutoff of 5 hours, 
the sensitivity and specificity of the SPM were 65% and 87%, respectively, for 
diagnosis of gastroparesis.  These values are comparable or superior to those of 
scintigraphy at 4 hours (sensitivity 44%, specificity 93%).  These findings support 
an equivalency of the SPM GET with the scintigraphy methodology advocated by 
the recent consensus guidelines.  As a consequence of this trial and after 
presentation of data suggesting an excellent safety profile of the method, the SPM 
system was approved by the United States Food and Drug Administration (FDA) in 

 
 
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July 2006 for determination of delayed gastric emptying and for measurement of 
whole gut transit. 
 
Concerns have been raised by clinicians and insurance providers in response to 
this initial clinical trial that mandate additional investigation.  The first critique relates 
to the sample size of the gastroparesis patients recruited for this study.  Although all 
61 patients had undergone prior scintigraphy demonstrating delays in gastric 
emptying, pH data was reliably acquired in only 48 individuals.  Of these patients, 
only 24 exhibited >10% retention of a solid meal on scintigraphy at 4 hours.  It has 
been suggested that this small cohort may be inadequate to support the routine use 
of the SPM for determination of delayed gastric emptying.  A second issue pertains 
to the cutoff to discriminate normal from delayed gastric emptying.  The FDA has 
approved the SPM for measurement of gastric emptying based on a cutoff of 4 
hours; this value was determined by optimizing both the sensitivity and specificity 
from the ROC curves from the initial study.  However after review of the raw data 
from this initial trial, it was elected to emphasize the specificity of the SPM GET to 
minimize the numbers of falsely positive delays in emptying that would be 
diagnosed using the 4 hour cutoff.  Taking this approach, a GET cutoff of 5 hours 
was found to provide a specificity of 87% for diagnosing gastroparesis based on a 
prior diagnosis of the condition.  Also in the initial study, subjects with confirmed 
gastroparesis on prior scintigraphy were recruited.   
This trial is designed to study the intended population in which the device will be 
used, subjects with suspected gastroparesis based on their self-reported symptom 
profile.  Finally published payer policies call for evidence that conduct of a SmartPill 

 
 
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Motility Monitoring System test will impact patient management. The study will 
compare patient management decisions based on results of gastric emptying 
scintigraphy tests to decisions based on SmartPill Motility Monitoring System study 
to assess both impact on patient management and diagnostic gain associated with 
the latter test.       
 
Study Purpose and Rationale 
This protocol is designed to validate use of the SPM for diagnosis of delayed gastric 
emptying in patients with symptoms of gastroparesis and assess impact of a 
SmartPill study on patient management in the gastroparetic populations.  Patients 
with symptoms of gastroparesis will be recruited.  
Patients will undergo concurrent gastric scintigraphy and SPM testing to determine 
the presence or absence of delayed gastric emptying based on predetermined 
diagnostic cutoffs for each technique.   
 
 
24 months will be required in order to enroll 275 subjects eligible for the trial.  
 
 
 

 
 
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2. Tested Device 
 
.2.1 
Intended purpose 
The SmartPill GI Monitoring System measures whole gut and regional gut 
(stomach, small bowel, and colon) transit times. Measurements of gastrointestinal 
(GI) tract transit times are used for evaluating motility disorders.  
The system measures pH, pressure, and temperature throughout the GI tract. 
Pressure contraction data from the antrum and duodenum can be used to calculate 
motility indices. 
 
.2.2 
Device Description 
The SmartPill Motility Monitoring System was cleared by the United States Food 
and Drug Administration (FDA) and caries a CE mark, from July 2006. The SPM 
system includes an ingestible capsule, a receiver, a laptop computer and analysis 
software.  .   
pH 
pH is measured every 5 seconds for the first 24 hours, every 10 seconds from 24-
48 hours, and every 2.5 minutes after 48 hours.  pH changes from 0.05-9.0 are 
detected with a sensitivity of +0.5 pH units.   
Pressure 
Pressure measurements from 0-350 mmHg are acquired every 0.5 seconds during 
the first 24 hours and every 1 second thereafter and are accurate to +5 mmHg for 
values <100 mmHg and +10% for pressures >100 mmHg.   

 
 
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Temperatures 
Temperatures from 25-49oC are obtained every 20 seconds in the first 24 hours 
and every 40 seconds thereafter and are accurate to +1oC.   
Data is uploaded and stored on the laptop computer.  Transit data is analyzed using 
MotiliGI Monitoring System software, while pressure data is quantified using GIMS 
Data Viewer software.   
The device does not incorporate any medicinal product, human blood derivative or 
tissues of animal origin. 
The SPM system is fully compliant with all safety and radio standards and 
regulations similar to the currently marketed Platform Systems. 
 
SmartPill Capsule Pack 
Each capsule pack contains a single-use capsule, calibration buffer, instructions for 
use and a patient diary 
The SPM capsule measures 26.8 x 11.7 mm and houses sensors for pH, pressure, 
and temperature and transmits data at a carrier frequency of 434 MHz to a receiver 
worn by the subject 
 
 
Data Receiver 
The data receiver records biomedical data sent by the capsule. It is worn by the 
patient on a belt clip or a lanyard (around the neck). The data receiver features an 

 
 
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Event button that when pushed places a marker in the electronic data. A patient 
diary for recording the time and reason for the event button use is stored on the 
backside of the receiver. The data receiver weighs approximately 225g (0.5 lb). 
 
Docking Station 
The docking station establishes electronic communication between the data 
receiver and the system computer for data download and serves as a charging 
stand for the data receiver. The docking station weighs approximately 200 grams 
(0.45 lbs). 
 
Activation Fixture 
The activation fixture turns the capsule on and off using strong magnets that 
interact with the capsule’s internal power switch.  
 
System Computer and MotiliGI Software 
MotiliGI software version 3.0 comes installed on the system computer. MotiliGI 
receives and processes downloaded data from the data receiver, stores test data, 
provides data analysis tools, and graphically displays test results. MotiliGI features 
algorithms that calculate GET, SBTT, CTT, WGTT, and motility indices of the 
antrum and duodenum. 
 
.2.3 
Packaging, distribution, labeling and caution statements 
Caution 

 
 
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SPM should not be used in patients with the following diseases or conditions:  
 history of gastric bezoar  
 swallowing disorders  
 suspected or known strictures, fistulas, or physiological/mechanical GI obstruction  
 GI surgery within the past 3 months  
 severe dysphagia to food or pills  
 Crohn’s disease or diverticulitis  
 implanted or portable electro-mechanical medical device such as a cardiac 
pacemaker, defibrillator or infusion pump  
 younger than 18 years old.  
Data transmission from the capsule to the data receiver is influenced by patient 
BMI. Significant data dropout can occur in severely obese patients (>40 BMI). 
Labeling  
All equipment associated with the clinical trial will be identified with visible markings 
stating “Exclusively for clinical investigations MA-501 only”  
Packaging and storage 
The SPM should be stored in a dry place, at ambient room temperature (-15-40°C) and 
humidity (rH 30-90%) and away from magnetic sources. To prevent capsule activation, 
the SPM capsule should be kept in the box until use.  
Even if stored in their original containers and according to recommendations, the SPM 
capsule should not be used past the expiration date on the capsules. 
 

 
 
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.2.4 
Inventory Control 
Sponsor will initiate shipment of product from the sponsor to the site upon receiving all 
required documents. (e.g. approval/favorable opinion from IRB/IEC). The sponsor will 
maintain tracking for all shipment documentation. Prior to any shipment, the site will be 
informed by the sponsor on the upcoming shipment, expected arrival date and content 
of the shipment. The site should confirm receipt of the shipment. The site will file 
Sponsor’s Shipping Receipt in the Sponsor’s Study File. 
An Investigator’s Device Accountability form will be conducted under the Regulatory 
Binder at each site and will be monitored by the site’s CRA. 
In case of technical failure the site will approach the technical support team which will 
help solve the problem and will notify the site’s CRA.  
 
For each dispensed capsule, the following information should be recorded: the subject 
study number, date dispensed and the capsule ID number. At the termination of the 
study, all unused study material must be returned with the corresponding 
documentation as directed by Given Imaging. 
 
.2.5 
Findings from non-clinical and clinical trials 
In an initial published comparison trial versus gastric scintigraphy in 87 healthy subjects 
and 61 patients with a previously established scintigraphic diagnosis of gastroparesis, 
correlation of the percent retention of an Egg Beaters® meal at 4 hours by scintigraphy 
and the GET of the SPM capsule at 4 hours was 0.73 (18).  The diagnostic accuracy of 
the SPM GET (0.83) was comparable to that of the standardized 4 hour scintigraphy 

 
 
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method (0.82).  Using a cutoff of 5 hours, the sensitivity and specificity of the SPM were 
65% and 87%, respectively, for diagnosis of gastroparesis.  These values are 
comparable or superior to those of scintigraphy at 4 hours (sensitivity 44%, specificity 
93%).  These findings support an equivalency of the SPM GET with the scintigraphy 
methodology advocated by the recent consensus guidelines.  As a consequence of this 
trial and after presentation of data suggesting an excellent safety profile of the method, 
the SPM system was approved by the United States Food and Drug Administration 
(FDA) in July 2006 for determination of delayed gastric emptying and for measurement 
of whole gut transit. 
 
.2.6 
Manufacturer of investigational device  
Given Imaging Ltd. is the manufacturer of the investigational device  
 
.2.7 
Description of & justification for route of administration & treatment 
period(s) 
SPM capsule is ingested by the patient after an 8 hour fast and consumption of the 
technetium radiolabeled eggbeater meal, two pieces of toast with jam(13) . with 50ml of 
water. The test requires fasting for accurate results.  
Procedure will take up to two weeks + 6 months follow up. 

 
 
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.2.8 
Training and experience needed to use the investigational device 
The medical staff and investigators who will perform the SPM procedure will go through 
a training session on the SPM system and Procedure, performed by the sponsor of the 
study.  
 
.2.9 
Risk Anlysis 
Benefits-There may be no direct benefit to patients with possible gastroparesis from 
participation in this study.  However, some patients may receive diagnostic information 
that helps the care provider plan a treatment program.  Indirect benefits of this study 
include improved insight into the importance of gastric emptying disorders in patients 
with symptoms of gastroparesis and the role of different methods in the diagnosis of 
impaired gastric motor function in this disorder.  
Alternatives to Study Participation- Participation in the study is voluntary.  Subjects may 
discontinue the study at any time without penalty or loss of any benefits to which they 
are otherwise entitled 
The SPM capsule is in compliance with relevant medical device standards. Our facilities 
have been certified to relevant medical device quality system requirements. Internal 
Verification and Validation testing has been successfully completed. All required 
Certifications and test reports are on file and have been reviewed for acceptability. The 
risk management summary demonstrates that the risks associated with the SPM 
capsule products are well mitigated and are as low as reasonably practicable as defined 
by the applicable standards. 

 
 
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3. Objectives  
The study population consists of patients with symptoms of gastroparesis 
 
.3.1 
Primary objective 
To evaluate device agreement in the diagnosis of delayed gastric emptying between 
SmartPill Motility Monitoring System (SPM) gastric emptying time (GET >5 hours) and 
the non-reference standard gastric scintigraphy test (>10% retention of a solid meal at 4 
hours) in patients with symptoms of gastroparesis 
 
.3.2 
Secondary objectives 
Several secondary hypotheses can be tested from data generated by this investigation 
which include but are not exclusive to: 
 
1. Objective: To assess the device agreement of SPM with GES for detection of 
severe gastroparises Hypothesis:  Severe gastric delay identified with 
scintigraphy (>35% at 4 hours) (35)  is associated with severe prolongation of 
SPM GET (>8 hours) and impaired contractility (36)   
2. Objective: To assess the correlation of gastroparetic symptoms measured by 
the PAGI-SYM symptom survey and PAGI-QUL survey instruments with SPM 
transit and fed response contractility parameters and with gastric emptying 
scintigraphy. Hypothesis: Gastroparetic symptoms correlate with discreet SPM 
measures  
3. Objective: To quantify the additional abnormal motility (diagnostic gain) detected 
with SPM relative to GES . Hypothesis:  The GI transit and contractility 

 
 
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measures provided with SPM  result are additional abnormal motility findings 
(diagnostic gain) over the conventional test gastric emptying scintigraphy  in the 
symptomatic gastroparetic population 
4.  Objective: To assess the impact of the diagnostic gain associated with SPM on 
patient management Hypothesis: The diagnostic gain realized with SPM results 
impact patient management decisions.   
4. Study Endpoints 
.4.1 
Primary Endpoint 
Per patient device agreement for the diagnosis of delayed gastric emptying between 
SmartPill Motility Monitoring System (SPM) gastric emptying time (GET >5 hours) 
(18) and the non-reference standard, gastric Emptying scintigraphy test (>10% 
retention of a solid meal at 4 hours)(13)  in patients with symptoms of gastroparesis 
 
.4.2 
Secondary Endpoint 
1. Agreement between Gastric emptying time of smartpill capsule (GET>8hrs= 
severe) and gastroduodenal contractility (36)  and percent of radiolabeled meal 
retained at  4 hours on scintigraphy (>35% = severe) (35) 
2. Correlation between total GCSI scores, GCSI subscale scores for 
nausea/vomiting,  postprandial fullness/early satiety, bloating , PAGI-SYM score 
for upper abdominal pain,  PAGI-QOL score and SPM GET, SPM SBTT, SPM 
CTT, SPM fed response gastroduodenal contractility (frequency and AUC) and 
percent retention of radiolabeled meal measured with scintigraphic camera at 4 
hours,  

 
 
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3. Number of abnormal SPM GET, SBTT,CTT(20) and antroduodenal contractility 
findings (36)  (contraction frequency and AUC) and number of abnormal 
radiolabeled meal emptying findings  measured with scintigraphic camera(13) 
4. Documented patient management plans recording therapy, Dx tests, nutrition, 
and surgery decisions based on SPM results and based on GES and 
assessment of patient management change in accordance with following 
guidelines   
a. Change in Therapy: A change in category of drug therapy or the addition 
of a new category of drug therapy constitutes a change in management. 
Thus a change in treatment from prokinetic to antiemetic, 
neuromodulator or laxative category constitutes a change in patient 
management.   A change of therapy within category such as switching 
from one prokinetic drug to another prokinetic drug does not constitute a 
change in patient management unless the drug is intended to impact a 
different GI region.   
b. Dietary guidelines: Changes to diet constituting a change in patient 
management include: recommendation of diets specific for 
gastroparesis, recommendation of a liquid diet, initiation of TPN or G or 
J feeding tube.   
c. Surgery: Relocation of feeding tube to new location (G tube changed to 
J Tube ) constitutes change in management but not relocation of G tube 
to new gastric location.  Either initiation or elimination of surgical referral 
constitutes change in management.   

 
 
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d. Diagnostic Testing: Any avoidance or additional diagnostic testing 
related to patient GI symptoms whether to detect abnormal motility or 
rule out alarm conditions constitute a change in management.   
5. Study Design 
.5.1 
Overall design 
This is a multi-center, prospective study which aims to evaluate positive and negative 
device agreement in the diagnosis of delayed gastric emptying between SPM system 
gastric emptying time (GET >5 hours) and the non-reference standard gastric emptying 
scintigraphy test (>10% retention of a solid meal at 4 hours) in patients with symptoms 
of gastroparesis.  
The study will include 275 patients with symptoms of gastroparesis aged 18-80 years, 
who have no evidence of metabolic and/or organic disease. 
Each subject will go through a Gastric scintigraphy test concurrently conducted with 
SPM testing after an overnight fast. The subject will be instructed to maintain a diary of 
times of meal consumption, bowel movements, and sleep.   
Patient and physician will complete survey instruments (detailed in section 7 of this 
protocol). 
Subject will return the SPM receiver 5+2 days after ingestion day. 
Physician will complete 3 management plans:  
 Between 5-28 days (visit 4)  after SPM and gastric scintigraphy test day- 3 
management plans based first on one motility test blinded to the second test and 
then independently based on second test but not blinded to the first test result. 

 
 
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The PI will then develop a third patient management plan based on both test 
results.  This plan will be presented to the patient at the follow-up visit (visit 4) 
Subjects will be contacted at 3 and 6 months post SPM procedure for followup 
assement of symptoms. 
Subjects will be compensated for completing the study.  
 
All observations/ assessments to be conducted are displayed in the Trial Flow Chart 
(Appendix- A) and detailed in the sections below 
 
Study Duration 
 Each subject is expected to participate in the study for two to five weeks (including 
medication wash) and up to 6 months follow up. Each subject will report to the study 
site for at least 3 visits and up to 6 visits. 
Up to 24 months will be required to enroll 275 patients following IRB approval of the 
study. The completion of the study will require 30 months due to data collection and 
validation, data analysis, and the final clinical report. 
6. Subject Eligibility 
Patients must meet all the inclusion criteria and none of the exclusion criteria in order to 
be eligible for the study. 
 

 
 
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.6.1 
Inclusion criteria 
 Males and females between ages of 18-80 years of age with symptoms of 
gastroparesis for at least 12 weeks.   
 Presenting with 2 or more of the following symptoms or signs which, in the opinion of 
the site investigator, are suggestive of a diagnosis of gastroparesis: 
.1 Nausea, vomiting, or retching (dry heaves) 
.2 Postprandial fullness or early satiety 
.3 Bloating or visible abdominal distention 
.4 Postprandial discomfort or pain 
 Ability to stop proton pump inhibitors for 7 days and histamine2 receptor antagonists, 
prokinetic agents, narcotic agents, anticholinergic drugs, and cannabinoids 3 days 
prior to SPM and gastric scintigraphy testing.  
 No evidence of metabolic disease (hypothyroidism, uncontrolled diabetes 
[hemoglobin A1c >10% within the past 6 months], electrolyte imbalance).  
 An upper endoscopy or upper gastrointestinal barium series within the past 3 years 
showing no organic disease that is potentially causative of symptoms.   
 High probability of compliance and completion of study. 
 
.6.2 
Exclusion criteria 
 Participation in previous SmartPill clinical trials.  
 Previous history of bezoars (the presence of retained liquid, bile, or small amounts of 
poorly organized food residue is permitted). 
 Dysphagia to solid food or pills. 

 
 
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 Prior surgery involving the luminal gastrointestinal tract (cholecystectomy, 
appendectomy, and hysterectomy are permitted if performed > 3 months prior to 
SPM test). 
 Any abdominal or pelvic surgery within the past 3 months 
 Known or history of inflammatory bowel disease. 
 History of diverticulitis, diverticular stricture, and other intestinal strictures. 
 Chronic daily use of nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen, etc.) 
 Tobacco or alcohol use within eight hours prior to capsule ingestion. 
 BMI > 40 kg/m2. 
 Allergies to eggs, bread, or jam.  
 Females of childbearing age who are not practicing birth control and/or are pregnant 
or lactating.  (Urine pregnancy testing will be performed on female subjects of child-
bearing potential prior to capsule ingestion and gastric scintigraphy). 
 Use of cardiac medical devices such as pacemakers and defibrillators (gastric 
stimulators, bladder stimulators, spinal stimulators, medication infusion devices, 
insulin pumps, continuous glucose monitors are permitted). 
 Uncontrolled diabetes with a hemoglobin A1c >10%. 
 Patient is expected to undergo MRI examination within 7 days after ingestion of the 
capsule 
 
Prohibited Medications 
Medications Which May Alter Gastric pH:   

 
 
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(i) Proton pump inhibitors (omeprazole, lansoprazole, esomeprazole, 
dexlansoprazole, pantoprazole, rabeprazole) for 7 days prior to study including 
the day of SPM ingestion. 
(ii) Histamine2 receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine) for 
3 days prior to study including the day of SPM ingestion. 
(iii) Antacids (containing magnesium, aluminium, or calcium carbonate) for 1 day 
prior to study including the day of SPM ingestion. 
 
Medications That May Affect Gastrointestinal Motility:  The following medications 
must be discontinued for 3 days prior to study including the day of SPM ingestion 
(if subject develops nausea to the degree that study discontinuation is 
contemplated, he or she may take promethazine, prochlorperazine, or 
ondansetron as rescue antiemetics in doses recommended by the site 
investigator): 
(i) Prokinetic agents (metoclopramide, domperidone, erythromycin, azithromycin, 
bethanechol, pyridostigmine) 
(ii) Narcotic analgesics (codeine, hydrocodone, oxycodone, methadone, fentanyl, 
etc.) 
(iii) Anticholinergic agents (dicyclomine, hyoscyamine, scopolamine) 
(iv) Cannabinoids (dronabinol, marijuana) 
 
 
Permitted Medications  

 
 
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Prescription medications for maintenance of stabilized conditions (e.g., 
hyperlipidemia, thyroid disease, chronic anxiety or depression, birth control, etc.) are 
permitted if the condition and the dose are stable for three months prior to study 
participation. 
 
.6.3 
Withdrawal criteria 
Patients may withdraw from the study for the following reasons: 
 
At their own request, or at the request of their legally acceptable representative. 
The investigator may withdraw a patient from the study at any time for the following 
reasons:  
 
Severe side effects clearly related to the study device. 
 
Presence or appearance of exclusion criteria. 
 
Appearance of accompanying diseases rendering further participation in the 
study impossible. 
 
A significant protocol violation, as determined either by the sponsor or the 
investigator  
 
Subject noncompliant with investigational procedures 
 
Subject noncompliant with visits 
 
At the specific reasonable request of the sponsor 
 
The sponsor must be informed in each withdrawal case. The reason for withdrawal must 
be recorded in the case report form and in the patient file. The study can be stopped 

 
 
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following unforeseen events or other factors that do not permit continuation of the study. 
The Investigator and/or Given Imaging and/or local ethics committee and/or regulatory 
authority can decide whether the study is to be terminated. The appropriate ethics 
committees will be notified of discontinuation of the trial for any reason no later than 5 
working days after the sponsor makes this determination and no later than 15 working 
days after the sponsor receives a notice from the ethics committee and/or regulatory 
authority. 
7. Study  Plan 
7.1 Enrollment of participants 
Eligibility to participate in the study will be assessed by the investigator based on 
inclusion and exclusion criteria.  
7.2 Informed Consent Process 
Each subject will receive a full oral explanation of the study and will receive a copy of 
the subject Informed Consent Form.  The subject will be requested by the investigator 
or his designee to sign the Informed Consent Form.  Informed consent will be obtained 
before or during visit 1, prior to any study procedures being conducted including 
medication wash out period. 
Consent to participate in this study must be given in writing. The signed informed 
consent will remain in the file of the subject; a signed copy will be given to the subject.  

 
 
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An enrollment log will be kept at the site listing all subjects who signed an informed 
consent for participating in the trial. The log will include the subject’s full name, ID, 
subject’s study code and date of enrollment. 
In case that new information shall be provided to the subject a new informed consent 
form, which will include the new information, will be signed by the subject 
In case of a subject who is unable to give a written informed consent an independent 
witness will sign the Informed consent on behalf of the subject, considering the subject 
gave his oral consent.  
 
7.3 Survey Instruments 
Brief Rapid Assessment of Subject History (BRASH) - Appendix B  
 The BRASH is a protocol-specific document that will be completed by a site 
investigator on the day of the screening visit.  The survey consists of several items 
that provide details into demographic factors (age, gender, ethnicity, race) as well 
as factors related to the subject’s symptoms prompting evaluation to measure 
gastric emptying.  This will include the investigator’s assessment of the presumed 
etiology of disease (idiopathic, diabetic [including type 1 vs. type 2, insulin 
requirements, and age of onset], other) and the profile of disease (duration of 
symptoms, acuity of onset, infectious prodrome, prior gastric scintigraphy or 
SmartPill testing, use of marijuana, use of opiates).  A complete medication list will 
be included in the BRASH including doses and timing and whether they are to be 
taken on a scheduled or as needed basis. 

 
 
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Patient Assessment of Gastrointestinal Disorders—Symptoms (PAGI-SYM) -  
Appendix C  
The PAGI-SYM will be completed by the patient at visits 1and 2 and again at the 3 
and 6 month follow up time points (visits 5 and 6). For this study, symptoms will be 
quantified by total GCSI scores, GCSI nausea/vomiting subscale scores, GCSI 
postprandial fullness/early satiety scores, GCSI bloating scores, and PAGI-SYM 
upper abdominal pain and discomfort scores.   
Patient Assessment of Gastrointestinal Disorders—Quality of Life (PAGI-QOL)- 
Appendix D   
The PAGI-QOL will be completed by the patient at visits 1and 2, and at the 
scheduled 3 and 6 month follow up time point (visits 5 and 6).  
  
Rome III Modules - Appendix F  
 The Rome III Modules will be completed by the patient at visit 1 
Visual Analog Scales (VAS) -  Appendix G: 
The VAS will be completed by the patient at visits 1 and 2. During visit 2 subjects 
will complete a separate VAS after each set of images at 0, 1, 2 and 4 hours 
Bristol Stool Form Scale  Appendix H:  
The Bristol Stool Form Scale will be completed by the patient at visits 1 and 2.  
 
 

 
 
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7.4 
Screening- Assessment of eligibility (Visit 1) 
After obtaining the consent, subjects will be assessed for eligibility to participate based 
on the inclusion and exclusion criteria. 
Subject baseline condition will be assessed to include: 
 Date of birth, gender, height, weight, BMI index, prior abdominal surgery, G.I 
symptoms, and reason for referral. 
 General medical history will be assessed based on clinical condition categorized by 
category codes specified in the case report form  
 Concomitant medications will be assessed to include name, frequency, dose and 
duration.  
 Documentation of previous GI procedure  
 Review of prior hemoglobin A1c levels to exclude values >10% 
 Female subjects will be assessed for childbearing potential, and if they do have 
childbearing potential, they will undergo a urine pregnancy test at visit one and prior 
to the SPM and gastric scintigraphy procedure. If the test is positive, they will be 
excluded from the study. If the pregnancy test is negative, the subjects will be 
eligible to participate, but must agree to use medically accepted contraceptive 
methods, throughout the course of their study participation.  
 Complete BRASH document symptom surveys, PAGI-SYM and PAGI-QOL 
questionnaires (see appendix B, C, D) 
 Full ROME III along with Rome III criteria worksheet (see appendix F) 

 
 
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 Diabetic patients will have blood drawn to provide an updated measure of 
hemoglobin A1c.  
 
Wash Out Period 
1. Subjects will be instructed to discontinue agents that affect intragastric acidity 
including proton pump inhibitors (omeprazole, lansoprazole, esomeprazole, 
pantoprazole, rabeprazole) for 7 days prior to study including the day of SPM 
ingestion, histamine2 receptor antagonists (cimetidine, ranitidine, famotidine, 
nizatidine) for 3 days prior to study including the day of SPM ingestion, and 
antacids (containing magnesium, aluminum, or calcium carbonate) for 1 day prior 
to study including the day of SPM ingestion.  Several medications with the 
potential to alter gut motility will be discontinued for 3 days prior to study 
including the day of SPM ingestion including prokinetic agents (metoclopramide, 
domperidone, erythromycin, azithromycin, bethanechol, pyridostigmine), narcotic 
analgesics (codeine, hydrocodone, oxycodone, methadone, fentanyl, etc.), 
anticholinergic agents (dicyclomine, hyoscyamine, scopolamine), and 
cannabinoids (dronabinol, marijuana).   
2. Patients will stop treatments for constipation at least 3 days (a full 72 hours) prior 
to Day 1, Ingestion Day and continuing for the duration of the monitoring period 
(4 to 7 days). These treatments include enemas, cathartics, PEG solutions 
(including Miralax, Enulose).  

 
 
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3. Patients may take medications to help stimulate a bowel movement with either 
milk of magnesia, 2.4 to 4.8 grams (30-60 ml), or magnesium citrate, 11 to 25 
grams daily in 1 or more doses, up to 48 hours prior to SmartPill ingestion. 
 
 
7.5 
SmartPill Testing and Gastric Scintigraphy (Visit 2) 
The following protocol will be followed on the day of study: 
 The subject will report to the study center after overnight fasting and will be 
asked to void his/her bladder prior to study.   
 Women of childbearing potential will undergo urine pregnancy testing to exclude 
pregnancy.   
 Diabetic patients will undergo finger stick testing of blood glucose.  If this value 
exceeds 270 mg/dl, the study will be postponed and rescheduled. 
 Prior to testing, the subject will complete the PAGI-SYM, and the PAGI-QOL 
(appendices C,D respectively) 
 The SmartPill capsule will be activated and calibrated. 
 Radiolabelled EggBeaters sandwich will be prepared by study team containing 
egg substitute (120 grams Egg Beaters®), 2 slices of bread, 30 grams strawberry 
jam (255 kcal, 72% carbohydrates, 24% protein, 2% fat, 2% fiber).  To prepare 
the meal, the Egg Beaters® will be poured into a bowl, sprinkled with 0.5-1 mCi 
99mTc-sulfur colloid marker, mixed, and cooked in a microwave oven with 
stirring until the mixture achieves the consistency of an omelet.  Jam will be 

 
 
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spread on the bread and a sandwich will be made using the bread and cooked 
Egg Beaters®.   
 The subject will then consume the radiolabelled EggBeaters sandwich with 70 ml 
water within 20 minutes. 
 Immediately after meal completion, the subject will swallow the SPM capsule with 
50 ml water.  Additional water may be provided if necessary to swallow the SPM 
capsule. 
 One minute anterior and posterior images will be obtained in the 99mTc window 
(140 keV+10%) with the patient sitting or standing immediately after meal 
completion and at 1, 2, and 4, hours afterwards. Additional GES scans will be 
allowed according to site standard of care. Results of 0, 1, 2 and 4 scans will be 
collected and recorded for this study. 
 Subjects will complete a separate VAS (appendix G) after each set of images at 
0, 1, 2, and 4 hours. 
 During free time in the 4 hour scintigraphy study, subjects also will complete the 
Bristol Stool Form Scale (appendix H) 
 During the initial 6 hours after capsule ingestion, the subject will be permitted to 
sit, stand, or walk in close proximity to the nuclear medicine department and 
gastroenterology laboratory.  The subject will not be permitted to sleep to prevent 
its inhibitory effects on gut motor function.  After 6 hours, the subject will be 
discharged from the study site. 
 The subject will be asked to continue to avoid solid food intake until 8 hours after 
capsule ingestion.  Then, the subject will be instructed to consume 240 ml 

 
 
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Ensure® ( 1 can supplied by clinical site) and one hour later can resume a 
normal diet.  Fifty ml of water will be permitted every hour after completion of the 
4 hour scintigraphy period up to 9 hours after capsule ingestion if desired by the 
subject; liquid intake will be unrestricted thereafter. 
 The subject will be instructed to maintain a diary of times of meal consumption, 
bowel movements, and sleep.  An event marker on the receiver will be 
depressed for each diary entry.  The subject will be told to maintain the receiver 
in close proximity at all times over the next 5 to 7 days to ensure adequate signal 
acquisition from the SPM capsule.  After each bowel movement, the subject will 
be asked not to flush to toilet for 5 minutes to ensure that accurate temperature 
measurements can be obtained by the SPM capsule after evacuation.   
 The subject will be given contact information and instructed to notify the site 
investigator if he/she experiences abdominal pain, nausea, vomiting, fever, or 
rectal bleeding prior to the follow-up visit. 
 The subject will be scheduled for the follow-up visit 5-7 days after the study visit 
performed either on study clinic or by phone. 
 
Diabetic patients on insulin will be instructed to use half of their normal long-acting dose 
the morning prior to testing and to refrain from use of short-acting insulin until directed 
by the site investigator.  Finger stick glucose levels will be obtained prior to meal 
ingestion and 4 hours after consuming the Egg Beaters® meal.  Hypoglycemia (glucose 
<70 mg/dl) or hyperglycemia (glucose >270 mg/dl) will be treated in accordance with the 
usual practice for each subject and recommended by his/her personal care provider.   

 
 
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7.6 
Follow up visit (Visit 3)  
The subject will return to the study site, or contacted by phone, for a follow-up visit 5+2 
days after Visit 2.  At that time, the subject will turn in the receiver and completed diary 
forms. In case the visit performed by phone receiver will be sent to study site by Fedex. 
The subject will confirm if capsule passage was visualized during defecation.  The 
SmartPill receiver will be examined for the presence of a signal from the capsule.  If no 
signal is detected, the subject can be discharged. If a capsule signal is detected with a 
pH >4.5 and the subject in not on a proton pump inhibitor, this suggests the capsule has 
passed into the small intestine or colon.  In this instance, the subject can be discharged.  
If a capsule signal is detected at 5-7 days after capsule ingestion and shows a pH <4.5 
suggestive of gastric retention in the stomach, the subject will be prescribed 
erythromycin liquid suspension to be taken at a dose of 250 mg orally before meals and 
at bedtime for the next 7-9 days (if not allergic).  In case of patient allergic to 
Erythromycin patient will be followed up per instructions in visit 4. 
 
 
7.7 
Follow up visit (Visit 4)  
All subjects return to the study site between day 14 to day 28, from capsule ingestion, to 
receive their patient management plans. Subjects who did not report or the MotiliGI data 
does not demonstrate capsule expulsion will receive an abdominal plain radiograph to 
assess for capsule retention according to PI discretion.  If the radiography shows 
capsule retention, or if the subject reports symptoms or exhibits signs of mechanical 

 
 
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obstruction, the site Principal Investigator or another qualified gastroenterologist will 
perform a comprehensive evaluation and suggest appropriate management. 
Management Plan 
Between day 5 and days 14 to 28 the PI completes patient management plan based 
first on one motility test blinded to the second test and then independently based on 
second test but not blinded to the first test result.  The PI will alternate between the 
conventional test result and SmartPill test result for bases of initial blinded patient 
management plan with each successive patient.  The PI will then develop a third patient 
management plan based on both test results.  This plan will be presented to the patient 
at the follow-up visit (visit 4).  
The PI will select a patient management plan from a maximum of two of six categories 
listed below consistent with guidelines described in section 9.2.     
1. Prokinetic  
2. Antiemetic 
3. Neuromodulator 
4. Laxative  
5. Enteral feedings 
6. Surgery 
7. Is additional diagnostic testing required?  Yes__ 
No__ 
 
Management of test results data to assure blinding of PI to test results   
The Scintigraphy test results (delayed or normal emptying) and the SmartPill GDF file 
will be supplied to the sponsor Data Management (DM) team within a timely manner of 

 
 
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SPM test completion.  The sponsor DM team will provide the SmartPill data along with 
the patient study code (initials and number) to a central reader for data extraction.  
Upon receiving the SPM results from the central reader the sponsor DM team  will then 
provide both test results (SPM &GES) to the site PI per the order described above 
assuring the second test result is not available to the PI until the management plan is 
complete based on the first test result. All above procedures should take place in a 
timely manner in order to assure 3 management plans ready by patient visit 4 
scheduled visit, 14-28 days from capsule ingestion. 
 
 
7.8      3 month follow-up (visit 5) 
At 3 months +7 days after visit 4 each site will conduct a follow up interview with their 
patients.  Patients may be called or return to their respective clinical study sites to report 
their current GI symptom profiles using the survey instruments (PAGI-SYM, PAGI-QOL, 
forms appendices C, D,).  The prior three month patient history will be documented 
including additional diagnostic tests for GI symptoms, emergency room visits, GI 
specialist visits and medication use.  Data will be confirmed where possible with patient 
medical records.    
 
7.9   6 Month Follow UP (Visit 6) 
At 6 months +7 days after visit 4 each site will conduct a follow up interview with their 
patients.  Patients may be called or will return to their respective clinical study sites and 
report current GI symptom profiles using the survey instruments (PAGI-SYM, PAGI-

 
 
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QOL, forms appendices C, D).  The prior three month patient history will be documented 
including additional diagnostic tests for GI symptoms, emergency room visits, GI 
specialist visits and medication use.  Data will be confirmed where possible with patient 
medical records. 
An Economic Analysis survey (appendix I) will be filled by study team, if 
applicable) 
 
7.10 Data organization and shipment 
For each patient the following information will be sent to the sponsor: 
 
a. Completed CRF  
b. Completed BRASH  
c. 4 completed PAGI-SYM  
d. 4 completed PAGI-QOL 
f.  1 completed ROME III modules 
g. 5 completed VAS  
h. 2 Bristol stool form indexes 
i. 3 patient management plans (1 from visit #1 and 3 from visit #4) 
j. SPM raw data (.GDF files) 
k. SPM report  
l. Gastric scintigraphy report 
m. Economic Analysis survey, if applicable 
 
 

 
 
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All data recorded on the eCRF will be supported by a source document  
 
8. Assesments of the SPM and Gastric Scintigraphy systems 
This is a non-randomized prospective study of 275 patients with symptoms of 
gastroparesis designed to assess the agreement between SmartPill and the predicate, 
gastric emptying scintigraphy (% retention at 4 hours), through characterization of the 
device agreement for delayed versus normal gastric emptying.  As part of the review of 
collected data, all quantification of SPM results will be performed by central readers and 
scintigraphic gastric emptying results will be performed by radiologists at each study 
site.  The principal investigators will create initial patient management plans based on 
the results of either the scintigraphy or SPM test while blinded to the alternate test 
result.  The test the PI is blinded to will alternate with each successive patient and be 
managed by the sponsor DM team. 
The following parameters will be measured; 
8.1 
Assessment of efficay 
SmartPill 
Several parameters will be quantified for this study:  
SPM gastric emptying time (GET) will be calculated from the time the capsule is 
ingested to the time it passes into the duodenum.  Capsule passage into the duodenum 
is defined when pH abruptly rises >2 units from the lowest postprandial value to >4 and 
does not decrease to <4 for >10 minutes at any subsequent time.   

 
 
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Small intestine and colon transit values, for secondary outcomes, will be calculated.  
Ileocecal capsule passage is defined when pH decreases >1.0 unit at least 30 minutes 
after gastric capsule evacuation; such a pH decrease has been observed in >95% of 
patients in the recent colon transit validation trial (19).  Small intestine transit will be 
calculated from the time of duodenal entry to the time of ileocecal passage.  Anal 
capsule expulsion is determined by abrupt 0.045oF/second decreases.  Colon transit will 
be calculated from the time of ileocecal passage to anal expulsion as described 
previously (20).  In cases where ileocecal passage cannot be detected secondary to a 
lack of a well-defined >1 pH unit decrease, combined small intestine-colon transit will be 
calculated.   
Whole gut transit times will be calculated from the time of capsule ingestion to the time 
of anal expulsion.   
Two validated pressure parameters will be calculated for this study (21).  Numbers of 
contractions >10mmHg in the stomach and small bowel and >25 mmHg in the colon 
amplitude will be standardized to contractions per minute and per 15 minutes 
respectively to compare recording periods of different length.  Areas under pressure 
curves (AUC) >10mmHg in the stomach and small bowel per minute and >25 mmHg 
per 15 minutes in the colon will be calculated in units of mmHg x minutes.    
 
Gastric Scintigraphy 
Scintigraphic images will be acquired after meal consumption and then at 1, 2 and 4 
hour intervals.  For scintigraphic testing, the subject will be placed in front of a gamma 
camera and 1 minute anterior and 1 minute posterior images will be taken in the 140 

 
 
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keV 99mTc peak with a 20% window (140 keV ± 10%).  Regions of interest will be drawn 
around gastric images for each time frame.  Geometric means will be calculated as 
square roots of the product of the counts measured on the anterior and posterior 
images.    
 
8.2 
Assessment of Saftey 
Safety parameters 
To monitor safety, subjects will be asked at each visit and during telephone contacts 
about changes in their medical conditions. Adverse events should be assessed in 
terms of their seriousness, duration, intensity, and relationship to the study device. All 
anticipated and unanticipated adverse events will be collected. Subjects will be able to 
contact the investigator at any time during the study if they note any change in their 
medical condition. The outcome of each adverse event will be observed and 
documented.  
  
8.3 
 Adverse Events Definitions and Reporting Requirements 
An adverse event (AE) is any complaint or untoward medical occurrence that is an 
unintended disease or injury or untoward clinical sign (including abnormal laboratory 
findings) in a subject, users or other persons, whether or not related to the investigational 
medical device. AEs are non device related, non serious medical occurrences. 
A Serious adverse event (SAE) is an untoward medical occurrence in a subject that is not 
related to the investigational device, comparator, or trial procedures, but that meet the 
criteria of “serious. A serious Adverse event is one that:  

 
 
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 Led to a death  
 Led to a serious deterioration in the health of the subject that: 
 resulted a life-threatening illness or injury; 
 resulted in permanent impairment of a body structure or body 
function and required inpatient hospitalization or prolongation 
of existing hospitalization; 
 resulted in medical or surgical intervention to prevent life 
threatening illness or permanent impairment to body structure 
or body function.  
 Led to fetal distress, fetal death, congenital abnormality or birth 
defect. 
An Adverse Device Effect (ADE) is an occurrence related to or caused by the 
investigational device, procedure or comparator that is not serious. 
A Serious Adverse Device Effect (SADE) is an adverse device effect, comparator, or 
procedure that has resulted in any of the consequences characteristic of a serious 
adverse event and is serious, but is not unanticipated.  
An Unanticipated Serious Adverse Device Effect (USADE) (also called an unanticipated 
device effect in per 21 CFR Part 812) is any medical occurrence or unintended disease 
or injury or serious adverse effect (including abnormal laboratory findings) on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application, or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subject. 

 
 
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 A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety and performance.  
 
Adverse events will be collected and documented until the end of CE procedure follow 
up period, which will be considered to be the end of the study. 
All adverse events will be graded as follows: 
Mild: Sign or symptom, usually transient, requiring no special treatment and generally 
not interfering with usual activities. 
Moderate: Sign or symptom, which may be ameliorated by simple therapeutic 
measures, may interfere with usual activity. 
Severe: Sign or symptom that are intense or debilitating and that interfere with usual 
activities. Recovery is usually aided by therapeutic measures and the discontinuation of 
the study device may be required. 
 
The relationship of the adverse event to the study is defined as follows: 
Definitely: An adverse event was shown to be related to the study device 
Probably: An adverse event has a strong temporal relationship to study device, and 
another etiology is unlikely or significantly less likely. 
Possibly: An adverse event has a strong temporal relationship to the study device, and 
an alternative etiology is equally or less likely compared to the potential relationship to 
study device. 
Probably not: An adverse event has little or no temporal relationship to the study device 
and/or a more likely alternative etiology exists. 

 
 
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Unrelated: An adverse event has no temporal relationship to study device or has a much 
more likely alternative etiology. 
 
8.4 
Anticipated adverse events reactions associated with SPM ans Gastric 
Scintigraphy 
The potential risks of this study include those related to the SmartPill capsule, those 
occurring during gastric scintigraphy, and those related to radiation exposure from 
abdominal radiography. 
Capsule Retention:  The risk of retention of the SmartPill capsule is minimal. Other FDA 
released medical capsule devices such as the Given PillCam and the Heidelberg pH 
capsule are similar in size and shape and are considered to pose similar risk. In 435 
healthy and 443 non-healthy individuals who ingested the Heidelberg pH capsule, there 
were no complications in the healthy subjects and one complication in a non-healthy 
subject with pyloric stenosis (29).  In this individual, the retained capsule in the stomach 
was retrieved using upper endoscopy.  More than 1,500,000 capsule endoscopies have 
been performed since Given Imaging introduced the first ingestible video capsule for 
human use in 2000.  Today, capsule endoscopy is considered to be well tolerated and 
safe.  Capsule retention has not been reported in normal volunteers or patients with 
diverticulosis and no history of diverticulitis (30).  Less than 1% of patients with localized 
diseases develop capsule retention (31, 32).  However, the risk of capsule retention 
may be as high as 13% in patients with a history of Crohn’s disease and also is 
reportedly increased in individuals on chronic use of non-steroidal anti-inflammatory 
drugs (33, 34).   

 
 
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Thirty one potential adverse events were logged in shipments of 8451 SmartPill 
capsules including twenty eight for prolonged retention (>5days).  Two of the remaining 
events involved retention of SPM in the esophagus and one incident involved an 
episode of vomiting after capsule ingestion. Retention in the colon accounted for 
seventeen of the twenty-eight incidents of prolonged retention, three incidents involved 
retention in the small bowel and the capsule was retained in the stomach in the 
remaining eight subjects. Subjects with prolonged retention in colon all resolved without 
intervention beyond laxative therapy. One small bowel retention, resolved with 
administration of bowel prep, resulted in detection of a malignancy prompting surgery to 
remove a previously undetected tumor that had created a stricture in the small bowel. 
The second small bowel retention passed without incident.  A third incident of small 
bowel retention required surgery for resolution and also resulted in detection of a 
previously undetected tumor.  Endoscopic intervention was used to retrieve the capsule 
in seven of the eight cases of gastric retention and prokinetic therapy was used to 
stimulate peristalsis and move the capsule out of the stomach into the small bowel in 
the remaining case where it then passed naturally from the body on its own.   In the two 
incidents of capsule retention in the esophagus patients reported no difficulty breathing 
and the capsules were removed with routine endoscopy without further incident.  In 
summary, there were 31 potential adverse events out of shipments of 8451 capsules for 
a potential adverse event rate of 0.4% with intervention beyond laxatives required in 11 
cases or 0.1% . 
 

 
 
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In three prior multicenter clinical studies involving administration of SmartPill to 175 
healthy subjects, 59 subjects with gastroparesis, and 260 subjects with chronic 
constipation, one adverse event involving capsule retention in the stomach in a 
gastroparetic subject was reported.  The capsule emptied from the stomach after IV 
erythromycin administration and passed normally.  In this study, subjects will be 
instructed to examine their stools for evidence of capsule passage.  Capsule excretion 
verification will be performed as described in sections number 7.6 and 7.7.   
Other Capsule Risks:  Other potential adverse events considered in prior clinical trials of 
the SmartPill capsule included nausea, vomiting, aspiration of the capsule or test meal, 
abdominal pain, diarrhea or constipation.  Technical issues that can occur include 
premature battery termination (failure) of either the capsule or receiver, signal loss 
within 6 hours or before the capsule emptying from the stomach, signal loss after 6 
hours but before 48 hours, loss of capsular structural integrity, and failures to receiver or 
capsule electronics.  In previous studies with adult subjects (N=326), 28 adverse events 
were reported: 19 were not device related, 7 were probably not device related, 1 was 
possibly related (substernal pain), and 1 was definitely related (19, 20).  In this 
individual, the capsule failed to exit the stomach 9 days after its ingestion secondary to 
entrapment in a bulking agent consumed by the subject.  Capsule evacuation from the 
stomach was effected within 24 hours by administration of the prokinetic agent 
erythromycin as described above; no endoscopic or surgical intervention was required 
for this related adverse event.   
Scintigraphy Risks:  The risks associated with gastric scintigraphy include radiation 
exposure and allergy to the test meal components.  The total effective radiation dose 

 
 
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equivalent for gastric scintigraphy is <200 millirem.  The organ with the greatest 
exposure (860 millirem) during testing is the upper small intestine.  This degree of 
radiation exposure is less than the yearly background exposure received by a typical 
resident of the United States.  The risks of allergic reaction to the egg substitute, bread, 
and jam are slight.  Any subject with such an allergy will be prohibited from study 
participation.  
Radiography Risk: Those individuals undergoing abdominal radiography to confirm 
capsule expulsion will be exposed to a whole body radiation dose of 127 millirem.  This 
value is less than the yearly background exposure received by a typical resident of the 
United States. 
 
An unanticipated Adverse Event, which, based on the investigator’s judgment, is device 
related should be notified to Given Imaging within 24 hours after the investigator is 
made aware of the event. 
A subject will be followed up after an occurrence of an adverse event until the resolution 
of the event and/or the investigator’s decision.  
Recording and documentation of adverse events 
Every adverse event should be recorded in the case report form. The following data 
must be documented: 
 
Type of event 
 
Subject number 
 
Time of occurrence: date, time 

 
 
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 
Time of resolution: date, time 
 
Severity degree: mild / moderate / severe / unknown 
 
Relationship to study device: probable/possible/unlikely/not related  
Measures taken 
 
Outcome of event: unchanged / worsened / improved / resolved / unknown 
/ death 
Reporting responsibilities:  
• An investigator shall submit to the sponsor and to the reviewing IRB a report of 
any unanticipated serious adverse events, adverse device effect and device 
deficiencies that could have led to a serious adverse device effect occurring 
during an investigation within 24 hours of learning of the event, but in no event 
later than 10 working days after the investigator first learns of the effect.  
• A sponsor who conducts an evaluation of an unanticipated adverse device 
effect under 812.46(b) shall report the results of such evaluation to FDA and to 
all reviewing IRB's and participating investigators within 10 working days after the 
sponsor first receives notice of the effect. Thereafter the sponsor shall submit 
such additional reports concerning the effect as FDA requests. (21 CFR Part 
812.150)  
 
8.5 
Device Deficiency  
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety and performance. Given Imaging Customer service 
is responsible to manage and document all device deficiencies related to the identity, 

 
 
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quality, durability, reliability safety or performance of an investigational medical device 
throughout the clinical investigation 
 
9.       Statistical consideration 
9.1    Determination of Sample size 
 
 In that accurate assessment of 
PPA

and 
NPA

is of utmost importance in this study, the 
sample size of 275 is based on the expected precision associated with our estimates 
expressed in terms of confidence interval width and 10% additional patients in order to 
compensate for 1 interim analysis performed.  It is expected that 10% of data will be lost 
to follow-up or not evaluable resulting in an effective sample size of approximately 
248.  The precision associated with each estimate is a function of the true unknown 
value of the parameter being estimated, and the percentage of delayed diagnoses by 
the predicate in the case of positive percent agreement and the percentage of negative 
diagnoses by the predicate in the case of negative percent agreement.  For the purpose 
of our calculations of the expected confidence interval half width, it is assumed that 40% 
of patients will be delayed by the predicate.  A range of possible scenarios for the true 
value of the parameter were considered for 
PPA

and 
NPA

and calculations of the 
expected interval half width appear in the table below: 
True value 
50% 
60% 
70% 
80% 
90% 
PPA 
10.3 
10.1 
9.5 
8.3 
6.2 

 
 
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NPA 
8.4 
8.3 
7.7 
6.7 
5.1 
 
 
Note that a true value for 
PPA

or 
NPA

of 50% represents the worst-case scenario with 
regards to precision and therefore may be taken as an upper bound of expected 
accuracy.  Calculations reveal that both confidence intervals will have a half width of at 
most 9.8  
 
9.2 
Interim Analysis 
Upon enrollment of 150 subjects an intermediate analysis for primary end point will be 
performed 
 
9.3 
 Description of statistical methods  
 Any deviation from specified statistical plan will be in addition to “per protocol” analysis 
and will be reported as such. Post-hoc analysis will be conducted according to the 
existing data gathered, if necessary 
Continuous variables will be summarized using tables of descriptive statistics: number 
of patients with recorded observations, mean, standard deviation, median, minimum, 
and maximum.  Categorical variables will be summarized using counts and 
percentages.  Descriptive statistics will be presented by diagnosis and clinical center.  
Diagnostic outcome will be tabulated and compared for SPM and conventional test and 
percentage gain determined.  Frequency of patient management change resulting from 

 
 
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SPM test relative to conventional test will be recorded for categories of: therapy, 
elimination of diagnostic testing, diet and surgery.  Parameters ascribed to the safety of 
patients will be summarized by diagnosis and clinical center.  No method of imputation 
will be used for missing data.  All available data from patients who fail to complete this 
study will be included in all safety summaries.  A summary of missing data will be 
provided according to the number of subjects, the time points where the data are 
missing and clinical center.  For each clinical center, number and percent of subjects 
with no missing data will be presented in tabular form.    
Primary Analyses 
Since a clearly defined universally accepted physiological definition of disease in this 
population does not exist, the diagnostic test under evaluation (SPM GET) will be 
compared to a non-reference standard test method, the percent retention of a 
radiolabelled solid meal at 4 hours on gastric scintiscanning.  Device agreement will be 
examined through use of the positive percent agreement (PPA) and negative percent 
agreement (NPA). (38), the Statistical Evaluation of Medical Tests for Classification and 
Prediction.  Oxford University Press Inc, New York.  Let 
PPA

 represent the true positive 
percent agreement defined as the probability of a positive SPM test result given the 
non-reference is positive and let 
NPA

represent the probability of a negative SPM test 
result given the non-reference is negative.  The primary analyses of this trial is 
estimation of these parameters in order to assess the equivalence between the 
diagnostic test under evaluation and the non-reference standard.  Maximum likelihood 
estimates of 
PPA

 and 
NPA

will be computed based on collected data i.e., conditional 

 
 
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relative frequencies in addition to corresponding 95% confidence intervals based on the 
methodology of Clopper and Pearson (28). Additional measures such as estimates of 
the overall percent agreement and Cohen’s kappa will be calculated. 
 
Secondary Analyses 
1.  The correlation between diagnoses of profound gastric retention on scintigraphy 
(>35% at 4 hours) with severe prolongation of SPM GET (>8 hours) and impaired 
contractility will be examined using relative frequencies.  Ninety-five percent confidence 
intervals will also be provided.  
2.   Total GCSI scores as well as GCSI nausea/vomiting, GCSI postprandial 
fullness/early satiety, and GCSI bloating subscale scores, PAGI-SYM upper abdominal 
pain scores and PAGI-QOL scores will be correlated with SPM GET, SPM SBTT, SPM 
CTT scintigraphic gastric retention at 4 hours and SPM gastroduodenal and fed 
response contractility profiles.  Since validity of the standard confidence interval 
corresponding to the Pearson correlation requires distributional assumption which will 
not be met based on the nature of the data to be collected, bootstrap methodologies will 
be utilized alternatively to construct said intervals. 
3.  The relative frequency will be computed for SPM transit and contractility results that 
provide diagnostic gain (additional abnormal motility findings) compared to conventional 
test results.  A corresponding 95 percent confidence interval will also be provided. 
4.  The percent of changes to patient management plans will be estimated.  
Frequencies of the types of changes will be summarize and presented in tabular form.   
 

 
 
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Primary Safety Stopping Rule 
A decision for discontinuation of the study may be made in consultation with the 
investigator if more than 5 patients require a gastroenterologist consultation for 
evaluation and removal of a retained capsule within the gastrointestinal tract. 
9.4 
Adverse Events 
Individual listings of adverse events including type of device, age, weight, height, 
gender, adverse events (reported term), start, duration, relationship to device and 
severity will be provided 
 
10. 
Suspension or premature termination 
The study can be terminated following unforeseen events or other aspects that do not 
permit continuation of the study. Given Imaging and/or local ethics committee and/or 
regulatory authority can decide whether the study is to be terminated. The appropriate 
ethics committees will be notified of discontinuation of the trial for any reason no later 
than 5 working days after the sponsor makes this determination and no later than 15 
working days after the sponsor receives a notice from the ethics committee and/or 
regulatory authority. 
 

 
 
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11. 
Data collection and quality control 
11.1  Data collection 
It is the responsibility of the investigator to ensure the completeness and accuracy of the 
case report forms. One case report form must exist for each subject participating in the 
study. Each clinical site may receive validated electronic case report form (eCRF) 
software for electronic capture of data.  The CRA will maintain eCRF validation records 
or provide access to them.  Electronic case report form entries will be user-identifiable 
and will include an audit trail. Erroneous values and/or text must not be obliterated. 
Instead, the error must be crossed out with a single line in black ink, the correct value/text 
added, and the correction signed, initialized and dated by the clinical coordinator.   
Once CRFs have been collected by the study monitor no changes should be made to 
the CRFs. In case that corrections are required due to Illogical data, missing data / empty 
fields, misspellings, contradictory data or other reasons, the data analysis team will 
generate a query on designated forms and sent it to the CRA for resolution. 
As the queries are resolved: 
the study coordinator correct the CRF at the site and send the corrected CRF’s to the 
data analysis team or return sign and complete data query sheet back to the data 
analysis team for data entry. 
All CRF’s will be verified against source data by a dedicated study monitor. 
 
11.2  Archiving 
All source documents and case report forms will be kept for a period of no less than five 
years after the later of the following dates: the date of which the study is terminated or 

 
 
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completed or; the date that the records are no longer required supporting marketing 
applications.  
 
11.3 Monitoring Plan 
The study will be monitored in accordance with the site recruitment rate for data 
verification and data collection. 
  
12. 
Ethical and legal aspectes 
12.1 Independent Ethics Committee (IEC)/ Institutional Review Board (IRB) 
Documented approval from appropriate Ethics Committee will be obtained prior to 
study start, according to ICH GCP, local laws, regulations and organization.  When 
necessary, an extension, amendment or renewal of the Ethics Committee approval 
must be obtained.  The Ethics Committees must supply to the sponsor, a list of the 
Ethics Committee membership and a statement to confirm that the Ethics Committee is 
organized and operates according to GCP and applicable laws and regulations. 
 
12.2  Ethical conduct of the study 
This clinical investigation shall not begin until the required approval/ favorable opinion 
from the IRB or regulatory authority have been obtained. The procedures set out in this 
study protocol, pertaining to the conduct, evaluation, and documentation of this study, 
are designed to ensure that the sponsor and investigator abide by Good Clinical 
Practice Guidelines (GCP in the appropriate current version) and that this clinical 
investigation will be conducted in accordance with the ethical principles that have their 

 
 
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origin in the Declaration of Helsinki.  The study will also be carried out in keeping with 
ISO 14155 and applicable local law(s) and regulation(s). This may include an 
inspection by Given Imaging representatives and/or Regulatory Authority 
representatives at any time.  The investigator must agree to the inspection of study-
related records by the Regulatory Authority/Given Imaging representatives, and must 
allow direct access to source documents to the Regulatory Authority/ Given Imaging 
representatives.  Regulatory Authority approvals/ authorizations/ notifications, where 
required, will also be in place and fully documented prior to study start. 
Furthermore, any additional requirements imposed by the IRB or regulatory authority 
shall be followed. 
 
12.3 Amendments and Deviations from clinical investiagtion plan 
 Protocol changes will be approved by the sponsor, investigator/s and ethical 
committee before change is implemented in the study. 
 The investigator is not allowed to deviate from the CIP, except for sponsored 
approved deviations and under emergency circumstances and deviations to 
protect the rights, safety and well-being of human subjects 
 Deviations, deviations for emergency use, and violations will be analyzed by the 
sponsor and their significance assessed and reported by the sponsor to 
competent authority.  
 Deviation for emergency use for non-significant risk study will be reported to IRB 
within five days or as required by national law 

 
 
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 Corrective and preventive actions and PI disqualification criteria: as per section 
2.3 of the study investigator agreement 
 
12.4 Subject Information and Consent 
A core information and consent form will be provided. Prior to the beginning of the trial, 
the investigator must have the Ethics Committee written approval/favorable opinion of 
the written informed consent form and any other written information to be provided to 
subjects.  The written approval of the Ethics Committee together with the approved 
subject information/informed consent forms must be filed in the study files. 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s), and must adhere to GCP and to the ethical principles 
originating in the Declaration of Helsinki.  Written informed consent must be obtained 
before any study specific procedure takes place.  Participation in the trial and date of 
informed consent given by the subject should be documented appropriately in the subject 
files. 
 
12.5 Insurance 
All subjects participating in the trial will have insurance coverage by the Sponsor, which 
is in line with applicable local laws 
 
12.6 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.  

 
 
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Subject names will be kept confidential.  Only the subject number and initials will be 
recorded in the case report form, and if the subject name appears on any other document 
(e.g. GES report), it must be obliterated. In cases where the local low does not allow 
using the subject initials serial number will be appointed (e.g. AAA, BBB). Study findings 
stored on a computer will be stored in accordance with local data protection laws.  The 
subjects will be informed in writing that representatives of the sponsor, IEC or Regulatory 
Authorities may inspect their medical records to verify the information collected, and that 
all personal information made available for inspection will be handled in strictest 
confidence and in accordance with local data protection laws. Subjects will also be 
informed that information regarding the study that does not include patient identifiers will 
be posted on clinicaltrials.gov. 
If the results of the trial are published, the subject’s identity will remain confidential.  
The investigator will maintain a list to enable subjects’ records to be identified. 
 
12.7 Use of Data and Publications  
All data and results and all intellectual property rights in the data and results derived 
from the study will be the property of Given Imaging, who may utilize the data in various 
ways, such as for submission to government regulatory authorities or disclosure to other 
investigators, educational, further product development and marketing uses. The 
investigator acknowledges that the system tested in the study, the Given SmartPill 
Motility Monitoring System is a product available commercially in the United States.   
The investigator, while free to utilize data derived from the study for scientific purposes, 
must discuss any publication with the sponsor prior to release and obtain written 

 
 
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consent of the sponsor on the intended publication. The sponsor recognizes the right of 
the investigator to publish the results upon completion of the study. However, the 
investigator must send a draft manuscript of the publication or abstract to the sponsor 
forty-five days in advance of submission in order to obtain approval prior to submission 
of the final version for publication. This will be reviewed promptly and approval will not 
be withheld unreasonably. In case of a difference of opinion between the sponsor and 
the investigator(s), the contents of the publication will be discussed in order to find a 
solution which satisfies both parties. 
 
 
 

 
 
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13. 
References 
1) 
Abell TL, Bernstein RK, Cutts T, et al.  Treatment of gastroparesis:  a 
multidisciplinary clinical review.  Neurogastroenterol Motil 2006; 18: 263-283. 
2) 
Gastroparesis Clinical Research Consortium.  Clinical features of patients with 
idiopathic gastroparesis and relationship to gender, body weight, and gastric 
emptying:  analysis of 118 patients (abstract).  Gastroenterology 2009; 136: 
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3) 
Soykan, I, Sivri B, Saroseik I, et al.  Demography, clinical characteristics, 
psychological and abuse profiles, treatment, and long-term follow-up of patients 
with gastroparesis.  Dig Dis Sci 1998; 43: 2398-2404. 
4) 
Longstreth GF, Malagelada JR, Kelly KA. Metoclopramide stimulation of gastric 
motility and emptying in diabetic gastroparesis.  Ann Intern Med 1977; 86: 195-
196.  
5) 
Koch KL, Stern RM, Stewart WR, Vasey MW.  Gastric emptying and gastric 
myoelectrical activity in patients with diabetic gastroparesis: effect of long-term 
domperidone treatment.  Am J Gastroenterol 1989; 84: 1069-1075. 
6) 
Lin HC, Sanders SL, Gu YG, Doty JE.  Erythromycin accelerates solid emptying 
at the expense of gastric sieving.  Dig Dis Sci 1994; 39: 124-128. 
7) 
Gupta P, Rao SS.  Attenuation of isolated pyloric pressure waves in 
gastroparesis in response to botulinum toxin injection:  a case report.  
Gastrointest Endo 2002; 56: 770-772. 

 
 
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prior written permission from Given Imaging. 
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8) 
Hasler WL.  Methods of gastric electrical stimulation and pacing: a review of their 
benefits and mechanisms of action in gastroparesis and obesity.  
Neurogastroenterol Motil 2009; 21: 229-243. 
9) 
Lacy BE, Crowell MD, Schettler-Duncan A, et al.  The treatment of diabetic 
gastroparesis with botulinum toxin injection of the pylorus.  Diab Care 2004; 27: 
2341-2347. 
10) 
Russo A, Stevens JE, Giles N, et al.  Effect of the motilin agonist KC 11458 on 
gastric emptying in diabetic gastroparesis.  Aliment Pharmacol Ther 2004; 20: 333-
338. 
11) 
Lehmann R, Honegger RA, Feinle C, et al.  Glucose control is not improved by 
accelerating gastric emptying in patients with type 1 diabetes mellitus and 
gastroparesis. a pilot study with cisapride as a model drug.  Exp Clin Endo Diab 
2003; 111: 255-261. 
12) 
House A, Champion MC, Chamberlain M.  National survey of radionuclide gastric 
emptying studies.  Can J Gastroenterol 1997; 11: 317-321.  
13) 
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. 
14) 
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. 

 
 
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prior written permission from Given Imaging. 
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15) 
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.  J Nucl Med Technol 2008; 
36: 44-54. 
16) 
Braden B, Adams S, Duan LP, et al.  The [13C] acetate breath test accurately 
reflects gastric emptying of liquids in both liquid and semisolid test meals.  
Gastroenterology 1995; 108: 1048-1055. 
17) 
Odunsi ST, Camilleri M, Szarka LA, Zinsmeister AR.  Optimizing analysis of 
stable isotope breath tests to estimate gastric emptying of solids.  
Neurogastroenterol Motil 2009; 21: 706-e38. 
18) 
Kuo B, McCallum RW, Koch KL, et al.  Comparison of gastric emptying of a 
nondigestible capsule to a radio-labelled meal in healthy and gastroparetic 
subjects.  Aliment Pharmacol Ther 2008; 27: 186-196. 
19) 
Camilleri M, Thorne NK, Ringel Y, et al.  Wireless pH and motility capsule for 
colonic transit:  prospective comparison with radiopaque markers in chronic 
constipation.  (Submitted to Am J Gastroenterol).   
20) 
Rao SS, Kuo B, McCallum RW, et al.  Investigation of wireless manometry 
capsule for colonic and whole gut transit: a comparative study with radioopaque 
markers in health and constipation.  Clin Gastroenterol Hepatol 2009; 7: 537-544. 
21) 
Hasler WL, Saad RJ, Rao SS, et al.  Heightened colon motor activity measured 
by a wireless capsule in patients with constipation: relation to colon transit and 
IBS.  Am J Physiol—Gastrointest Liver Physiol. 2009; 297: G1107-G1114. 

 
 
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in connection with matters authorized by Given Imaging and no part of it is to be without  
prior written permission from Given Imaging. 
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22) 
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: 1737-1749. 
23) 
Revicki DA, Rentz AM, Dubois D, et al.  Development and validation of a patient-
assessed gastroparesis symptom severity measure:  the Gastroparesis Cardinal 
Symptom Index.  Aliment Pharmacol Ther 2003; 18: 141-150. 
24) 
De la Loge C, Trudeau E, Marquis P, et al.  Cross-cultural development and 
validation of a self-administered questionnaire to assess quality of life in upper 
gastrointestinal disorders.  Qual Life Res 2004; 13: 1751-1762. 
25) 
Ware JE, Kosinski M, Keller SK.  SF-36® Physical and Mental Health Summary 
Scales: A User's Manual. Boston, MA, The Health Institute, 1994. 
26) 
Tack J, Talley NJ, Camilleri M, et al.  Functional gastroduodenal disorders.  
Gastroenterology 2006; 130:1466-1479. 
27) 
Longstreth GF, Thompson WG, Chey WD, et al.  Functional bowel disorders.  
Gastroenterology 2006; 130:1480-1491. 
28) 
Clopper CJ, Pearson ES.  The use of confidence or fiducial limits illustrated in the 
case of the binomial.  Biometrika 1934; 26: 404-413. 
29) 
Faegenburg D, Kryle LS, Kashiwaba H, et al.  Intestinal obstruction causes by 
ingestion of a Heidelberg capsule:  report of a case.  Am J Gastroenterol 1985; 
80: 787-789.  

 
 
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in connection with matters authorized by Given Imaging and no part of it is to be without  
prior written permission from Given Imaging. 
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30) 
Raju GS, Gerson L, Das A, Lewis B.  American Gastroenterological Association 
(AGA) Institute technical review on obscure gastrointestinal bleeding.  
Gastroenterology 2007; 133: 1697-1717. 
31) 
Bankin JS, Friedman S.  Wireless capsule endoscopy requiring surgical 
intervention:  the world’s experience.  Am J Gastroenterol 2002; 97: S298. 
32) 
Sears DM, Avots-Avotins A, Culp K, Gavin MW.  Frequency and clinical outcome 
of capsule retention during capsule endoscopy for GI bleeding of obscure origin.  
Gastrointest Endosc 2004; 60: 822-827. 
33) 
Cheifetz AS, Kornbluth AA, Legnani P, et al.  The risk of retention of the capsule 
endoscope in patients with known or suspected Crohn's disease.  Am J 
Gastroenterol 2006; 101: 2218-2222. 
34) 
Li F, Gurudu SR, De Petris G, et al.  Retention of the capsule endoscope: a 
single-center experience of 1000 capsule endoscopy procedures.  Gastrointest 
Endosc 2008; 68: 174-180. 
35) 
T. Abel. Consensus Recommendations for Gastic Emtpying Scintigraphy: A Joint 
Report of the American Nuerogastroenterology and Motility Society, AJG 2008; 
103:753 
36) 
L. Kloetzer, B. Kuo.  Motility of the antroduodenum in healthy and gastroparetics 
characterized by wireless motility capsule.  Neurogastroenterology and Motility 
2010; 21: 1-8 
37) 
Pepe, M.S. (2003).  The Statistical Evaluation of Medical Tests for Classification 
and Prediction.  Oxford University Press Inc, New York. 

 
 
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38) 
Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit 
time. Scand J Gastroenterol 1997;32:920–924 
39) 
Deniss A. Revicki et al. Reliablity and Validity of the gastrointestinal symptom 
rating scale in patinets with gastroesophageal reflux disease. Quality of Life 
Reasearch, 1998;7: 75-83 
 
 
 

 
 
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14. 
 Appendices 
Appendix A: Schedule of Assessment  
Visit 
Visit 1 
  
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
 
  
screening 
visit 
Med 
Wash 
SPM and 
GES 
Return 
SPM 
receiver 
Management 
plan 
3 
months 
follow 
up 
6 
months 
follow 
up 
 
 
Days 
Day (-14)-(-1) 
Day (-7)-0 
Day 0 
Day 5+2 
Day 14-28 
90+7 
after 
visit 4 
180+7 
after 
visit 4 
 
 
Informed 
Consent1 
X 
  
  
  
  
  
  
 
 
Assess 
Inclusion/ 
Exclusion 
criteria 
X 
  
  
  
  
  
  
 
 
Urine 
pregnancy 
test   
O 
  
O 
  
  
  
  
 
 
Previous 
hemoglobin 
A1c levels 
O 
  
  
  
  
  
  
 
 
Previous GI 
procedures 
X 
  
  
  
  
  
  
 
 
BRASH 
X 
  
  
  
  
  
  
 
 
PAGI-SYM 
X 
  
X 
  
  
X 
X 
 
 
PAGI-QOL 
X 
  
X 
  
  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Visit 
Visit 1 
  
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
 
  
screening 
visit 
Med 
Wash 
SPM and 
GES 
Return 
SPM 
receiver 
Management 
plan 
3 
months 
follow 
up 
6 
months 
follow 
up 
 
 
Days 
Day (-14)-(-1) 
Day (-7)-0 
Day 0 
Day 5+2 
Day 14-28 
90+7 
after 
visit 4 
180+7 
after 
visit 4 
 
 
ROME III 
MODULES 
X 
  
 
 
 
 
 
 
 
VAS 
X 
  
X* 
  
  
 
 
 
 
Bristol 
Stool Form 
Scale 
X 
 
X 
 
 
 
 
 
 
Patient 
manageme
nt plan 
X 
  
  
  
 X** 
 
  
 
 
 blood 
drawn to 
provide 
hemoglobi
n A1c  
measure  
O 
  
  
  
  
  
 
 
 
finger stick 
testing of 
blood 
glucose 
  
  
O 
  
  
  
  
 
 
SPM test 
  
  
X 
  
  
  
  
 
 
Gastric 
scintigraph
y 
  
  
X 
  
  
  
  
 
 

 
 
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Visit 
Visit 1 
  
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
 
  
screening 
visit 
Med 
Wash 
SPM and 
GES 
Return 
SPM 
receiver 
Management 
plan 
3 
months 
follow 
up 
6 
months 
follow 
up 
 
 
Days 
Day (-14)-(-1) 
Day (-7)-0 
Day 0 
Day 5+2 
Day 14-28 
90+7 
after 
visit 4 
180+7 
after 
visit 4 
 
 
return 
receiver & 
diary 
  
  
  
X 
  
  
  
 
 
Verify 
capsule 
excretion 
  
  
  
X 
O 
  
  
 
 
abdominal 
plain 
radiograph  
  
  
  
  
O 
  
  
 
 
prior three 
month 
patient 
history 
  
  
  
  
  
X 
  
 
 
prior six 
month 
patient 
history 
  
  
  
  
  
  
X 
 
 
Follow-up 
telephone 
call 
  
  
  
  
  
X 
X 
 
 
Adverse 
events 
O 
O 
O 
O 
O 
O 
O 
 
 
  
 
1 Informed concent will be obtained prior to the conduct of any study procedure  
O If applicable 
*Subjects will complete a separate VAS after each set of images at 0, 1, 2 and 4 hours 

 
 
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**PI will complete 3 managemnet plans and present to the patinet the one based on both SPM and 
Scintigraphy 
 
 

 
 
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Appendix B: BRIEF RAPID ASSESSMENT OF SUBJECT HISTORY (BRASH) 
Query 
Response 
Subject ID number 
 
Date of study 
 
Age 
 
Gender 
 
Ethnicity 
Hispanic _____          Not Hispanic ______ 
Race 
White _____    
Black/African-American _____    
Asian _____ 
American Indian/Alaskan Native _____    
Hawaiian/Pacific Islander _____ 
Refused _____ 
Height (inches) 
 
Weight (pounds) 
 
1.  Is subject diabetic? 
1.  Yes-type 1 ______     Yes-type 2 ______      No ______ 
2.  Yes ______                       No ______ 
3.  Yes ______                       No ______ 

 
 
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Query 
Response 
2.  Is diabetes 
etiologic (in opinion of 
investigator)? 
3.  Does subject take 
insulin? 
4.  Age of onset of 
diabetes? 
4.. _____ years 
Are other diseases 
potentially etiologic? 
Yes ______    No ______    Potential etiology ______________ 
Duration of symptoms 
Years ______               Months ______ 
Was the onset of 
symptoms acute? 
Yes ______                       No ______ 
1.  Was symptom 
onset preceded by an 
infectious prodrome? 
2.  If so, characterize 
the infection. 
1.  Yes ______                       No ______ 
2.  Respiratory ____  Upper GI ____  Lower GI ____  Other _____ 

 
 
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Query 
Response 
Results of prior gastric 
scintigraphy 
Delayed _____  Normal _____  Rapid _____  Never done ______ 
Results of prior 
SmartPill gastric 
emptying time 
measurement 
Delayed _____  Normal _____  Rapid _____  Never done ______ 
Marijuana use 
Yes _____     If so, quantity ____________ 
No _____ 
Opiate use 
Yes ______                       No ______ 
Medications 
Drug                   Dose                 Scheduled vs. PRN 
1. _________________________________________________ 
2. _________________________________________________ 
3. _________________________________________________ 
4. _________________________________________________ 
5. _________________________________________________ 
6. _________________________________________________ 
7. _________________________________________________ 

 
 
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Query 
Response 
8. _________________________________________________ 
9. _________________________________________________ 
10. _________________________________________________ 
11. _________________________________________________ 
12. _________________________________________________ 
13. _________________________________________________ 
14. _________________________________________________ 
15. _________________________________________________ 
16. _________________________________________________ 
17. _________________________________________________ 
18. _________________________________________________ 
19. _________________________________________________ 
20. _________________________________________________ 

 
 
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Appendix C: PATIENT ASSESSMENT OF UPPER GASTROINTESTINAL 
DISORDERS—SYMPTOMS (PAGI-SYM) 
This questionnaire asks you about the severity of symptoms you may have related to 
your gastrointestinal problem.  For each symptom, please circle the number that best 
describes how severe the symptom has been during the prior 2 weeks.  If you have not 
experienced this symptom, circle 0.  If the symptom has been very mild, circle 1.  If the 
symptom has been mild, circle 2.  If it has been moderate, circle 3.  If it has been 
severe, circle 4.  If it has been very severe, circle 5.  There are no right or wrong 
answers.  Please answer each question as accurately as possible.  Please be sure to 
answer every question.  
 
None 
Very 
Mild 
Mild 
Moderate 
Severe 
Very 
Severe 
Nausea (feeling sick to your 
stomach as if you were going 
to vomit or throw up) 
0 
1 
2 
3 
4 
5 
Retching (heaving as if to 
vomit, but nothing comes up) 
0 
1 
2 
3 
4 
5 
Vomiting 
0 
1 
2 
3 
4 
5 
Stomach fullness 
0 
1 
2 
3 
4 
5 
Not able to finish a normal-
sized meal 
0 
1 
2 
3 
4 
5 

 
 
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None 
Very 
Mild 
Mild 
Moderate 
Severe 
Very 
Severe 
Feeling excessively full after 
meals 
0 
1 
2 
3 
4 
5 
Loss of appetite 
0 
1 
2 
3 
4 
5 
Bloating (feeling like you 
need to loosen your clothes) 
0 
1 
2 
3 
4 
5 
Stomach or belly visibly 
larger 
0 
1 
2 
3 
4 
5 
Upper abdominal pain 
(above the Navel) 
0 
1 
2 
3 
4 
5 
Upper abdominal discomfort 
(above the navel) 
0 
1 
2 
3 
4 
5 
Lower abdominal pain 
(below the navel) 
0 
1 
2 
3 
4 
5 
Lower abdominal discomfort 
(below the navel) 
0 
1 
2 
3 
4 
5 
Heartburn during the day 
(burning pain rising in your 
chest or throat) 
0 
1 
2 
3 
4 
5 

 
 
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None 
Very 
Mild 
Mild 
Moderate 
Severe 
Very 
Severe 
Heartburn when lying down 
(burning pain rising in your 
chest or throat) 
0 
1 
2 
3 
4 
5 
Feeling of discomfort inside 
your chest during the day 
0 
1 
2 
3 
4 
5 
Feeling of discomfort inside 
your chest at night (during 
your sleep time) 
0 
1 
2 
3 
4 
5 
Regurgitation or reflux during 
the day (fluid or liquid from 
your stomach coming up into 
your throat) 
0 
1 
2 
3 
4 
5 
Regurgitation or reflux when 
lying down (fluid or liquid 
from your stomach coming 
up into your throat) 
0 
1 
2 
3 
4 
5 
Bitter, acid or sour taste in 
your mouth 
0 
1 
2 
3 
4 
5 

 
 
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None 
Very 
Mild 
Mild 
Moderate 
Severe 
Very 
Severe 
Constipation 
0 
1 
2 
3 
4 
5 
Diarrhea 
0 
1 
2 
3 
4 
5 
 
 

 
 
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83 
 
Appendix D: PATIENT ASSESSMENT OF UPPER GASTROINTESTINAL 
DISORDERS—QUALITY OF LIFE (PAGI-QOL) 
 
The following questions ask about how some of the gastrointestinal problems you may 
be experiencing (such as pain, discomfort or other problems) may have affected your 
overall quality of life and well-being in the past 2 weeks.  Please answer every question 
by circling the number that best represents your opinion.  There are no right or wrong 
answers. 
During the past 2 weeks, 
because of your 
gastrointestinal 
problems, how often… 
None of 
the time 
A little of 
the time 
Some of 
the time 
A good 
bit of the 
time 
Most of 
the time 
All of 
the time 
Had to depend on others 
for daily activities? 
0 
1 
2 
3 
4 
5 
Have you avoided daily 
activities? 
0 
1 
2 
3 
4 
5 
Had difficulty 
concentrating? 
0 
1 
2 
3 
4 
5 
Has it taken longer than 
usual to perform daily 
activities? 
0 
1 
2 
3 
4 
5 

 
 
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During the past 2 weeks, 
because of your 
gastrointestinal 
problems, how often… 
None of 
the time 
A little of 
the time 
Some of 
the time 
A good 
bit of the 
time 
Most of 
the time 
All of 
the time 
Have you felt tired? 
0 
1 
2 
3 
4 
5 
Have you lost desire to 
socialize? 
0 
1 
2 
3 
4 
5 
Have you worried about 
stomach symptoms in 
public? 
0 
1 
2 
3 
4 
5 
Have you avoided physical 
activities or sports? 
0 
1 
2 
3 
4 
5 
Have you avoided 
travelling? 
0 
1 
2 
3 
4 
5 
Have you felt frustrated 
about limitations? 
0 
1 
2 
3 
4 
5 
Have you felt constricted in 
the clothes you wear? 
0 
1 
2 
3 
4 
5 

 
 
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During the past 2 weeks, 
because of your 
gastrointestinal 
problems, how often… 
None of 
the time 
A little of 
the time 
Some of 
the time 
A good 
bit of the 
time 
Most of 
the time 
All of 
the time 
Have you felt frustrated 
about not dressing as you 
like? 
0 
1 
2 
3 
4 
5 
Have you felt concerned 
about what you can eat? 
0 
1 
2 
3 
4 
5 
Have you avoided certain 
foods?  
0 
1 
2 
3 
4 
5 
Have you restricted eating 
out? 
0 
1 
2 
3 
4 
5 
Have you felt less 
enjoyment in food? 
0 
1 
2 
3 
4 
5 
Have you felt changing 
foods could trigger your 
symptoms? 
0 
1 
2 
3 
4 
5 

 
 
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During the past 2 weeks, 
because of your 
gastrointestinal 
problems, how often… 
None of 
the time 
A little of 
the time 
Some of 
the time 
A good 
bit of the 
time 
Most of 
the time 
All of 
the time 
Have you felt frustrated 
about not being able to 
choose your foods? 
0 
1 
2 
3 
4 
5 
Have you felt frustrated 
about not being able to 
choose your drinks? 
0 
1 
2 
3 
4 
5 
Has your relationship with 
your spouse or partner 
been disturbed? 
0 
1 
2 
3 
4 
5 
Has your relationship with 
your children or relatives 
been disturbed? 
0 
1 
2 
3 
4 
5 
Has your relationship with 
your friends been 
disturbed? 
0 
1 
2 
3 
4 
5 

 
 
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During the past 2 weeks, 
because of your 
gastrointestinal 
problems, how often… 
None of 
the time 
A little of 
the time 
Some of 
the time 
A good 
bit of the 
time 
Most of 
the time 
All of 
the time 
Have you been in a bad 
mood? 
0 
1 
2 
3 
4 
5 
Have you been 
depressed? 
0 
1 
2 
3 
4 
5 
Have you felt anxious? 
0 
1 
2 
3 
4 
5 
Have you felt angry? 
0 
1 
2 
3 
4 
5 
Have you felt irritable? 
0 
1 
2 
3 
4 
5 
Have you felt discouraged? 
0 
1 
2 
3 
4 
5 
Have you been stressed 
0 
1 
2 
3 
4 
5 
Have you felt helpless?  
0 
1 
2 
3 
4 
5 
 
 

 
 
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Appendix F: ROME III MODULES  
 

 
 
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92 
 
 

 
 
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94 
 
 
 
 

 
 
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95 
 
 

 
 
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98 
 
 
 
 

 
 
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99 
 
 
 
 
 

 
 
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100 
 
 

 
 
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March 15, 2015 
101 
 
 

 
 
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102 
 
Appendix G: VISUAL ANALOG SCALES FOR ASSESSING SYMPTOMS OF 
GASTROPARESIS IN REAL TIME 
When you are told, please draw a vertical line through each of the lines below to rate 
how severe each symptom is at this moment in time. 
 
Nausea 
 
None  
 
 
 
 
 
 
 
 
Severe 
 
Stomach Fullness 
 
None  
 
 
 
 
 
 
 
 
Severe 
 
Hunger 
 
Very Hungry  
 
 
 
 
 
 
 
None 
 
 

 
 
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Bloating 
 
None  
 
 
 
 
 
 
 
 
Severe 
 
Belly Visibly Larger 
 
None  
 
 
 
 
 
 
 
 
Severe 
Upper Abdominal Pain (Above the Belly Button) 
 
None  
 
 
 
 
 
 
 
 
Severe 
 
Upper Abdominal Discomfort (Above the Belly Button) 
 
None  
 
 
 
 
 
 
 
 
Severe 
 
Retching (Dry Heaves) in the Past Hour 
None _____ 
 
 
Once _____ 
 
 
Multiple times _____ 
 

 
 
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Vomiting in the Past Hour 
None _____ 
 
 
Once _____ 
 
 
Multiple times _____ 
 

 
 
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prior written permission from Given Imaging. 
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version 3 
March 15, 2015 
105 
 
Appendix H: THE BRISTOL STOOL FORM SCALE 
 
Date and time of bowel movement:   
 
 
 
 
    
 
Please describe your bowel movement (stool) as:  
(Check the most appropriate answer for the form of your stool) 
 
___Type 1: Separate hard lumps, like nuts (hard to pass). 
 
___Type 2: Sausage-shaped but lumpy. 
 
___Type 3: Like a sausage or snake but with cracks on its surface. 
 
___Type 4: Like a sausage or snake - smooth and soft. 
 
___Type 5: Soft blobs with clear-cut edges (easy to pass). 
 
___Type 6: Fluffy pieces with ragged edges, a mushy stool. 
 
___Type 7: Watery, no solid pieces. 
 
 
 
 

 
 
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Appendix I: Sample of Economic Analysis survey 
 
Patient Information 
Age 
  
Gender 
M / F 
Race 
  
Diabetic 
History 
Y/N 
  
Prior GI Medical 
History 
GI Surgery(ies) 
  
  
  
  
  
  
  
  
Hysterectomies 
  
  
  
  
  
  
  
  
Initial patient 
management plan 
Category of 
Motility Drug 
Use 
Prokinetic 
ASP per 
  
  
  
  
  
  
Antiemetic 
ASP per 
  
  
  
  
  
  
Neuromodulator ASP per 
  
  
  
  
  
  
PPI 
ASP per 
  
  
  
  
  
  
Laxative 
ASP per 
  
  
  
  
  
  
Category of 
Non-Motility 
Drug Use 
  
ASP per 
  
  
  
  
  
  
  
ASP per 
  
  
  
  
  
  
  
ASP per 
  
  
  
  
  
  
Other 
ASP per 
  
  
  
  
  
  
Dietary plan 
  
Cost 
  
  
  
  
  
  
Emergency room 
visit for 
Nausua/Vomiting 
E/M Level 
  
Procedure 
code 
  
Avg. 
cost 
per 
  
  
  
  
Testing Modality 
Scintigraphy 
Time to test 
  
Procedure 
code 
  
Cost 
per 
  
# of 
tests 
  
SmartPill 
Time to test 
  
Procedure 
code 
  
Cost 
per 
  
# of 
tests 
  
 
 

 
 
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Additional Dx 
AD Manometry 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
SBFT 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
ROM 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
ARM 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
CT scan 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
MRI 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
Ultrasound 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
hydrogen breath 
test 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
C13 breath test 
  
Procedure 
code 
  
Cost 
per 
  
  
  
  
Other 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
Other 
  
Procedure 
code 
  
APC 
  
Cost per 
  
  
 
 

 
 
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Physician Services 
Service 
  
Procedure 
code 
  
APC 
  
Avg. 
payment   
  
Service 
  
Procedure 
code 
  
APC 
  
Avg. 
payment   
  
Service 
  
Procedure 
code 
  
APC 
  
Avg. 
payment   
  
Service 
  
Procedure 
code 
  
APC 
  
Avg. 
payment   
  
Service 
  
Procedure 
code 
  
APC 
  
Avg. 
payment   
  
Service 
  
Procedure 
code 
  
APC 
  
Avg. 
payment   
  
Subsequent patient 
management plan 
Category of 
Motility Drug 
Use 
Prokinetic 
ASP per 
  
  
  
  
  
  
Antiemetic 
ASP per 
  
  
  
  
  
  
Neuromodulator ASP per 
  
  
  
  
  
  
PPI 
ASP per 
  
  
  
  
  
  
Laxative 
ASP per 
  
  
  
  
  
  
Category of 
Non-Motility 
Drug Use 
  
ASP per 
  
  
  
  
  
  
  
ASP per 
  
  
  
  
  
  
  
ASP per 
  
  
  
  
  
  
Other 
ASP per 
  
  
  
  
  
  
Dietary change 
  
Cost 
  
  
  
  
  
  
Surgery change  
G tube changed 
to J tube 
Y / N 
Procedure 
code 
Cost 
  
  
  
  
 
 
 
 

 
 
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Appendix J: CLINICAL STUDY SITES 
 
Investigator 
Institution 
Contact details 
Braden Kuo, MD 
Massachusetts General 
Hospital, Boston, MA 
MGH Digestive Healthcare 
Center 165 Cambridge St., 
9th floor Boston, MA   02114 
Henry Parkman, MD 
Temple University, 
Philadelphia, PA 
Temple Clinical Research 
Institute (TCRI) Student 
Faculty Center 3340 N. Broad 
Street, 427 C Philadelphia, 
PA 19140 
William Hasler, MD 
 
University of Michigan, Ann 
Arbor, MI 
University of Michigan 
Medical Center 3912 
Taubman Center, SPC 5362 
Ann Arbor, MI 48109 
S. Satish Rao, MD  
 
Georgia Health Sciences 
University, Augusta GA 
Georgia Regents Medical 
Center, BB R2538 
1120 15th Street 
Augusta, GA 30909 
 
 
 
Linda Nguyen MD 
Stanford University Medical 
Center.   Stanford, CA 
300 Pasteur Dr., Room 
H0262, MC: 5244 
Palo Alto, CA 94305 
Richard McCallum 
Texas Tech University,  El 
Paso TX 
Texas Tech University Health 
Sciences Center 

 
 
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Investigator 
Institution 
Contact details 
3601 4th Street, STOP 8146 
Lubbock, TX 79430-8146 
John Wo 
Indiana University School of 
Medicine, Indianapolis, IN 
Indiana University Health UH 
1634550 North University 
Blvd. l Indianapolis, IN, 46202 
Richard Krause 
 ClinSearch, LLC 
Chattanooga, TN  
Clinsearch,LLC 
6035 Shallowford Road,Suite 
109 Chattonooga,TN 37421 
Michael Schulman 
Florida Digestive Health 
Specialists FL 
 
Florida Digestive Health 
Specialists 
8250 Bryan Dairy Road, Suite 
200 Largo, FL 33777 
Allen Lee 
Fletcher Allen Health Care 
 
Fletcher Allen Health Care 
 
Moshiree Baharak 
Miami Miller School of 
medicine 
University of Miami Leonard 
Miller School of Medicine 
Division of Gastroenterology 
1120 NW 14th Street 
 
 
 
REV.# 
DESCRIPTION 
DATE 

 
 
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1 
New Issue 
according to 
DMS data 
2 
Omitting GSRS survey, updating sites lists and CRO 
role 
according to 
DMS data 
3 
a. Omit GES scans results provided to sponsor 
within 3 days of procedure. GES results will be 
provided to sponsor in a timely manner 
b. Allow per protocol performance of site standard 
of care Scintigraphy scan 
c. Allow per protocol of visit #3 performance by 
phone, sending receiver by FedEx  
d. EGD inclusion criteria to be extended to 3 years 
prior to enrollment 
e. Add primary end point interim analysis after 
enrollment of 150 patients 
f. Sample size increase to 275 subjects in order to 
compensate for 1 interim analysis 
g. Omit SF-36 survey- as per admin change #1 
h. Omit ROME III modules filled by the subjects on 
visits 2, 5 and 6 – as per admin change #1 
i. 
Omit Screening visit patient management plan- 
as per admin change #1 
j. 
Correct Ensure meal volume to 240ml (1 can)- as 
per admin change #2 
k. Correct Amount of radiolabeled substance 
(99mTc-sulfur colloid) to be mixed within the 
eggbeaters meal to be Between 0.5 and 1 mCi 
99mTc-sulfur colloid marker- as per admin 
change #2 
 
according to 
DMS data