Clinical trial NCT02505945
Conditions: GERD Gastroesophageal Reflux Disease
Keywords: Esophageal Reflux Gastric Acid Reflux Disease Heartburn
Sponsor: Torax Medical Incorporated
Start date: 2015-06-01; Completion date: 2018-08-01
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study compares mechanical sphincter augmentation (LINX Reflux Management System) to double-dose proton pump inhibitors (PPIs) for the management of reflux symptoms related to gastroesophageal reflux disease (GERD).

Detailed description:
Prospective, multicenter, 2:1 randomized, cross-over, two arms

* Control arm: Double-dose PPI \[Omeprazole 20 mg BID (twice a day)\]
* Treatment arm: LINX Reflux Management System Up to 20 study centers throughout the U.S. will participate. Approximately150 patients will be enrolled into the study. Subjects will be randomized 2:1 into the double-dose PPIs arm (100 subjects) and the LINX arm (50 subjects).

Arms: arm 1: Double-dose PPI \[Omeprazole 20 mg BID (twice a day)\] arm 2: LINX Reflux Management System
Interventions: intervention 1: Omeprazole intervention 2: LINX Reflux Management System
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
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The CALIBER Study 
Randomized Controlled Trial of  
LINX versus Double-Dose Proton Pump Inhibitor 
Therapy for Reflux Disease  
 
 
 
Protocol Number 
4959 
Protocol Date 
June 8, 2015 
Sponsor 
 
Torax Medical, Inc. 
4188 Lexington Avenue North 
Shoreview, MN 55126 
Phone:  651-361-8900 
Fax:  651-361-8910 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY AGREEMENT 
This document is a confidential communication of Torax Medical.  Acceptance of this document 
constitutes the agreement by the recipient that no published information contained within will be 
published or disclosed without prior written approval, except that this document may be 
disclosed to the appropriate Institutional Review Board and Regulatory Authority under the 
condition that they are requested to keep it confidential. 


 
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PROTOCOL SUMMARY  
 
Title 
The CALIBER Study 
Randomized Controlled triAL of LINX versus douBle-dosE 
pRoton-pump inhibitor therapy for reflux disease  
Sponsor 
Torax Medical, Inc.  
Purpose 
To compare mechanical sphincter augmentation (LINX Reflux 
Management System) to double-dose proton pump inhibitors (PPIs) 
for the management of reflux symptoms related to gastroesophageal 
reflux disease (GERD). 
Study Premise 
LINX may provide superior reflux control, as defined by control of 
reflux symptoms, and in particular regurgitation, when compared to 
double-dose PPIs in patients who were refractory to once daily PPI. 
Study Design 
Prospective, multicenter, 2:1 randomized, cross-over, two arms 
• 
Control arm:  Double-dose PPI [Omeprazole 20 mg BID 
(twice a day)] 
• 
Treatment arm:  LINX Reflux Management System 
Study Centers 
Up to 20 study centers throughout the U.S. will participate.  
Enrollment 
Approximately150 patients will be enrolled into the study. Subjects 
will be randomized 2:1 into the double-dose PPIs arm (100 
subjects) and the LINX arm (50 subjects).  
Primary Inclusion 
Criteria 
• 
Patient seeks consultation for troublesome symptoms related 
to reflux despite use of once daily PPIs. 
• 
Dependent upon once daily PPIs for > 8weeks 
• 
Moderate or severe regurgitation per the Foregut Symptom 
Questionnaire while taking PPI therapy 
• 
Abnormal distal esophageal pH while off GERD medications 
for at least 7 days by total % time or DeMeester Score 
Primary Exclusion 
Criteria 
• 
Patient is currently on double-dose PPIs (twice a day dosing)  
• 
Patient is unable to take double-dose PPIs due to 
contraindication to medication or known medical condition 
• 
Patient has contraindications, warnings or precautions related to 
LINX  
Study Duration 
The following estimates the randomization and visit schedule: 
• 
First subject randomized:  Q3 2015 
• 
Last subject randomized:  Q1 2016 
• 
Last 6-month visit:  Q3 2016 
• 
Last 12-month visit:  Q2 2017 
Schedule of 
Evaluations 
See Table 1 


 
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Study Groups (after 
6-month evaluations) 
After completion of the 6-month follow-up visit, subjects assigned 
to the double-dose PPI arm will:  
1.) Have their PPI dose stepped-down to single-dose (Omeprazole 
20 mg daily) and continued until the 12 month visit, unless 
symptoms return and double-dose PPIs are restarted 
  OR  
2.) Have the option to cross-over to LINX if cross-over criteria are 
met  
See Figure 1 
Cross-Over Criteria 
(after 6 month 
evaluations) 
The following criteria must be met for cross-over to LINX: 
• 
Abnormal total number of distal reflux episodes as assessed by 
the 6-month impedance testing completed on double-dose PPIs  
• 
Presence of moderate or severe regurgitation reported on the 6-
month Foregut Symptom Questionnaire completed on double-
dose PPIs 
• 
Patient consents to LINX procedure 
Primary Endpoint 
and Additional 
Effectiveness 
Measures 
Primary Endpoint  
Percentage of subjects treated with LINX compared to percentage 
of subjects treated with double-dose PPIs who have elimination of 
moderate or severe regurgitation per the Foregut Symptom 
Questionnaire at 6-months  
 
Additional Effectiveness Measures  
• 
Impedance measurements at 6 months 
• 
Moderate or severe regurgitation at 12 months 
• 
Esophageal pH exposure at 12 months 
• 
GERD-Health Related Quality of Life (GERD-HRQL) total 
score at 6 and 12 months 
• 
Reflux Disease Questionnaire score at 6 and 12 months  
Evaluation of Side 
Effects 
The GERD-HRQL, Foregut Symptom Questionnaire and the 
Reflux Disease Questionnaire include questions to evaluate 
potential side effects (such as difficulty swallowing, gas/bloat, 
nausea, etc.).  These data will be analyzed to evaluate for 
differences in side effect profiles between the LINX and double-
dose PPI arms. 
Evaluation of Safety 
Rate of occurrence of serious adverse events (SAEs) related to 
LINX or double-dose PPIs will be evaluated throughout the 
duration of the study. No formal statistical hypothesis test will be 
conducted.  Additionally, the number of related events, number of 
study subjects with events, and the percent of subjects with an event 
will be summarized. 


 
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Table 1.  Schedule of Data Collection 
Data Collected/Testing 
Completed 
Visit Schedule 
Screening/ 
Baseline 
Randomization 
6  
Month 
12 
Month 
Demographics 
X 
 
 
 
Height/Weight 
X 
 
X 
X 
Medical History 
X 
 
X 
X 
GERD Medication  
X 
 
X 
X 
Foregut Symptom Questionnaire 
X1 
 
X2 
X3 
GERD-HRQL 
X1 
 
X2 
X3 
Reflux Disease Questionnaire  
X1 
 
X2 
X3 
Esophagogastroduodendoscopy 
(EGD) 
X 
 
 
X3 
Manometry/Motility and/or Barium 
Esophagram per Standard of Care 
X 
 
 
 
Esophageal pH Monitoring 
X1 
 
 
X3 
Treatment Assignment/Implant  
 
X 
 
 
Cross-Over/Step-Down Information 
 
 
X  
(PPI arm) 
 
Impedance Monitoring 
 
 
X2 
 
Adverse Events 
 
X 
X 
X 
1Screening/baseline questionnaires completed twice:  once on GERD medication and once off GERD medications 
for at least 7 days, with the exception of antacids which can be taken up until the morning of assessment.  
Esophageal pH monitoring conducted off GERD medications for at least 7 days, with the exception of antacids 
which can be taken up until the morning of assessment. 
2At 6-month follows-up, testing/questionnaires completed per treatment assignment:  PPI arm completed while on 
double dose PPIs with no other GERD medications for at least 7 days, with the exception of antacids which can be 
taken up until the morning of assessment; LINX arm completed off all GERD medications for at least 7 days, with 
the exception of antacids which can be taken up until the morning of assessment (in the event PPIs had been 
restarted).   
3At 12-month follow-up:  LINX or Cross-Over LINX complete testing/questionnaires off GERD medications for at 
least 7 days, with the exception of antacids which can be taken up until the morning of assessment.  Step-down PPI 
subjects complete testing/questionnaires while on single-dose PPI, with all other GERD medications stopped for at 
least 7 days ( including a second dose of PPI), with the exception of antacids which can be taken up until the 
morning of assessment.  Exception to note:  For those subjects crossing-over to LINX after the 6-month visit, the 12-
month visit is 6 months +30 days from the implant procedure date. 
 
Figure 1.  Study Groups (after 6 month evaluation) 
 
 
After 6 Month 
Follow-up
Randomization 
2:1
Baseline
Single-Dose 
PPI and 
Moderate/
Severe 
Regurgitation
Double-Dose 
PPI (N=100)
LINX Cross-
Over
Step-Down 
Dose
LINX (N=50)
LINX 


 
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TABLE OF CONTENTS 
 
BACKGROUND ................................................................................................................................... 7 
 
RATIONALE ........................................................................................................................................ 8 
 
PURPOSE ............................................................................................................................................ 8 
 
PRIMARY OBJECTIVE ......................................................................................................................... 9 
 
SECONDARY OBJECTIVES .................................................................................................................. 9 
 
THE LINX REFLUX MANAGEMENT SYSTEM .................................................................................... 10 
 
OMEPRAZOLE .................................................................................................................................. 11 
 
NUMBER OF SUBJECTS PLANNED ...................................................................................................... 12 
 
INCLUSION CRITERIA ....................................................................................................................... 12 
 
EXCLUSION CRITERIA ...................................................................................................................... 13 
 
METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUP ........................................................... 14 
 
EFFICACY......................................................................................................................................... 14 
6.1.1 
Primary Efficacy Endpoint ................................................................................................. 14 
6.1.2 
Additional Efficacy Outcomes ............................................................................................ 15 
 
SIDE EFFECTS .................................................................................................................................. 15 
 
SAFETY  .......................................................................................................................................... 15 
 
CLINICAL STUDY REGISTRATION ..................................................................................................... 17 
 
STUDY CENTER SELECTION AND PARTICIPATION ............................................................................ 17 
 
INSTITUTIONAL REVIEW BOARD ...................................................................................................... 17 
 
INFORMED CONSENT ........................................................................................................................ 17 
 
SITE ACTIVATION ............................................................................................................................ 18 
 
STANDARD OF CARE ........................................................................................................................ 18 
 
SCHEDULE OF DATA COLLECTION ................................................................................................... 18 
 
DATA COLLECTION WINDOWS......................................................................................................... 19 
 
PPI DOSING ..................................................................................................................................... 19 
 
QUESTIONNAIRES ............................................................................................................................ 20 
 
SCREENING/BASELINE/ENROLLMENT VISIT ..................................................................................... 20 
 
RANDOMIZATION/IMPLANT VISIT .................................................................................................... 21 
 
6-MONTH VISIT ............................................................................................................................... 21 
 
12-MONTH VISIT ............................................................................................................................. 22 
 
LINX IMPLANT PROCEDURE ............................................................................................................ 22 
 
CROSS-OVER TO LINX .................................................................................................................... 22 
 
PPI STEP-DOWN .............................................................................................................................. 23 
 
PPIS AFTER LINX ............................................................................................................................ 23 
 
SUPPLEMENTAL GERD MEDICATION .............................................................................................. 23 
 
ADVERSE EVENTS ............................................................................................................................ 23 
 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................................................... 24 


 
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POTENTIAL RISKS AND BENEFITS .................................................................................................... 25 
 
SUBJECT POPULATION FOR ANALYSIS ............................................................................................. 25 
 
PRIMARY EFFICACY ENDPOINT ........................................................................................................ 25 
 
ADDITIONAL EFFICACY OUTCOMES ................................................................................................. 26 
 
SAFETY  .......................................................................................................................................... 26 
 
INVESTIGATOR ................................................................................................................................. 26 
 
STUDY COORDINATOR ..................................................................................................................... 26 
 
CONFIDENTIALITY ........................................................................................................................... 27 
 
SOURCE DOCUMENTS ...................................................................................................................... 28 
 
CASE REPORT FORMS ...................................................................................................................... 28 
 
RECORDS RETENTION ...................................................................................................................... 28 
 
APPENDICES 
Appendix A:  LINX Instructions for Use (IFU) 
Appendix B:  Drug Information for Omeprazole 
Appendix C:  Request for Randomization 
Appendix D:  Informed Consent (Template) 
Appendix E:  Sample Case Report Forms (CRFs) 
Appendix F:  LINX Post-Operative Care Brochure 
 
 


 
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INTRODUCTION  
 
Background 
Gastroesophageal reflux disease (GERD) is a condition where gastric content refluxes 
into the esophagus and causes troublesome symptoms and/or complications.1  Normally, 
food travels from the mouth, down through the esophagus, and into the stomach.  In those 
who have GERD, the lower esophageal sphincter (LES) does not close properly, allowing 
acid and other contents of the digestive tract to move up (reflux) into the esophagus.  
GERD, which primarily manifests as heartburn, regurgitation, or both, is a chronic 
disorder associated with substantial morbidity, potential malignancy and a major adverse 
impact on quality of life.2  In industrialized nations the disease has become increasingly 
common, with an estimated prevalence of 7% in the general population based on the 
presence of daily symptoms.3 
The predominant medical therapy for GERD is acid suppression with proton-pump 
inhibitors (PPIs).  PPIs are a group of drugs whose main action is a pronounced and 
long-lasting reduction of gastric acid production. They are the most potent inhibitors 
of acid secretion available.  Although PPIs remove most of the acid from the reflux, 
these medications do not eliminate reflux.  As a result, PPIs are most effective for 
heartburn and progressively less effective for regurgitation, chest pain and extra-
esophageal symptoms.4  Approximately 10 to 40 percent of patients with GERD fail to 
respond symptomatically, either partially or completely, to a standard dose PPI.5-7  
Lack of satisfactory symptomatic response to PPI once a day is sufficient to consider 
it as a treatment failure.8  Doubling the PPI dose has become a common practice in 
patients with GERD who have failed PPI once daily (single-dose) with confirmed 
abnormal esophageal acid exposure by pH monitoring.4,8  Once symptoms are better 
managed, studies have shown patients who are prescribed a higher dose of PPI can 
decrease or “step down” the dose without return of symptoms or decrease in quality of 
life.5   
In the case of persistent symptoms despite PPIs, anti-reflux surgery is an alternative.  The 
LINX® Reflux Management System (LINX) is indicated for patients with abnormal 
esophageal pH testing who have persistent symptoms despite medical therapy.  The 
device was approved by the FDA for commercial use March 22, 2012.  In clinical studies, 
the LINX has demonstrated improved reflux control through reduction in esophageal acid 
exposure, elimination of regurgitation, improvement in GERD-related quality of life 
scores, and freedom from daily dependence on PPIs, while minimizing the side effects 
commonly associated with Nissen fundoplication.9-14  LINX is the only anti-reflux 
surgical option to mechanically restore competency to the reflux barrier without using the 
gastric fundus.   


 
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Rationale 
No randomized controlled trials have been conducted comparing LINX to double-dose 
PPIs for control of reflux symptoms in patients who continue to have symptoms while on 
single-dose PPIs.  This study will provide clinical data to compare the clinical outcomes 
of two different approaches for managing persistent reflux symptoms:  increased acid 
suppression therapy versus mechanical augmentation of the LES.  Since acid suppression 
does not eliminate reflux but rather decreases the acidity of the refluxate, a mechanical 
approach may provide better reflux control and symptom improvement.15-17  The 
scientific rationale for the design of the LINX device is based on the premise that an 
incompetent (weak) LES will remain susceptible to gastroesophageal reflux until the LES 
barrier function is restored.  The LINX is designed to augment the LES function and is 
placed, via a laparoscopic approach, on the external aspect of the esophagus in the region 
of the LES.  The device is comprised of a series of titanium beads with magnetic cores 
that are linked together with independent titanium wires.  As a series, the device forms an 
annular shape (See Section 4.1 for device description).  Based on the premise that the 
origin of GERD is largely a mechanical issue of a weak or incompetent LES unable to 
prevent abnormal reflux, which may lead to troublesome symptoms, the LINX addresses 
the mechanical dysfunction of the LES with a mechanical approach.  The commercial 
availability of PPIs and LINX is at least 25 years and 3 years, respectively.  The use of 
PPIs is well-established as a treatment for GERD, whereas the role of LINX in the 
treatment continuum for GERD is still evolving.  Clinical studies of the LINX have 
shown that mechanical augmentation of the LES with a magnetic ring can eliminate the 
symptom of moderate or severe regurgitation as well as heartburn.  In comparison, acid 
suppression therapy is very effective at managing acid-related symptoms like heartburn, 
but less effective at regurgitation.  This study is important to evaluate control of 
regurgitation in a randomized controlled trial comparing mechanical augmentation of the 
LES with LINX to acid suppression with double-dose PPIs, and how control of acid-
related symptoms like heartburn symptoms compares between LINX and double-dose 
PPIs. 
 
 
STUDY PURPOSE AND OBJECTIVES 
 
Purpose 
To compare mechanical sphincter augmentation with LINX to double-dose PPIs for the 
management of reflux symptoms related to GERD. 


 
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Primary Objective 
The primary objective of this study is to assess if LINX in comparison to double-dose 
PPIs provides superior elimination of moderate and severe regurgitation at 6 months in 
patients who were refractory to single-dose PPIs at baseline. 
 
Secondary Objectives 
Secondary objectives of this study are to compare the following between the randomized 
arms: 
• Impedance measurements at 6 months 
• Presence of moderate or severe regurgitation at 12 months 
• Esophageal pH measurements at 12 months 
• Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) 
scores at 6 and 12 months 
• Reflux Disease Questionnaire (RDQ) scores at 6 and 12 months 
 
 
STUDY DESIGN 
• Prospective, multicenter, randomized controlled, cross-over trial conducted at up to 
20 centers in the U.S. 
• Subjects will be randomized to either LINX or double-dose PPIs (twice a day dosing) 
• Randomization 2:1 and enrollment of approximately 150 subjects (100 double-dose 
PPI and 50 LINX) 
• Subjects will complete follow-up at 6- and 12-months after randomization or LINX 
implant 
• Primary endpoint evaluation will be based on 6-month data per the subject’s 
randomization assignment 
• After the 6-month follow-up, subjects in the PPI arm will either step-down PPI dose 
to once a day dosing, or be offered the LINX procedure if the cross-over criteria are 
met. 
 


 
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STUDY TREATMENTS 
 
The LINX Reflux Management System 
The LINX Reflux Management System is intended for use in those patients diagnosed 
with pathologic GERD as defined by abnormal pH testing and who continue to have 
chronic GERD symptoms despite maximum medical therapy.  The device received FDA 
approval March 22, 2012.  The LINX device is a permanent implant placed at the area of 
the lower esophageal sphincter (LES) and is designed to augment a weak LES and 
minimize or eliminate GERD-related symptoms. 
The LINX device consists of a series of titanium beads each with a magnetic core 
connected together with independent titanium wires to form an annular shape, when 
implanted (Figure 1).  The attractive force of the magnetic beads is designed to provide 
additional strength to keep a weak LES closed.  During swallowing, the magnetic beads 
slide away from each other on the independent titanium wire “links” to allow esophageal 
distention as the bolus passes by (Figure 2).  
After 6 Month 
Follow-up
Randomization 
2:1
Baseline
Single-Dose PPI 
and Moderate/
Severe 
Regurgitation
Double-Dose PPI 
(N=100)
LINX Cross-Over
Step-Down Dose
LINX (N=50)
LINX 


 
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The LINX System allows a surgeon, using existing laparoscopic techniques and 
instruments, to augment a weak sphincter and restore the barrier function of the LES.  
The mechanism of action for the LINX device is to augment the sphincter’s capacity to 
resist gastric pressure by using magnetic forces.  For reflux to occur following 
implantation of the LINX device, gastric pressure must overcome both the native 
sphincter resistance and the magnetic bond between the LINX beads.  At rest, the LINX 
device encircles the LES with each bead resting against an adjacent bead, which avoids 
compression of the esophagus and allows the patient to belch or vomit as necessary.  
Upon swallowing, the magnetic bond between the beads is overcome by the higher 
pressures of peristaltic swallowing forces, and the device expands to accommodate a 
normal swallow (Figures 3-5).  See Appendix A for Instructions for Use. 
 
Figure 3: 
Preventing Reflux 
Figure 4: 
During Swallow 
Figure 5: 
Non-Compressive 
 
 
 
Omeprazole 
LINX device creates resistance 
with magnetic forces to prevent 
the LES from opening. 
Higher pressures from swallowing 
overcome the magnetic forces, 
causing the device to expand. 
LINX device does not compress the 
esophageal wall. 


 
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Acid suppression is the mainstay of medical therapy for GERD. The American 
Gastroenterological Association (AGA) and the American College of Gastroenterology 
(ACG) recommend PPIs as first-line therapy for the treatment of severe GERD-related 
symptoms or erosive esophagitis (EE).18,19  In current clinical practice, seven PPIs are 
available and considered roughly equal in effectiveness and safety.  For the purpose of 
standardization, all subjects in this study randomized to double-dose PPIs will be treated 
with omeprazole 20 mg BID (twice a day).   
Omeprazole is a selective and irreversible proton pump inhibitor. It suppresses stomach 
acid secretion by specific inhibition of the H+/K+ ATPase system found at the secretory 
surface of gastric parietal cells.  The inhibitory effect of omeprazole occurs within 1 hour 
after oral administration. The maximum effect occurs within 2 hours. The duration of 
inhibition is up to 72 hours.  When omeprazole is stopped, baseline stomach acid 
secretory activity returns after 3 to 5 days.  The inhibitory effect of omeprazole on acid 
secretion will plateau after 4 days of repeated daily dosing.20  See Appendix B for Drug 
Information for Omeprazole. 
 
 
SELECTION OF SUBJECTS 
 
Number of subjects planned 
A total of approximately 150 subjects will be enrolled in the study, with approximately 
100 subjects randomized to double-dose PPIs and approximately 50 subjects randomized 
to LINX. 
 
Inclusion Criteria 
Patients are eligible for the study if all of the following criteria are met: 
1. Patient seeks consultation for troublesome symptoms related to reflux despite use 
of once daily PPIs. 
2. PPI taken once a day at a standard dose for symptomatic GERD or healing of 
esophagitis for at least 8 weeks. 
3. Age >21 years old. 
4. Abnormal distal esophageal pH determined by total % time pH <4 or DeMeester 
Score.  Testing to be completed off GERD medications for at least 7 days, with 
the exception of antacids, which may be taken up until the morning of assessment. 
5. Moderate or severe regurgitation per the Foregut Symptom Questionnaire while 
taking once daily PPIs. 
6. A total GERD-HRQL score of >11 while off GERD medications for at least 7 
days, with the exception of antacids, which may be taken up until the morning of 
assessment. 


 
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7. Suitable surgical candidate (i.e. is able to undergo general anesthesia and 
laparoscopic surgery). 
8. Patient has provided written informed consent for participation in the randomized 
study. 
9. Patient is willing to be randomized to either LINX or double-dose PPIs and to 
follow the treatment plan and follow-up examinations per protocol to which 
he/she has been assigned. 
 
Exclusion Criteria 
Patients will not be included in the study if any of the following criteria apply:   
1. Currently taking double-dose PPIs (twice daily dosing). 
2. Currently being treated with an investigational drug or investigational device. 
3. Patient is contraindicated for double-dose PPIs or has a medical history or 
condition where use of double-dose PPIs is not advised. 
4. History of gastric surgery, gastroesophageal surgery, anti-reflux procedures, or 
gastroesophageal/gastric cancer. 
5. Prior endoscopic anti-reflux intervention for GERD and/or previous endoscopic 
intervention for treatment of Barrett’s esophagus. 
6. Suspected or confirmed esophageal or gastric cancer. 
7. Hiatal hernia >3cm as determined by endoscopy. 
8. Distal esophageal motility (average of sensors 3 and 4) is less than 35 mmHg 
peristaltic amplitude on wet swallows or <70% (propulsive) peristaltic sequences. 
9. Esophagitis Grade C or D (Los Angeles classification). 
10. Body mass index >35. 
11. Symptoms of dysphagia more than once per week within the last 3 months. 
12. Diagnosed with Scleroderma. 
13. Diagnosed with an esophageal motility disorder such as, but not limited to 
Achalasia, Nutcracker Esophagus, or Diffuse Esophageal Spasm or Hypertensive 
LES. 
14. Esophageal stricture or gross esophageal anatomic abnormalities (Schatzki’s ring, 
obstructive lesions, etc.).  
15. Esophageal or gastric varices. 
16. History of/or known Barrett’s esophagus. 
Note:  The diagnosis of Barrett’s esophagus requires both endoscopic and 
histologic evidence of metaplastic columnar epithelium.  Endoscopically, there 
must be columnar epithelium within the esophagus. Histologically, the epithelium 
must be metaplastic, as defined by the presence of goblet cells.by  
17. Pregnant or nursing, or plans to become pregnant during the course of the study. 


 
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18. Medical illness (i.e. congestive heart failure) that may cause the patient to be non-
compliant with or able to meet the protocol requirements, or is associated with 
limited life expectancy (i.e. less than 3 years). 
19. Uncontrolled major depression or diagnosis of DSM-5 psychiatric disorder (e.g. 
bipolar, schizophrenia, etc.). 
20. Suspected or known allergies to titanium, stainless steel, nickel or ferrous 
materials. 
21. Patient has an electrical implant or metallic, abdominal implants. 
 
Methods of Assigning Subjects to Treatment Group 
The study management team (Torax Medical) will allocate treatment based on a pre-
specified randomization sequence of sealed envelopes or other method, generated by the 
biostatistics group, using the study center as a stratification parameter.  Study centers will 
be blinded to the determinants for the randomization sequence (block size, stratification, 
etc.) 
After eligibility is documented based on the inclusion/exclusion criteria, the study center 
will complete and submit the “Request for Randomization” form to the study 
management team (Appendix C).  The study management team will review to confirm 
eligibility.  The next sequentially assigned sealed envelope for the study center will be 
selected and opened to conduct the randomization.  The treatment assignment will be 
documented on the Request for Randomization form and returned to site along with a 
copy of the randomization envelope. 
All subjects randomized are irrevocably in the study, whether or not they are 
subsequently found to be eligible or actually receive the allocated treatment, and they 
should be followed until the end of the study. 
The allocated treatment should take place as soon as possible after randomization (on the 
same day for double-dose PPIs and within 6 weeks for LINX). 
 
 
MEASUREMENT OF CLINICAL OUTCOMES 
 
Efficacy 
6.1.1 Primary Efficacy Endpoint 
Percentage of LINX subjects who have elimination of moderate or severe 
regurgitation per the Foregut Symptom Questionnaire at 6-months compared to 
subjects treated with double-dose PPIs.  
 
 


 
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6.1.2 Additional Efficacy Outcomes 
• Elimination of moderate or severe regurgitation at 12 months. 
• Esophageal pH at 12 months (% of subjects with normalization or 50% 
reduction in total % pH<4 compared to baseline; summary statistics of 
DeMeester components at follow-up compared to baseline). 
• GERD-HRQL total score at 6 and 12 months (% of subjects with at least 
50% reduction in total score compared to baseline off PPI score; summary 
statistics of GERD-HRQL score at follow-up compared to baseline on and 
off PPIs). 
• RDQ score at 6 and 12 months (summary statistics of scores at follow-up 
compared to baseline on and off PPIs). 
• Impedance at 6 months (summary statistics of number of reflux episodes; 
% of subjects with normal number of reflux episodes). 
 
 
Side Effects 
The GERD-HRQL, Foregut Symptom Questionnaire and RDQ include questions to track 
potential side effects (such as difficulty swallowing, gas/bloat, nausea, etc.).  The data 
from these questionnaires will be analyzed to evaluate differences between the LINX and 
double-dose PPIs at 6 months as well as stepped-down dose of PPIs at 12 months. 
 
Safety 
Rate of occurrence of serious adverse events (SAEs) related to LINX or PPIs will be 
evaluated throughout the duration of the study. No formal statistical hypothesis test will 
be conducted.  Number of related events, number of study subjects with events, and the 
percent of subjects with an event will be summarized. Because the LINX is a surgical 
procedure, there are inherent risks not applicable to medical therapy (PPIs).  An 
acceptable level of risk has been documented for the LINX procedure.  It is expected that 
re-hospitalization or device removals will not exceed 6% (upper confidence limit of 
12.6%) at the 12-month visit based on the clinical experience from the LINX Pivotal 
Trial in support of FDA approval, which established this level of risk did not outweigh 
the benefit of treatment with the LINX device.   


 
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STUDY FLOWCHART 
 


 
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STUDY PROCEDURES 
 
Clinical Study Registration 
The study will be registered by the Sponsor at www.clinicaltrials.gov.   
 
Study Center Selection and Participation 
Study centers interested in participating in this study will be assessed for their ability to 
fully and appropriately participate in the study.  In general, study centers will be selected 
if patient volume is adequate to support enrollment of patients into the study and the 
participating physician(s) are qualified by education, training and surgical experience.   
No site will enroll more than 15 randomized subjects without prior written approval 
provided by the Sponsor. 
 
Institutional Review Board 
This protocol, informed consent form (ICF), and authorization for the use and disclosure 
of health information (as applicable) must be reviewed and approved by the study 
center’s IRB before any study patient is enrolled.  Changes to the protocol must be 
approved in writing by Torax Medical and the IRB (as applicable) before the change is 
implemented. 
Prior to study patient enrollment, a signed copy of the IRB approval letter addressed to 
the Investigator and the final approved ICF must be submitted to Torax Medical.  The 
letter should reference this protocol by title, date or number/revision number as well as 
the approved ICF and HIPAA Authorization (as applicable).  Investigators are 
responsible for submitting and obtaining initial approval and continuing approval from 
the IRB and forwarding copies of the approval letters to Torax Medical.  The original 
letters are to be kept in the study center’s regulatory file designated for this study. 
The Investigator will notify the Sponsor within five (5) working days of withdrawal of 
IRB approval. 
 
Informed Consent 
Prior to IRB submission, the Investigator or designee will prepare an ICF in accordance 
with this study protocol and all regulatory requirements (e.g. where applicable, 21 CFR 
Part 50 and in accordance with the Declaration of Helsinki) using the sample ICF 
provided (Appendix D).  A copy of the final IRB approved ICF must be submitted to 
Torax Medical and a site must be activated by Torax Medical prior to enrolling patients 
at that investigational center.  All study patients (or their legal guardian) must document 
their consent by signing an IRB-approved ICF prior to completing any protocol-specific 
assessments that are not considered standard of care.   


 
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Site Activation 
A study center may not begin enrolling subjects until the Sponsor provides notification 
that the site has provided all required study start-up documents and completed training.  
At minimum, the Principal Investigator at the study center will be notified in writing of 
“Site Activation” when start-up activities have been completed.  Upon receipt of this 
notification, the study center may begin enrolling subjects.   
 
Standard of Care 
As part of screening/baseline, all patients will undergo an anti-reflux surgery work-up in 
the event of randomization to LINX.  This work-up can be used in the event of cross-over 
to LINX as well, provided subjects have not had significant changes to their health.  The 
anti-reflux surgery work-up used for the study enrollment should be completed within the 
1-year time period prior to signing of the study ICF.  Subjects who cross-over to LINX 
after the 6 months visit are not required to repeat the anti-reflux surgical work-up, unless 
deemed necessary by the Investigator. 
For purposes of the study, the questionnaires (GERD-HRQL, Foregut Symptom 
Questionnaire, and RDQ) will be considered standard of care to facilitate pre-screening 
of patients.  However, only questionnaires completed by a subject who has provided 
informed consent for the study will be accessible to the Sponsor.   
 
Schedule of Data Collection 
The Screening/Baseline visit will determine the eligibility of a subject to be randomized 
to either LINX or double-dose PPIs.  After randomization, subjects will be followed at 6 
months and 12 months.  All follow-up assessments should be completed during an office 
visit, with the exception of the questionnaires, which may be completed by a phone call 
or electronically mailed as needed.  Sample case report forms are provided in Appendix 
E.  Table 1 shows the schedule of data collection.   
 
Table 1.  Schedule of Data Collection 
Data Collected/Testing 
Completed 
Visit Schedule 
Screening/ 
Baseline 
Randomization 
6  
Month 
12 
Month 
Demographics 
X 
 
 
 
Height/Weight 
X 
 
X 
X 
Medical History 
X 
 
X 
X 
GERD Medication  
X 
 
X 
X 
Foregut Symptom Questionnaire 
X1 
 
X2 
X3 
GERD-HRQL 
X1 
 
X2 
X3 
Reflux Disease Questionnaire  
X1 
 
X2 
X3 
Esophagogastroduodendoscopy 
(EGD)  
X 
 
 
X3 
Manometry/Motility and/or Barium 
Esophagram per Standard of Care 
X 
 
 
 
Esophageal pH Monitoring 
X1 
 
 
X3 


 
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Treatment Assignment/Implant  
 
X 
 
 
Cross-Over/Step-Down Information 
 
 
X  
(PPI arm) 
 
Impedance Monitoring 
 
 
X2 
 
Adverse Events 
 
X 
X 
X 
1Screening/baseline questionnaires completed twice:  once on GERD medication and once off GERD medications for 
at least 7 days, with the exception of antacids which can be taken up until the morning of assessment.  Esophageal pH 
monitoring conducted off GERD medications for at least 7 days, with the exception of antacids which can be taken up 
until the morning of assessment. 
2At 6-month follows-up, testing/questionnaires completed per treatment assignment:  PPI arm completed while on 
double dose PPIs with no other GERD medications for at least 7 days, with the exception of antacids which can be 
taken up until the morning of assessment; LINX arm completed off all GERD medications for at least 7 days, with the 
exception of antacids which can be taken up until the morning of assessment (in the event PPIs had been restarted).   
3At 12-month follow-up:  LINX or Cross-Over LINX complete testing/questionnaires off GERD medications for at 
least 7 days, with the exception of antacids which can be taken up until the morning of assessment.  Step-down PPI 
subjects complete testing/questionnaires while on single-dose PPI, with all other GERD medications stopped for at 
least 7 days ( including a second dose of PPI), with the exception of antacids which can be taken up until the morning 
of assessment.  Exception to note:  For those subjects crossing-over to LINX after the 6-month visit, the 12-month visit 
is 6 months +30 days from the implant procedure date. 
 
 
Data Collection Windows 
The data collection window for each visit is outlined in Table 2.  The 6-month follow-up 
visit is +/- 30 days from the anniversary date of the implant procedure or first dose of 
double-dose PPIs after randomization.  The 12-month follow-up visit is +/- 60 days from 
the anniversary date of the implant procedure or first dose of double-dose PPIs after 
randomization.  (Exception to note:  For those subjects crossing-over to LINX after the 6-
month visit, the 12-month visit is 6 months +30 days from the implant procedure date.) 
 
Table 2:  Follow-up Windows 
Visit 
Follow-up Window 
6 months (+30 days) 
150-210 days 
12 Months (+60 days)* 
305-425 days 
*12-month visit for cross-over subjects will be 6 months (+30 days) after the cross-over LINX 
implant procedure date. 
 
 
PPI Dosing 
At screening, a subject must be currently taking a once a day standard PPI dose for 
symptomatic GERD or healing of esophagitis for at least 8 weeks.  If a subject is 
randomized to double-dose PPIs, the subject will take Omeprazole 20 mg BID (twice a 
day). 
When doubling the PPI dose, one PPI dose should be given before breakfast and the other 
before dinner (ideally 30 minutes before the meal).  Subjects should be counseled on the 
importance of compliance with medical therapy. 


 
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Subjects randomized to double-dose PPIs who do not cross-over to LINX after the 6-
month follow-up will be stepped-down to a single-dose PPI (Omeprazole 20 mg QD).  
Four weeks after stepping-down the PPI dose, the subject will be contacted for symptom 
assessment.  If symptoms are not controlled on single-dose, subject may resume double-
dose PPI (Omeprazole 20 mg BID) if directed by the Investigator.  Use of supplemental 
GERD medications, after LINX are discussed in Section 8.19. 
 
Questionnaires 
At each visit, subjects will complete the following questionnaires to evaluate reflux-
related symptoms:  GERD-HRQL, Foregut Symptom Questionnaire, and Reflux Disease 
Questionnaire (RDQ).  Samples of these questionnaires are found in Appendix E.   
At the screening/baseline visit, the questionnaires will be completed twice:  once on 
GERD medications and once off GERD medications for at least 7 days, with the 
exception of antacids which can be taken up until the morning of assessment 
At the 6-month follow-up visit, the testing/questionnaires will be completed per treatment 
assignment:   
 
• Double-dose PPI arm completed while on double-dose PPIs with no other GERD 
medications for at least 7 days, with the exception of antacids which can be taken 
up until the morning of assessment. 
• LINX arm completed off all GERD medications for at least 7 days, with the 
exception of antacids which can be taken up until the morning of assessment.   
 
At 12-month follow-up, LINX and Cross-Over LINX will complete the testing/questionnaires off 
GERD medications for at least 7 days, with the exception of antacids which can be taken up until 
the morning of assessment.  Step-down PPI subjects (all subjects without LINX) will complete 
testing/questionnaires while on single-dose PPI (Omeprazole 20mg QD), with all other GERD 
medications stopped for at least 7 days (including a second dose of PPI), with the exception of 
antacids which can be taken up until the morning of assessment.   
 
Screening/Baseline/Enrollment Visit 
Informed consent will be obtained prior to any study specific assessments.  Data collected 
at baseline will include the following: 
• Date of birth 
• Demographics (gender and race) 
• Height and weight  
• Duration of PPI use  
• Years with GERD 
• Baseline GERD related medication use 
• GERD-HRQL (on and off GERD medications) 


 
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• Foregut Symptoms Questionnaire (on and off GERD medications) 
• Reflux Disease Questionnaire (on and off GERD medications) 
• Esophageal pH measurements (off GERD medications) 
• Esophagogastroduodendoscopy (EGD) 
• Manometry/motility or barium esophagram 
 
Randomization/Implant Visit 
LINX 
Subjects randomized to LINX should complete the implant procedure within 6 
weeks of randomization.  The following data will be collected: 
• Surgery date  
• Implanted device size 
• Concomitant procedures (e.g. hiatal hernia repair, cholecystectomy) 
• Discharge date and length of stay 
• Perioperative and device and/or procedure related adverse events 
Double-Dose PPI 
Subjects randomized to double-dose PPIs will start the increased acid suppression 
regimen as soon as possible after randomization.  All subjects randomized to 
double-dose PPIs will take Omeprazole 20 mg BID (twice a day).  Subjects will 
be instructed to take one dose (20mg) 30 minutes prior to breakfast and the 
second dose (20mg) 30 minutes prior to the evening meal.   
 
6-Month Visit 
Testing/questionnaires will be completed per treatment assignment.  The PPI arm will 
complete testing/questionnaires while on double-dose PPIs with no other GERD 
medications for at least 7 days, with the exception of antacids which can be taken up until 
the morning of.  The LINX arm will complete off all GERD medications for at least 7 
days, with the exception of antacids which can be taken up until the morning of 
assessment (in the event PPIs have been re-started).   
At the 6-month visit, the following assessments will be completed:   
• Height and weight 
• GERD-related medication use within the last 30 days 
• Questionnaires:  GERD-HRQL, Foregut Symptom Questionnaire and 
Reflux Disease Questionnaire 
• Impedance monitoring  
• Review of changes in health and medical history 
• Adverse events 


 
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Impedance monitoring will be performed per the instructions provided by the Core Lab 
and the report forwarded within one week of its completion to the Core Lab for 
reading and interpretation.   
 
12-Month Visit 
Subjects without LINX (stepped-down PPI) will complete testing/questionnaires while on 
single-dose PPI, with all other GERD medications stopped for at least 7 days (including 
any second dose of PPI), with the exception of antacids which can be taken up until the 
morning of assessment. 
At the 12-month follow-up visit, the LINX and Cross-Over LINX will complete 
testing/questionnaires off GERD medications for at least 7 days, with the exception of 
antacids which can be taken up until the morning of assessment.   
The following assessment will be completed at the 12-month visit: 
• Height and weight  
• GERD-related medication use within the last 30 days  
• Questionnaires:  GERD-HRQL, Foregut Symptom Questionnaire and Reflux 
Disease Questionnaire 
• Endoscopy 
• Esophageal pH testing 
• Review of changes in health and medical history 
• Adverse events 
 
 
LINX Implant Procedure 
The LINX implant procedure will be performed by a surgeon who has successfully 
completed the company required training for certification.  The subject should have 
routine post-operative visit about 2-4 weeks after the LINX implant procedure.  Subjects 
will be provided a copy of the LINX post-operative care brochure (see Appendix F). 
 
Cross-Over to LINX 
The following criteria must be met for cross-over to LINX: 
• Abnormal total number of distal reflux episodes as assessed by 6-month 
impedance testing completed on double-dose PPIs (abnormal defined in Core 
Lab’s Manual of Operation by manufacturer) 
• Presence of moderate or severe regurgitation reported on the 6-month Foregut 
Symptom Questionnaire completed on double-dose PPIs 
• Patient consents to LINX procedure 
If a subject crosses-over to LINX, the implant procedure must be completed within 6 
weeks of notification that the subject has met the cross-over criteria.  Timing of the 12-
month visit for cross-over subjects will be 6 months (+30 days) after the cross-over LINX 


 
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implant procedure date.  See Section 8.15 for additional information about LINX implant 
procedure. 
 
PPI Step-Down 
If cross-over criteria are not met, double-dose PPI will be stepped-down to single-dose 
(Omeprazole 20 mg QD).  Four weeks after stepping down the PPI dose, symptom 
assessment by either office visit or phone call will be conducted.  Double-dose PPIs may 
be resumed or other GERD medications started at the discretion of the Investigator.     
 
PPIs after LINX 
Subjects in the LINX arm may resume PPIs or other GERD medications after the LINX 
implant procedure as directed by the Investigator to manage reflux symptoms.  PPIs 
should be used at the lowest frequency and dose necessary for symptom relief.   
 
Supplemental GERD Medication 
As needed for symptom management, subjects may take other supplemental GERD 
medications.  GERD medications other than PPIs, H2 receptor antagonists (H2 blockers) 
or antacids are not allowed during the study. 
 
Adverse Events 
For all subjects starting at the time of randomization and proceeding throughout the 
duration of the follow-up period, the Investigator will closely monitor each subject for the 
development of device and/or procedure or GERD-medication-related adverse events 
(AEs).  For the purposes of this study, a reportable event will be defined as any untoward 
medical occurrence which has a strong relationship to the LINX device and/or implant 
procedure or PPI and another etiology is unlikely. 
The Investigator must decide whether each event meets the definition of a Serious 
Adverse Event (SAE).  All device and/or procedure related serious adverse events (SAE) 
must be reported immediately (within 5 days of discovery) to Torax Medical.  SAE 
reporting to the IRB is per institutional policy. 
An AE is considered serious if it meets one or more of the following criteria: 
• Is life-threatening or results in death 
Note:  The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were 
more severe. 
• Requires subject hospitalization > 24 hours 
• Requires prolongation of an existing hospitalization 
• Results in persistent or significant disability/incapacity 


 
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• Results in fetal distress, fetal death, or a congenital anomaly or birth 
defect 
• Requires intervention to prevent permanent impairment or damage 
 
The following definitions for rating the severity of adverse events will be used: 
 
Mild 
Awareness of signs of symptoms, but easily 
tolerated; are of minor irritant type; causing no 
loss of time from normal activities. 
Moderate 
Discomfort intense enough to cause interference 
with usual activities. 
Severe 
Incapacitating with inability to do work or usual 
activities. 
 
 
Unanticipated Adverse Device or Drug Effects 
Unanticipated adverse device or drug effects (UADEs) include any serious adverse 
effects on the health or safety of a study subject or any life-threatening problem or death 
caused by, or associated with, the LINX device or Omeprazole that are not typically 
associated with the procedure, device or drug.  All unanticipated adverse effects must be 
reported to the IRB within 10 working days and to Torax Medical within 24 hours after 
the Investigator first learns of the adverse effect.   
 
Subject Completion and Withdrawal 
All study subjects have the right to withdraw their consent to participate at any time 
during the study.  Whenever possible, the site staff should obtain written documentation 
from the subject of his/her request to withdraw consent.  If the site staff is unable to 
obtain written documentation, all information regarding the subject’s withdrawal must be 
recorded in the subject’s medical record.   
On completion of the study (either by completion of protocol requirements or 
withdrawal), the Withdrawal/Completion CRF will be completed.  
A subject may withdraw (or be withdrawn) from the study prematurely for the following 
reasons:  
• Withdrawal of consent by subject 
• Adverse event (Adverse Event Log or SAE CRF must be completed) 
• Protocol deviation 
• Lost to follow-up (In case of early withdrawal of a subject, at least three 
(3) documented attempts should be made to contact the subject and have 
them come into the clinic). 


 
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• Termination of study by the Sponsor 
• Investigator believes it is in the best interest of the subject 
• Other (must be specified) 
 
 
RISK ANALYSIS 
 
Potential Risks and Benefits 
The LINX Reflux Management System has been previously studied and known risks 
associated with the surgical procedure and device implant can be found in the 
Instructions for Use (Appendix A).  Risks associated with Omeprazole can be found in 
the Drug Information (Appendix B).  The study will monitor the subjects through the 
duration of the subject’s participation for adverse events.  
The potential benefits to subjects are the reduction or elimination of GERD-related 
symptoms that were not effectively managed with once daily PPI. 
 
 
STATISTICAL PLAN 
 
Subject Population for Analysis 
All randomized subjects who either start double-dose PPIs or undergo the implant 
procedure will represent the study population for the primary efficacy endpoint analysis 
at 6 months (Treatment Group).  Analyses will also include intent-to-treat (ITT) at 6 
months for elimination of moderate or severe regurgitation (all randomized subjects, 
whether treatment was started or not).  All other analyses will be performed on available 
data at the follow-up visit.   
 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be elimination of moderate or severe regurgitation 
assessed by the Foregut Symptom Questionnaire at 6 months.  The primary efficacy 
endpoint will be analyzed for the Treatment Group.  Subjects not evaluable at 6 months 
due to early withdrawal or missing data will be counted as failures of the primary 
efficacy endpoint. The randomized groups will be compared for the primary efficacy 
objective according to the following hypotheses: 
H0: ΠL ≤ ΠP 
HA: ΠL > ΠP  
where ΠL is the percent of study patients randomized to LINX with elimination of 
moderate or severe regurgitation and ΠP is the percent of subjects randomized to the PPI 
group with elimination of moderate or severe regurgitation.  The percent of randomized 


 
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subjects with a successful elimination of moderate or severe regurgitation will be 
compared between groups using a Pearson’s chi-square test.  The required sample size 
was calculated using SAS v9.3 under the following assumptions: 
• Type I error = 5% 
• Assumed success rate in LINX group = 70% 
• Assumed difference in success rates = 30% 
• Power = 85% 
Under these assumptions, a minimum of 108 subjects enrolled and followed to 6 months 
are required.  The study will enroll approximately 150 subjects. 
 
Additional Efficacy Outcomes 
Summary statistics will be used to display results of other efficacy outcomes at each 
study time point.  For categorical parameters, this includes the number and frequency; 
and for continuous parameters, the mean, median, standard deviation, range.  
 
Safety 
Safety will be assessed by the rate of (number and percentage of subjects experiencing) 
treatment-related adverse events after randomization and throughout the study to 12 
months. 
 
 
ROLE AND RESPONSIBILITIES 
Each investigational center will identify appropriate personnel to perform all study tasks.  
 
Investigator 
• This clinician will have responsibility to treat all subjects. 
• Documents all reportable adverse events that occur during the study. 
• Be responsible for signing the CRFs. 
• Be responsible for providing medical care to subjects during the study. 
• Have responsibility for determining eligibility. 
• Conduct baseline assessments of the subject’s GERD. 
• Interview subjects about their GERD symptoms. 
• Be available for each subject follow-up visit.   
 
Study Coordinator 
In addition to the Investigator, a Study Coordinator will be identified at each 
investigational center to facilitate and manage the study.   
 


 
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STUDY CENTER DOCUMENTATION 
A study center site will provide the following documentation to Torax Medical prior to a 
site being activated to enroll patients: 
• Study training/initiation completed for the Investigators and study staff listed 
on the delegation log  
• Signed clinical trial agreement (CTA) 
• Current signed curriculum vitae and medical licenses for all Investigators 
listed on the CTA 
• Financial disclosure for all Investigators listed on the CTA 
• IRB approval letter and approved ICF 
 
 
STUDY PATIENT RECRUITMENT AND RETENTION PLAN 
As needed, the Sponsor will provide study centers with materials and financial support to 
recruit patients for the study.  All recruitment activities will require prior approval by the 
IRB before implementation.   
Efforts will be made to ensure the retention and compliance of study patients once 
enrolled.  Examples of strategies for subject retention include: 
• Instruct study centers to obtain multiple contact numbers and addresses from a 
subject to make it easier to reach the participant. 
• Counsel patients about the importance of returning to follow‐up during informed 
consent and follow-up visits. 
• Accommodate a subject’s schedule as much as possible to make the follow-up as 
convenient as possible. 
• Encourage the study centers to continue open communication with enrolled 
subjects and to schedule follow-up visits early in the protocol-defined window.   
• Provide database-generated follow-up schedules to study centers and discuss 
dates of upcoming visits. 
• Monitor follow-up rates closely so that follow‐up problems can be identified and 
addressed as soon as possible.  
• Request that study centers thoroughly document all attempts to contact enrolled 
subjects. 
 
 
DATA HANDLING AND RECORD KEEPING 
 
Confidentiality 
Information about study subjects will be kept confidential and managed according to 
applicable laws, regulations and guidelines.  All subject information documented on 


 
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CRFs will be referenced by a subject’s identification (ID) number and initials only.  If 
supplemental laboratory or imaging reports are submitted into the study, the subject’s 
name or other prohibited identifiers must be deleted and the subject initials and ID 
number added to each item.  A subject’s privacy and personal health information will be 
protected as required by law. 
 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
surgical notes, memoranda, subjects’ diaries, questionnaires or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays, subject files, and records 
kept at the pharmacy and at the laboratories involved in the clinical trial. 
 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If 
a space on the CRF is left blank because the procedure was not done or the question was 
not asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  
All entries should be printed legibly in ink.  If any entry error has been made, to correct 
such an error, draw a single straight line through the incorrect entry and enter the correct 
data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE-OUT ERRORS.  For clarification of illegible or uncertain entries, print the 
clarification above the item, then initial and date it. 
 
Records Retention 
The Investigator/institution will retain the study-related essential documents until two 
years after the final data analysis is complete. 
 
 
QUALITY ASSURANCE AND QUALITY CONTROL 
The Principal Investigator at each study site is responsible for assuring that accurate and 
complete data are collected and sent to the Sponsor.  Data will be reviewed periodically 
by the Sponsor for missing data points, incomplete information, and discrepancies.  
When necessary, issues will be resolved by electronic mail, telephone, facsimile, or site 
visit.  The Investigator will permit study-related monitoring, audits, and inspections by 
the IRB, the Sponsor, government regulatory bodies, and institutional compliance and 
quality assurance groups of all study related documents (e.g. source documents, 


 
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regulatory documents, data collection instruments, study data etc.).  The Investigator will 
ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.).   
 
 
PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the Sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
written consent of Torax Medical.  Any Investigator involved with this study is obligated 
to provide the Sponsor with complete test results and all data derived from the study. 
 
 
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