Efficacy of Med Systems' Electro Flo Percussor Model 5000, Airway Clearance System, for Pulmonary Clearance of Secretions.
Conditions: Cystic Fibrosis, Pulmonary
Sponsor: Mack Biotech, Corp.

CLINICAL TRIAL PROTOCOL 
(Phase IV - Efficacy Trial) 
Medical Device: FDA K031876 ELECTRO FLO PERCUSSOR, MODEL 5000 
Non-randomized, multisite site, single arm study for the efficacy of current FDA 510k 
indication for adults between the ages of 18 and 55 (non-smokers). 
STUDY NUMBER: 2017-7 
STUDY NAME:  Med Systems Electro Flo 5000 Efficacy 2017 
VERSION DATE: 15 December 2018 
The Sponsor is: Med Systems, Inc. 
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of  Med Systems, Inc. (or any of its affiliated companies). The 
use of such confidential information must be restricted to the recipient for the agreed purpose 
and must not be disclosed, published or otherwise communicated to any unauthorized persons, 
for any reasons, in any form whatsoever without the prior written consent of Med Systems, Inc., 
(or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership 
or other entity which at the date of communication or afterwards (i) controls directly or indirectly 
Med Systems, Inc., (ii) is directly or indirectly controlled by Med Systems, Inc., with ‘control’ 
meaning direct or indirect ownership or more than 50% of the capital stock or the voting rights in 
such corporation, partnership or other entity.  

1.1 Study Synopsis:
8
2.0 Sponsor’s Intent and End Goals:
8
3.1 LIST OF GENERAL ABBREVIATIONS
9
3.2 LIST OF SPECIFIC TRIAL ABBREVIATIONS 
11
4. INTRODUCTION AND RATIONALE 
12
4.1 Role of the Electro Flo 5000
12
4.11  Introduction 
12
4.12 Clinical Application
13
4.13 Potential Participant Demographic
14
4.14 Classiﬁcation of Device
14
4.15 Adverse Medical Device Reactions / Medical Device Interactions
17
4.16 Administration of Ultrasound
17
4.17 Clinical Recommendations
17
4.18 Medical Device Interactions
17
4.19 Precautions and Warnings
17
4.2 Rationale for Evaluating the Beneﬁcial Effect of Electro Flo 5000 with Adult 
Participants. 
17
4.21 Key Facts
17
4.22 Device Description
18
4.23 Performance Data
18
4.24 Substantial Equivalence Summary
18
4.25 Proposed Device Indications
18
4.26 Predicate Device
18
4.27 Submitting Entity
19
4.29 Indication(s)
19
4.3 Rationale for this Trial Design
20
5. STUDY OBJECTIVES 
20
5.1 Primary Objective 
20
5.2 Secondary Objective
21
5.3 Other Objectives 
21
6. STUDY DESIGN 
21
6.1 Description of the Protocol 
21
6.2 Duration of Study Participation 
21

6.3 Interim Analysis 
21
6.4 Study Committees 
22
7. SELECTION OF PROCESS OF PARTICIPANTS 
23
7.1 Number of Participants Planned 
23
7.2 Inclusion Criteria 
23
7.3 Exclusion Criteria
24
7.3.1 Related to General Patient Characteristics 
24
7.3.2 Related to Other Conditions 
25
8. TREATMENTS 
25
8.1 Medical Device Description
25
8.2 Description of Blinding Methods 
25
8.3 Method of Assigning Participants to Treatment Group 
25
8.4 Packaging and Labeling 
25
8.5 Storage Conditions 
25
8.6 Access to the Randomization Code During the Study 
26
8.7 Responsibilities 
27
8.8 Retrieval and/or Destruction of Investigational Product 
27
8.9 Concomitant Treatment 
27
8.9.1 Prohibited Concomitant Treatment 
27
8.9.2 Permitted Concomitant Treatment 
28
8.10 Treatment Compliance 
28
8.11 Participant Reimbursement
28
9. ASSESSMENT OF INVESTIGATIONAL PRODUCT 
28
9.1 Efﬁcacy
28
9.1.1 Efﬁcacy Criteria
29
9.1.1.1 Primary Criterion 
29
9.1.1.2 Secondary Criterion 
29
9.1.2 Clinical Assessment Methods 
29
9.1.2.1 Deﬁnitions of Components of the Primary Efﬁcacy Endpoint 
29
10. PATIENT SAFETY
30
10.1 Adverse Events Monitoring 
30
10.2 Pregnancy 
32

10.3 Waiver 
32
11. HANDLING OF PATIENT WITHDRAWAL
33
11.1 List of Withdrawal Criteria 
33
11.2 Follow-up Procedures After Withdrawal 
33
11.3 Consequence 
34
12. STUDY PROCEDURES
35
12.1.1 Pre-Screening Procedures 
35
12.1.2 Baseline Visit 
35
12.2 Inclusion Procedures 
36
12.3 Description by Type of Visit 
36
12.4 Deﬁnition of Source Data 
36
13. STATISTICAL CONSIDERATIONS 
37
13.1 Statistical and Analytical Plans 
37
13.2 Determination of Sample Size 
37
13.3 Study Patient Description 
37
13.3.1 Disposition of Participants 
37
13.3.2 Clinical Trial Protocol Deviations 
37
13.4 Data Analysis Considerations 
38
13.4.1 Dataset Analyzed
38
13.4.1.1 Treatment Group Considered for Statistical Analysis 
38
13.4.1.3 General Statistical Approach 
38
13.4.2 General Convention 
39
13.4.2.1 General Rules for Handling of Missing, Unused or Inconsistent Data
39
13.4.2.2 Other Speciﬁc Conventions
39
13.5 Demographic and Baseline Characteristics
39
13.5.1 Patient Demographic Characteristics, Medical History and Diagnoses 
39
13.5.2 Previous Medications 
39
13.6 Investigational Product and Concomitant Therapy 
39
13.6.1 Investigational Product
40
13.6.1.1 Extent of Exposure 
40
13.6.1.2 Measurement of Treatment Compliance 
40
13.6.2 Concomitant Medication/Therapy 
40

13.7 Efﬁcacy/Activity Analysis
40
13.7.1 Primary Efﬁcacy Variable(s)
40
13.7.1.1 Description of the Primary Variable(s) 
40
13.7.1.2 Primary Analysis 
41
13.7.1.2.1 Handling of Dropouts or Missing Data
41
13.7.1.2.2 Data Transformation Before Analysis, If Any
41
13.7.1.2.3 Main Statistical Model and Adjustment for Covariates 
41
13.7.1.2.4 Multiple Comparisons/Multiplicity
42
13.7.1.2.5 Other Analyses for Primary Variable(s) 
42
13.7.2 Secondary/Other Efﬁcacy Variables 
42
13.7.2.1 Description of Secondary/Other Variables 
42
13.7.2.2 Statistical Analysis of Secondary/Other Variables 
42
13.8 Safety Analysis 
42
13.8.1 Adverse Events 
43
13.8.1.1 Deﬁnitions 
43
13.8.1.2 Adverse Events 
43
13.8.1.3 Deaths and Serious Adverse Events 
43
13.8.1.4 Adverse Events Leading to Treatment Discontinuation
43
13.8.3 Vital Signs 
44
14. SUBSTUDIES 
44
15. ETHICAL AND REGULATORY STANDARDS 
44
15.1 Ethical Principles 
44
15.2 Laws and Regulations 
44
15.3 Informed Consent 
45
15.4 Institutional Review Board/Independent Ethics Committee (IRB/EC) 
45
16. STUDY MONITORING
46
16.1 Responsibilities of the Investigator(s) 
46
16.2 Responsibilities of the Sponsor 
47
16.3 Source Document Requirements 
47
16.4 Use and Completion of Case Report Forms and Additional Requests 
47
17. ADMINISTRATIVE RULES 
48
17.1 Curriculum Vitae 
48

17.2 Record Retention at Study Site(s) 
48
18. CONFIDENTIALITY 
49
19. PROPERTY RIGHTS 
49
20. DATA PROTECTION 
50
21. INSURANCE COMPENSATION 
50
22. SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
51
23. PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-
OUT SITE 
51
23.1 Decided by the Sponsor in the Following Cases: 
51
23.2 Decided by the Investigator 
52
24. CLINICAL TRIAL RESULTS 
52
25. PUBLICATIONS AND COMMUNICATIONS 
52
26. CLINICAL TRIAL PROTOCOL AMENDMENTS 
53
27. BIBLIOGRAPHIC REFERENCES 
54
28. APPENDICES 
54
Appendix 1: The Optional Study Group Coordinating Center and Study Sponsor 
Responsibilities
54
Appendix 2: The Executive Committee 
58
Appendix 3: The Operations Committee 
59
Appendix 4: The Clinical Events Committee (CEC) 
59
Appendix 5: The Data Monitoring Committee (DMC)
62

1.1 Study Synopsis: 
2.0 Sponsor’s Intent and End Goals: 
This trial is in support of Med Systems® requesting a change in the HCPCS code for the Electro 
Flo® Percussor Model 5000  (hereby known as Electro Flo 5000) from E0840 Percussor, 
electric or pneumatic, home model to a new code E084x Airway Clearance System. E0840 is 
inadequate because: 
(1)  
E0840 is a broad category that includes percussors, vibratory massagers, and oscillatory 
sound wave devices. 
(2)  
The Electro Flo 5000 Force Multiplying Percussor and Self-Applicator System for Airway 
Clearance holds U.S. Patent No. 13/657,548. It consists of a programmable precision 
instrument that elicits sharp impacts combined with a strap for self-application to the front and 
back of the thorax as needed. The user controls power, speed, and force applied to obtain 
bronchial secretions and an improved 02/C02 gas exchange. Research has shown that greater 
percussive force applied results in a more effective treatment. The Electro Flo 5000 is the most 
powerful percussor available in airway clearance. 
(3)  
Insurers set the standard for reimbursement at the level of the lowest cost product within 
the code (vibratory massagers $340-600) even though the clinical outcome of the Electro Flo 
Airway Clearance System ($5,500) is comparable to that of High Frequency Chest Wall 
Compression (HFCWC) vests in a different code (E0483) which allows for reimbursement at a 
higher rate. A vibratory massager with a one-year warranty is the primary product being 
substituted for the Electro Flo 5000 Airway Clearance System with a three-year warranty. 
(4)  
The 7 lb. all-inclusive Electro Flo 5000 System provides compact, portable and effective 
treatment for loosening trapped mucus within the lungs to provide greater independence to the 
user. People who no longer find relief from vibratory massage or vests prefer it.  
(5)  
Use of the Electro Flo 5000 System helps persons avoid increased infections and 
hospitalizations. 

3.1 LIST OF GENERAL ABBREVIATIONS 
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT
Alanine Transaminase (liver enzyme)
AST
Aspartate Transaminase (liver enzyme)
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen (kidney function test)
C
Celsius
CAPA
Corrective and Preventive Action
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatinine Kinase (muscle enzyme)
CRA
Clinical Research Associate
CRC
Clinical Research Coordinator
CRF
Case Report Form
CRO
Contract Research Organization
CTMS
Clinical Trial Management System
CV
Curriculum Vitae
DCF
Data Clarification Form
IDMC
Independent Data Monitoring Committee
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ePRO
Electronic Patient Reported Outcomes
eTMF
Electronic Trial Master File
EDC
Electronic Data Capture
EKG
Electrocardiogram
EMR
Electronic Medical Record
EHR
Electronic Health Record
F
Fahrenheit
FEV1
Forced Expiratory Volume in 1 Second
GCP
Good Clinical Practices
GI
Gastrointestinal
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices

hCG
Human  Chorionic Gonadotrophin
HMO
Health  Maintenance Organization
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IP
Investigational Product
IRB
Institutional Review Board
IEC
Independent  Ethics Committee
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LAR
Legally Acceptable Representative
MAOI
Monoamine Oxidase Inhibitor
mcg
microgram
mmHg
Millimeters of mercury
NSAID
Non-Steroidal  Anti-Inflammatory Drugs(s)
PI
Principal Investigator
PK
Pharmacokinetics
PRO
Patient Reported Outcomes
p.r.n.
as needed
QA
Quality Assurance
QC
Quality Control
QTc
ECG/EKG QT interval corrected for heart rate
RBCs
Red Blood Cells
RBM
Risk Based Monitoring
SAE
Serious Adverse Event
SDV
Source Document Verification
SMO
Site Management Organization
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TMF
Trial Master File
WBCs
White Blood Cells, or leukocytes

3.2 LIST OF SPECIFIC TRIAL ABBREVIATIONS  
ATP: Adult Treatment Panel. 
BID: Twice daily. 
CEC: Clinical Events Committee. 
CRF: Case report forms. 
CT: Computed tomography. 
DMC: Data Monitoring Committee. 
DRF: Discrepancy resolution form. 
GCP: Good Clinical Practice. 
GMP: Good Manufacturing Practices 
ICH: International Conference on Harmonization. 
IP: Investigational product. 
IRB/EC: Institutional Review Board/Ethics Committee. 
ITT: Intent-to-treat. 
MedDRA: Medical Dictionary for Regulatory Activities. 
MRI: Magnetic resonance imaging. 
OD: Once daily. 
PSU: Partial shipment unit. 
SAE: Serious adverse event.  
ULN: Upper limit of normal range. 
WHO: World Health Organization. 
WOC: Withdrawal of consent.  

4. INTRODUCTION AND RATIONALE  
4.1 Role of the Electro Flo 5000 
4.11  Introduction  
The Electro Flo 5000 Airway Clearance System is a therapy for the directing application of a 
percussive force to the chest wall to loosen mucus. The system is comprised of: (1) a Self-
Administrator -- a self-applicator assembly including a ﬁrst strap overlaying and substantially 
coextensive with a second strap, wherein the ﬁrst and second straps are joined at their 
respective ends, and a pouch disposed between the ﬁrst and second straps for directing the 
pulse generated by the percussor to the body; and (2) the Electro Flo 5000 Force Multiplying 
Percussor -- consisting of a hammer and anvil having a force-receiving surface and a force-
delivering surface energized by an electric current and pulse generator. (See Attachment 1) 
Rapidly repeated impulses to the chest by the electronically cycled percussive hammer 
dislodges mucus adherent to airways within the lungs. Strategic placement of the system 
permits focused treatment of the affected lung regions. Patients apply the device directly to their 
frontal thorax or to their back by securing the device in the Self-Administrator and focusing the 
pulse where relief is desired. Users can apply Airway Clearance Therapy (ACT) directly on their 
back without the aid of another person. 
The Electro Flo 5000's Force Multiplying Technology allows users to control the pulse frequency 
and pulse force of the impact through a combination of 30 independently adjustable settings. 
There are ﬁve power and six speed settings. The Electro Flo 5000's pulse force ranges from 15 
to 35 pounds. 
The broad range in pulse force and greater power of the Electro Flo 5000 is a function of its 
unique design. The device is comprised of over 200 parts constructed from specialized 
machined magnetic material and high-impact molded plastics. 
The Electro Flo 5000 Airway Clearance System is an integrated approach to delivering care that 
is responsive to a patient's speciﬁc needs. It is a high-quality, high-value, cost-effective therapy. 

4.12 Clinical Application 
The Electro Flo 5000 Airway Clearance System is used to perform ACT. Patients with pulmonary 
diseases characterized by excess mucus generation, chronic infection, and inﬂammation of the 
airways with progressive destruction and loss of pulmonary function such as cystic ﬁbrosis, 
COPD, or bronchiectasis require daily ACT.1 Excess mucus caused by impaired mucociliary 
clearance can serve as a culture medium for pathogens, thereby increasing the rates of 
infection and inﬂammation as well as the rate of deterioration of lung function. By placing the 
Electro Flo 5000 on the thorax front or back and controlling the extent of the percussive force, a 
patient can break up and move the accumulated mucus from the small airways to the large, 
central airways of the lungs to be coughed out. (See Attachment 2) 
Traditionally, ACT consists of manual percussion combined with postural drainage. The manual 
removal of mucous through airway clearance is the primary therapy for cystic ﬁbrosis and 
results in the removal of excess mucous from lungs. However, manual percussion is time and 
labor intensive, and depends on a therapist or trained individual to perform the therapy on the 
patient. These disadvantages are most evident when patients undertake the treatment at home 
since poor compliance with the prescribed therapeutic regime can be an issue, especially 
among active individuals who work, travel, go to school or otherwise spend time away from 
home. 
The Electro Flo 5000 Airway Clearance System is preferable to manual percussion (and other 
therapies such as a vibratory massager) on multiple counts. It relieves a patient of the physical 
demands of hand percussion while at the same time generating stronger impacts and does not 
require the application by another person. It gives individuals maximum control over where and 
how ACT is applied. And because it is lightweight and portable, ACT can be performed when 
and where it is needed. 
To use the Electro Flo 5000, a patient either cups the percussive device in their hand or straps it 
into the Self-Administrator with the percussive head placed against the body. The patient adjusts 
the settings for the pulse force and speed on a control box. Pressing harder on the area where it 
is applied increases the impact force. Use of the Electro Flo 5000 alone is sufﬁcient for the 

frontal thorax while addition of the Self-Administrator makes it possible for a patient to reach 
individual back lobes. 
4.13 Potential Participant Demographic 
The Electro Flo 5000 is cleared by the U.S. Food and Drug Administration for use in the home, 
or institutional and hospital settings when the physician's choice of therapy is external 
manipulation of the thorax due to evidence of retained secretions. 
It is indicated for use by individuals with: cystic ﬁbrosis; bronchiectasis; chronic bronchitis; 
chronic obstructive pulmonary disease (COPD); chronic emphysema; occupational lung 
disease; pneumonia; pulmonary edema; asthma; neuromuscular diseases such as Guillain-
Barre syndrome; progressive muscle weakness such as myasthenia gravis; lung abscess; 
tetanus; cerebral palsy; muscular dystrophy; AlS; and other lung obstructive conditions. 
A major user population consists of those with cystic ﬁbrosis (CF). CF is the most common life-
shortening disease among Caucasians. In the US, there are close to 30,000 affected 
individuals.2 The disease affects all exocrine glands. When it was described as a distinct clinical 
entity 60 years ago, it was usually fatal during the ﬁrst year of life. Better understanding of the 
disease pathophysiology, as well as advances in medical therapies, has led to a continuous 
improvement in the survival and quality of life of affected individuals3, with the current median 
age of survival being approximately 39 years.4 
4.14 Classification of Device 
The Electro Flo 5000 Airway Clearance System is indicated for use by patients with a diagnosis 
characterized by excessive mucus production and difficulty clearing secretions (e.g. cystic 
fibrosis, bronchitis, bronchiectasis, COPD, and pulmonary edema, among others). This system 
mimics and enhances the relief gained from manual chest physiotherapy.  
Airway clearance devices are designed to deliver percussions to the chest wall or cause 
oscillatory air pressure changes to the airways that liberate obstructive airway secretions. The 
following are HCPCS codes associated with these devices:  

A.  
Flutter Device - S8185 
B.  
Oscillatory positive expiratory pressure (OEP) device - E0484 
C.  
Intrapulmonary percussive ventilation system - E0484 
D.  
High-frequency chest wall oscillation air-pulse generator system - E0483 
E.  
Percussor, electric or pneumatic, home model - E0480 
1.
Mechanism of Operation -- The mechanism driving the different devices listed in E0840 
consist of: (a) an off-center motor-driven weight that shakes the applicator head (GS 
Vibracare and Flimm Fighter); (b) an oscillating pneumatic valve that cycles the percussive 
device (Fluid Flo 2500); and an electronically cycled solenoid that supports independent 
adjustment of pulse force and frequency (Electro Flo 5000). Only the latter two are true 
percussors. 
2.
Type of Impact - In contrast to the other devices, the Electro Flo 5000 is the only one 
capable of producing a 35Ib. impact similar to a hammer blow. This difference is visible in 
the waveforms created by each instrument. While the other devices produce evenly spaced 
waves, the Electro Flo 5000 creates sharp amplitudes. (See Attachment 4) This too, 
distinguishes the true percussor (Electro Flo 5000} as opposed to the GS Vibracare and 
Flimm Fighter. The other technologies attempt to deliver a percussive-like impact through a 
vibratory massager. True percussors are have more complicated mechanics than vibratory 
massagers, contain more working parts, and are able to impart much greater pulse force. 
3.
Pulse Force -the Electro Flo 5000 is significantly distinct therapeutically from other products 
because it provides a percussive impact as opposed to the GS Vibracare or Flimm Fighter 
that are vibratory percussive massagers. Comparative pulse force tests of the Electro Flo 
5000 show that it generates significantly more pulse force than the other products. The GS 
Vibracare has 10 settings that can deliver a pulse force ranging from 2.9 to 10.75 lbs. The 
Flimm Fighter has 11 settings able to deliver a pulse force ranging from 1.5 to 13.75 lbs. The 
Fluid Flo 2500 has 4 settings and is able to reach a pulse force ranging from 17.2 to 19.0 
lbs. The Electro Flo 5000, on the other hand, has 30 settings with the ability of reaching a 
pulse force ranging from 15.0 to 33.7 lbs. (See Attachment 5) Greater pulse force has been 
found to have more therapeutic value among cystic fibrosis patients. Research published in 
the journal Respiratory Care draws a clear relationship between higher pressure and greater 
relief among cystic fibrosis patients.' The Electro Flo 5000 with Force Multiplying Technology 
has 30-targeted settings. Power and frequency can be precisely directed to individual lobes 
of the lungs. The independent adjustment of power and speed in contrast to other devices, 

gives patients greater ability to select the specific combination desired and direct the 
percussive power where needed. Respiratory therapists emphasize that lung clearance 
includes getting air behind the mucus in order to move it up and out of the airways while 
achieving greater sputum expectoration.6 With the Electro Flo 5000 with Force Multiplying 
Technology, patients control the movement and directionality of the obstruction whether from 
the front or the back. This capability is significantly different from the vest, which does not 
permit directed therapy or the GS Vibracare or Flimm Fighter since they lack percussive 
power. With the Electro Flo 5000, patients can achieve more effective treatment, such as 
adults who require vigorous pounding to release the congestion, or those with long lobes not 
reached by vests.  
4.
Unit Cost-The Electro Flo 5000 is a true percussor distinguished by its ability to deliver more 
powerful impacts than vibratory massagers. To impart its distinctive sharp and strong pulse 
force requires more complicated mechanics than vibratory massagers; it is made from 
specialized machined magnetic materials and high-impact molded plastics and is comprised 
of over 200 parts. As a result, it costs approximately ten times more than the vibratory 
massagers, yet half the cost of vests. 
This is the crux of the problem. Depending on the state, insurers will only reimburse between 
$340 and $600 the cost of vibratory massagers. Although the Electro Flo 5000 Airway 
Clearance System requires a prescription and in many cases is the only product that works for 
patients, insurers have determined what they consider to be a 'standard percussor' and the 
Electro Flo 5000 is excluded from their definition. Consequently, they will only pay for a vibratory 
massager. 

4.15 Adverse Medical Device Reactions / Medical Device Interactions 
None 
4.16 Administration of Ultrasound 
None 
4.17 Clinical Recommendations 
 Please see FDA 510K Indications 
4.18 Medical Device Interactions 
Not designed to be used in combination with any other medical devices unless specified by 
ordering physician. 
4.19 Precautions and Warnings 
Please see device manual and instructions. 
4.2 Rationale for Evaluating the Beneficial Effect of Electro Flo 5000 with Adult 
Participants.  
4.21 Key Facts 

4.22 Device Description 
Trade/Device Name: Electro Flo Percussor, Model 5000 
Regulation Number: 21 CFR 868.5665 
Regulation Name: Percussor, Powered-Electric 
Class: Class II  
Product Code: BYI 
4.23 Performance Data 
Please see User Manual 
4.24 Substantial Equivalence Summary 
We have reviewed your Section 510(k) premarket notiﬁcation of intent to market the device
referenced above and have determined the device is substantially equivalent (for the indications
for use stated in the enclosure) to legally marketed predicate devices marketed in interstate
commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments or to
devices that have been reclassiﬁed in accordance with the provisions of the Federal Food, 
Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval (PMA). You 
may, therefore, market the device, subject to the general controls provisions of the Act. The 
general controls provisions of the Act include requirements for annual registration, listing of 
devices, good manufacturing practice, labeling, and prohibitions against misbranding and 
adulteration.
4.25 Proposed Device Indications 
No Change
4.26 Predicate Device 
510(k) Number - K802399 

4.27 Submitting Entity 
MED SYSTEMS 
2631 Ariane Drive 
San Diego, CA 92117 
Phone 800.345.9061 Fax 858.483.9827
www.medsystems.com
4.28 Classification Regulation 
Trade/Device Name: Electro Flo Percussor, Model 5000 
Regulation Number: 21 CFR 868.5665 
Regulation Name: Percussor, Powered-Electric 
Class: Class II  
Product Code: BYI 
4.29 Indication(s) 
The intended use of the Med Systems Electro Flo Percussor Model 5000 is the same as the 
predicate device, which is to provide airway clearance therapy when external
manipulation of the thorax is the physician's choice of treatment. Indications for this
form of therapy are described by the American Association for Respiratory Care
(AARC) in the Clinical Practices Guidelines for Postural Drainage Therapy ('I (1991). According 
to AARC guidelines, speciﬁc indications for external manipulation of the
thorax include evidence or a suggestion of retained secretions, evidence that the
patient is having difﬁculty with the secretion clearance, or presence of atelectasis
caused by mucus plugging. In addition, the Med Systems Electro Flo Percussor Model 5000 is 
also indicated for external manipulation of the thorax to promote airway clearance or
improve bronchial drainage for purposes of collecting mucus for diagnostic
evaluation.
(1). Bronchial Hygiene Guidelines Committee, American Association for Respiratory
Care. AARC clinical practice guideline: postural drainage therapy. Respiratory
Care 1991; 36: 1418 - 1426.

Prescription Use X 
(Per CFR 801 Subpart D)
No parts are sterilized from the manufacturer.  The clinician is responsible for all cleaning and 
cleanliness of the device in accordance with standard of care procedures. 
4.3 Rationale for this Trial Design 
Since this study is designed to illustrate the efficacy of the device for the current 510K indications 
in a single arm, large sample multisite study.  A placebo control is not required since each subject 
will serve as a before and after treatment with measurable indicators. 
5. STUDY OBJECTIVES  
5.1 Primary Objective  
To speciﬁcally illustrate and measure both clinical and empirical efﬁcacy described by (AARC) in 
the Clinical Practices Guidelines for Postural Drainage Therapy (1991) for external manipulation 
of the thorax for postural drainage therapy and the secretion clearance, or presence of 
atelectasis caused by mucus plugging.
Outcome measured by:
Percentage change of oxygen levels in the blood (pulse oximetry). SpO2 will be monitored using 
the standard pulse oximeter system (K131111). Change from baseline before treatment and 
measure again up to 3.5 hours after treatment.

5.2 Secondary Objective 
To observe the quality of lung function that participants experience during the use of the device 
during the trial period.
Outcome measured by:
Percentage change of lung function. Evaluate expiratory forced vital capacity (FVC) and forced 
expiratory volume (FEV1) will be monitored with standard spirometer. Change from baseline 
before treatment and measure again up to 3.5 hours after treatment.
5.3 Other Objectives  
N/A 
 
6. STUDY DESIGN  
6.1 Description of the Protocol  
The present study is designed as a multi-center, non-randomized, single-blind, one arm group 
trial with 70 participants per arm. 
6.2 Duration of Study Participation  
The estimated study duration that served as the assumption for sample size calculations is 
eleven (24) month. Each participant shall be active in the trial for a period of 21 days following 
enrollment. All participants will be followed to a common study end date, which is estimated to 
occur when the last randomized patient has been followed for two (2) months, based on a one 
(2) week recruitment period.  
6.3 Interim Analysis  
Interim analysis during this study shall be conducted at Day 7, 14 and 21 for the 70 participants 
to ensure participant safety before the other participants enter into the trial. 

6.4 Study Committees  
The Mack Biotech, Corp. group will be in charge of the logistical coordination of the different 
study committees. Distinct responsibilities of  Mack Biotech, Corp. and the study Sponsor are 
provided in Appendix 1. 
Executive Committee  
The Executive Committee of the study is composed of Investigator/Academic Members from 
participating countries and Sponsor Representatives. This Committee, led by its Chairman, 
Leigh J. Mack, MD (Sponsor Lead Researcher), who will provide scientific and strategic 
direction for the trial and will have overall responsibility for its execution. Detailed responsibilities 
and membership for this committee are provided in Appendix 2.  
Operations Committee  
The Operations Committee is responsible for ensuring that study execution and management 
are of the highest quality. This Committee will be composed of the Chairman and co-Chairmen 
of the Executive Committee, as well as the National Principal Investigator and nonvoting 
Sponsor Representatives. It will determine its own guidelines and approve the criteria and 
guidelines of the other Committees prior to commencement of the study. The Operations 
Committee will convene regularly (at least every month) to discuss and report on the progress of 
the study. Detailed responsibilities and membership for this Committee are provided in Appendix 
3.  
Clinical Events Committee (CEC)  
The CEC is composed of multidisciplinary academic members. This Committee, coordinated by 
Mack Biotech, Corp., will be responsible for validating and classifying, in a blinded fashion, all 
the primary efficacy outcome events reported by the Investigators. Detailed responsibilities and 
membership for this Committee are provided in Appendix 4.  
Data Monitoring Committee  
The Data Monitoring Committee (DMC) is composed of Academic Members who are not 
otherwise participating in the trial. This Committee, led by its Chairman, Mack Biotech, Corp. will 
be responsible for the monitoring of patient safety, and it will be supported by an external DMC-
associated statistician. Detailed responsibilities and membership for this Committee are 
provided in Appendix 5.  

The DMC can request any analysis during the course of the study, on either a blinded or 
unblinded basis.  
The independent DMC-associated statistician will perform the planned analyses as well as the 
other analyses requested by the DMC, independently from the Sponsor. This independent 
statistician will be provided with the randomization code list, as well as with regular database 
transfers. He/she will prepare pro-forma tables, listings, and a report for submission to the DMC. 
Safety data will include serious adverse events (SAEs), outcome events, local laboratory 
values, plus other adverse events (AEs) as requested by the DMC. Demography, treatment and 
trial status data will be presented as requested by the DMC. The report will be based on current 
data, whether clean or not, and whether adjudicated or not. Although efficacy data will be 
provided, DMC review of these data does not constitute a formal interim analysis of efficacy, and 
any analyses of these data will not, in and of themselves, be used for stopping the trial.  
7. SELECTION OF PROCESS OF PARTICIPANTS  
7.1 Number of Participants Planned  
Based upon the anticipated event rates, premature treatment discontinuation and expected 
relative efficacy, approximately 70 participants will be enrolled in the study, with approximately 
70 participants in each arm.  
7.2 Inclusion Criteria  
- Previously diagnosed with cystic fibrosis (mild, moderate or severe) 
- Prescribed (licensed medical provider) airway clearance device/system for at home, self-
treatment for airway clearance 
- Physically able to perform self-treatment or treatment by an at home medical provider  

7.3 Exclusion Criteria 
- History of tobacco use
- History of excessive alcohol consumption, more than 2 drinks per day, 10 per week
- Any other medical condition that would preclude use of an airway clearance device
- Previously diagnosed with major cardiological disease
7.3.1 Related to General Patient Characteristics  
1. Presence of any severe medical or psychological condition that, in the opinion of the 
Investigator, would compromise the participant's safe participation. 
2. Immunocompromised by other types of viral infections or has a history of any other 
hepatitis form e.g. types A, C, D, E.    
3. Underlying diseases or other dermatologic conditions that require the use of 
interfering topical or systemic therapy or that might interfere with study 
assessments such as, but not limited to, atopic dermatitis or herpes zoster (shingles). 
This includes clinically significant abnormal findings, uncontrolled or serious disease, or any 
medical or surgical condition, that may either interfere with the interpretation of the clinical 
trial results, and/or put the subject at significant risk (according to Investigator's judgment) if 
he/she participates in the clinical trial. 
4. The subject has received, applied or taken some specified treatments within the 
specified timeframe prior to the Baseline visit 
5. The subject is unwilling to refrain from use of prohibited medication during the 
Clinical Trial. 
6. N/A 
7. Presence of any condition (medical, psychological, social, or geographical), actual or 
anticipated, that the Investigator feels would restrict or limit the participant's successful 
participation for the duration of the study. 

8. Receipt of any investigational treatment (medical device or drug) within 30 days prior to 
baseline visit. 
9. Previous participation in a  Electro Flo 5000 medical device study. 
10. Known allergy to any components of the device itself (e.g. plastics/polymers). 
7.3.2 Related to Other Conditions  
None
8. TREATMENTS  
8.1 Medical Device Description 
The Electro Flo 5000 is intended to assist in airway clearance therapy when the physician’s 
choice of therapy is external manipulation of the thorax. Additionally, the Electro Flo 5000 is 
indicated for external manipulation of the thorax to promote airway clearance and improve 
bronchial drainage.
 
8.2 Description of Blinding Methods  
Final data analysis shall be completed by a third party, data analysis and reporting agency.
8.3 Method of Assigning Participants to Treatment Group  
N/A - All included shall be assigned to the single arm. 
  
8.4 Packaging and Labeling  
Please see User Manual and instructions along with physician prescription. 
8.5 Storage Conditions  
Please see User Manual 

8.6 Access to the Randomization Code During the Study  
N/A for this trial
The Investigator will be supplied with participant information if medically needed or required for 
safety from the Sponsor.
Additional unblinding materials will be available and are to be kept in a safe place at CRU level 
(or subcontractor, if any) throughout the clinical trial. The Sponsor will retrieve all envelopes, 
whether opened or sealed, on study completion.  
In case of a Serious Adverse Event, the code should be broken only in exceptional 
circumstances when knowledge of the Investigational Product is essential for treating the 
patient. 
In case the physician at the investigational site believes unblinding is needed, he/she must first 
contact the Medical Advisor located at Mack Biotech for further direction. All calls will be 
documented as appropriate to include date and time of the call, name of the Optional Study 
Group Medical Advisor, name, qualification, and address of the physician contacting Optional 
Study Group, patient ID, documentation of the request, and decision for unblinding or not.  
If possible, a contact should be initiated with the Monitoring Team before unblinding. 
In case the decision to unblind is made, the Investigator must document it with the date, time of 
day, and reason for unblinding, and report this information in the appropriate page of the CRF 
and source document. 
Note that when documenting the reason for unblinding, the Investigator must not provide any 
detail regarding the nature of the Investigational Product. The Investigator should not divulge 
medication detail to any Med Systems, Inc.,  or Mack Biotech, Corp. staff member, Sponsor’s 
representative, or to any Study Committee members until database closure. Furthermore, when 
completing forms (eg, AE, SAE), the study treatment should not be disclosed on the forms. The 
unblinding envelopes will be sealed again and stored at the site level until the end of the study 
(envelopes opened by the CRU or a subcontractor must also be sealed again).  

8.7 Responsibilities  
The Investigator or other personnel allowed to store and dispense Investigational Product (IP) 
will be responsible for ensuring that the IP used in the study is securely maintained as specified 
by the Sponsor and in accordance with the applicable regulatory requirements.  
All IP shall be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IP issued and returned is 
maintained.  
Any quality issue noticed with the receipt or use of an IP (deficient IP in condition, appearance, 
pertaining documentation, labeling, expiry date, etc) should be promptly reported to the 
Sponsor, who will initiate a complaint procedure.  
Under no circumstances will the Investigator supply IP to a third party, allow IP to be used other 
than as directed by this Clinical Trial Protocol, or dispose of IP in any other manner.  
8.8 Retrieval and/or Destruction of Investigational Product  
All partially used or unused treatments will be retrieved by the Sponsor. A detailed treatment log 
of the returned IP will be established with the Investigator (or the pharmacist) and countersigned 
by the Investigator and the Monitoring Team.  
The Investigator will not destroy unused IP unless the Sponsor provides written authorization to 
the contrary.  
A potential defect in the quality of IP may be subject to initiation by the Sponsor of a recall 
procedure. In this case, the Investigator will be responsible for promptly ad-wash any request 
made by the Sponsor, in order to recall IP and eliminate potential hazards.  
8.9 Concomitant Treatment  
None
8.9.1 Prohibited Concomitant Treatment  
None

8.9.2 Permitted Concomitant Treatment  
Any medical devices other than those listed above are allowed, and should be administered, as 
necessary for the treatment of the patient, when possible with a stable dose, at the discretion of 
the Investigator.  All treatment with these medical devices should be recorded on the 
appropriate CRF.  
8.10 Treatment Compliance  
Compliance is assessed by counting the number of returned bottles if any at each visit. The 
Investigator (or delegate) must complete the appropriate pages of the treatment log form and of 
the CRF. A discontinuation is defined as a period with a least three consecutive days without 
study medical device intake.  
The study shall be open enrollment but patients must have access to the clinical location for 
clinical survey reporting. The survey must be completed two (2) times per week during the 21 
day long trial. Potential participants should reside in the United States. 
The monitor supervising the study will verify the data by comparing the recorded data with the 
investigational product retrieved.  
8.11 Participant Reimbursement 
Participants shall be reimbursed at a rate of seven dollars ($7.00) per day for each day that data 
for the two objectives is sent to the Principal Investigator.  The reimbursement is provided for 
the participant’s time for recording the data on a personal smart device, the cost of data transfer 
and overall phone costs for sending the information to the Principal Investigator. The total 
reimbursement amount that may be provided to the participant is no more than $210.00. The 
reimbursement shall be provided to the participant, by the Sponsor, after the participant 
completes the trial period by company check paid to the participant. 
9. ASSESSMENT OF INVESTIGATIONAL PRODUCT  
9.1 Efficacy 
The goal of this trial is to illustrate before and post treatment changes measured by spirometer.

9.1.1 Efficacy Criteria 
Primary: Physical exam by medical practitioner for initial diagnosis and changes in spirometer 
reading from before treatment compared to reading three (3) hours after treatment.  In addition, 
changes in iHealth Air pulse oximeter (FDA 510k K131111) reading from before treatment 
compared to reading three (3) hours after treatment.
 
9.1.1.1 Primary Criterion  
Composite success rate. Safety - no issues or reported adverse conditions. 
9.1.1.2 Secondary Criterion  
Percent change of spirometer reading from before treatment compared to  three (3) hours after 
treatment by the participant. Subjective participant opinion of the efficacy provided by semi-
weekly surveys. 
9.1.2 Clinical Assessment Methods  
Primary: Measurements of before and after with pulse oximetry device and spirometer. 
Secondary: Participant surveys completed. 
9.1.2.1 Definitions of Components of the Primary Efficacy Endpoint  
N/A

10. PATIENT SAFETY 
 
10.1 Adverse Events Monitoring  
Definitions:  
An adverse event is any untoward medical occurrence in a clinical investigation participant 
administered a medical device and which does not necessarily have to have a causal 
relationship with this treatment.  
A Serious Adverse Event is any untoward medical occurrence at any dose that:  
 • 
Results in death or;  
 • 
Is life-threatening or;  
Note: The term "life-threatening" in the definition of "serious" refers to an event in which 
the patient 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 inpatient hospitalization or prolongation of existing hospitalization or;  
 • 
Results in persistent or significant disability/incapacity or;  
 • 
Is a congenital anomaly/birth defect;  
 • 
Is a medically important event:  
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should also usually be considered serious.  

Adverse Events  
All Adverse Events regardless of seriousness or relationship to Investigational Product, 
including those from the first visit planned in the Clinical Trial Protocol/signature of the 
informed consent form, are to be recorded on the corresponding page(s) included in the  
Case Report Form. Whenever possible, symptoms should be grouped as a single 
syndrome or diagnosis. The Investigator should specify the date of onset, intensity, 
action taken with respect to Investigational Product, corrective treatment/therapy given, 
outcome and his/her opinion as to whether there is a reasonable possibility that the 
Adverse Event was caused by the Investigational Product.                                             
Serious Adverse Events  
In the case of a Serious Adverse Event the Investigator must immediately:  
 • 
SEND (within 1 working day, by email) the signed and dated corresponding page(s) in 
the Case Report Form to the representative of the Monitoring Team whose name, 
address and email number appear on the Clinical Trial Protocol, or to a designated 
Safety email number provided by the Monitoring Team, as well as to the Central 
Database number;  
 • 
ATTACH a photocopy of all examinations carried out and the dates on which these 
examinations were performed. Care should be taken to ensure that the participant's 
identity is protected and the participant's identifiers in the Clinical Trial are properly 
documented on all copies of source documents provided to the Sponsor. For laboratory 
results, include the laboratory normal ranges;  
 • 
Follow-up of any Serious Adverse Event that is fatal or life threatening should be 
provided within one additional calendar week. The treatment code will be unblinded for 
reporting of Serious Adverse Events that are unexpected and reasonably associated 
with the use of the Investigational Product.  
Serious Adverse Events  Follow-up 

 
• 
The Investigator should take all appropriate measures to ensure the safety of the 
participants, including referral to a specialist if indicated. Notably he/she should 
follow up the outcome of any adverse events (clinical signs, laboratory values or 
other, etc) until the return to normal or stabilization of the participant's condition;  
 
• 
In the case of any serious adverse event, the patient must be followed up until 
clinical recovery is complete and laboratory results have returned to normal, or 
until progression has been stabilized. This implies that follow-up may continue 
after the patient has left the Clinical Trial and that additional investigations may 
be requested by the Monitoring Team;  
 
• 
In case of any serious adverse event brought to the attention of the Investigator 
at any time after cessation of Investigational Product and considered by him/her 
to be caused by the Investigational Product with a reasonable possibility, this 
should be reported to the Monitoring Team.  
10.2 Pregnancy  
No known adverse interactions with pregnant or nursing mothers. 
10.3 Waiver  
Expected efficacy endpoints specified in this trial (primary and secondary efficacy criteria) will 
not be considered as AEs and will not be subject to expedited regulatory reporting. They will be 
reported on specific outcome event forms, which should be sent within one (1) working day, by 
Email, to the Central Database number.  

11. HANDLING OF PATIENT WITHDRAWAL 
  
11.1 List of Withdrawal Criteria  
Occurrence of an outcome event according to the judgment of the Investigator must not be 
considered as a reason for study medical device discontinuation.  
Depending on the Investigator’s judgment, permanent study medical device discontinuation is 
only clearly justified for an adverse event, when qualifying condition is not present, or when a 
patient demands to withdraw from study medical device treatment, and in such cases the 
appropriate follow-up until the study end date should still be continued.  
Although participants may withdraw from the study medical device at any time and for any 
reason, (or may be withdrawn at the Investigator’s decision), patient withdrawal should be 
avoided as much as possible. If this occurs, every attempt should be made to restart study 
medical device if medically appropriate, whatever the duration of discontinuation. The reason for 
study medical device discontinuation will be recorded on the CRF. In any case, appropriate 
follow-up for efficacy and safety endpoints should be continued.  
11.2 Follow-up Procedures After Withdrawal  
Participants who prematurely discontinue study medical device are not to be replaced. 
All randomized participants must be followed up according to the study flowchart until study end 
date or death, regardless of whether they discontinued study medical device prematurely or not. 
Any event occurring after early study medical device discontinuation will be recorded up through 
the study end date. 
In case of study medical device discontinuation (temporary or permanent) due to an adverse 
event, such participants will be closely monitored until the resolution or stabilization of this 
adverse event. This may mean that follow-up will continue after the participants have completed 
the study follow-up. Although data on that adverse event will continue to be captured, even 
beyond the last visit, for new efficacy or safety events, only those that occur up through the last 
visit should be recorded.  

In case of written withdrawal of consent (WOC) for follow-up visits, and unless otherwise stated 
by the patient in the informed consent form, Investigators will be encouraged to get information 
from the general practitioner, any other physician, or other medical-care provider, in order to 
follow the medical status of the participants (especially when they withdraw their consent after 
having experienced an AE/SAE or an efficacy endpoint). Investigators will also be expected to 
try as much as possible to re-contact those participants at the end of the trial, in order to obtain 
at least their follow-up of the efficacy assessment.  
For participants considered lost to follow-up, the CRF must be completed up to the last visit 
performed.  
11.3 Consequence  
If the medical device is stopped prematurely, every attempt should be made to restart it if 
medically appropriate, whatever the duration of discontinuation. 
 
If the patient withdraws his/her consent for study participation, although in such circumstances 
he/she may not be obliged to comply with all the protocol visits and phone calls, the 
Investigators, the study nurses and any other study coordinators are requested to try to obtain 
as much as possible, the vital status of the patient at study end date. This will be clearly stated 
in the informed consent form.  
Any direct communication with the general practitioner, any other physician or other medical-
care provider can be helpful for following the medical status of the patient. This is particularly 
important if the patient withdraws his consent after experiencing an AE/SAE or an efficacy 
endpoint since for safety and Regulatory purposes, it is necessary to obtain some information 
regarding worsening or resolution of the event (especially if this event is considered as to be 
related to the Investigational Product).  
In addition to the need for safety assessment, it is also important to avoid any lost to follow-up 
participants for the efficacy assessment and meaningful analysis of the study.  

12. STUDY PROCEDURES 
12.1 Visit Schedule 
After initial contact and pre-qualiﬁcation through enrollment in person. The participant shall be 
provided with an appointment for enrollment.  Patient shall provide full medical history with any 
known pulmonary, cardiovascular or neurological diagnosis.  This decision shall be that of the PI 
and the clinical health care provider at the location of the trial.
12.1.1 Pre-Screening Procedures  
Study participants will be recruited from email list recruitment, clinics, and diagnostic centers, 
under the responsibility of a participating Investigator. Prior to initiation of the recruitment phase, 
participating Investigators will identify a pool of potential study subjects. Each of these centers 
will identify potentially eligible participants in advance,  
 
12.1.2 Baseline Visit  
The patient will receive complete information about the study in writing and orally if they choose. 
Written informed consent must be obtained from the patient prior to any study-specific 
procedures and prior to randomization. Compliance with inclusion criteria (listed in Section 7.2) 
and exclusion criteria (listed in Section 7.3) will be checked on the basis of information 
collected, and recorded in the CRF.  
Key baseline patient characteristics obtained at the randomization visit will be recorded in the 
CRF, including demographics, height, weight, relevant past medical and surgical history, 
including neurological and psychiatric history, and abnormalities noted on physical exam, 
including any past dermatology exams. 
Medical history, physical examination, laboratory, or instrumental results confirming inclusion 
and absence of exclusion criteria will be maintained in the participant's file.  

12.2 Inclusion Procedures  
Once all inclusion/exclusion criteria are fulfilled, the patient becomes eligible for randomization 
and inclusion into the treatment period. Treatment allocation will be performed as stated above 
(Section 8.3). Study kit will be delivered as stated in Section 8.4.  
Participants will be counseled to follow a healthy diet, to increase their water consumption and 
to stop smoking, if they are smokers.  
12.3 Description by Type of Visit  
• Baseline enrollment form completed and submitted online (secure site), informed consent 
signed and submitted. 
• Follow up call, email and follow up summary completed by the Investigator at the end of the 
one month treatment period with written results. 
• Three (3) month participant courtesy email to confirm safety and answer any questions. 
There is no strict timing for the phone calls. In any case, it is better to call the patient 
after a delay, than to not call them at all (even in this case, the phone call record page of 
the CRF should be completed).  
The patient visit schedules will be given by the Investigator  as soon as the participant is 
randomized, so as the Investigator can plan in advance all the necessary appointments with the 
participant.  
12.4 Definition of Source Data  
All the data collected in the CRF come from source documents that are part of the patient 
dossier. Copies of some of those source documents will be collected after anonymization, in 
order to support documentation of outcome events eligible for validation by the Clinical Events 
Committee, ie:  
.  

13. STATISTICAL CONSIDERATIONS  
13.1 Statistical and Analytical Plans  
 
The material of this section is the basis for the Statistical Analysis Plan of this study. This plan 
may be revised during the study to accommodate Clinical Trial Protocol Amendments and to 
make changes to adapt to unexpected issues in study execution and data that affect planned 
analyses. These revisions will be based on blinded review of the study and data, and a ﬁnal 
plan will be issued prior to data lock.
13.2 Determination of Sample Size  
 
Based on the targeted population for the study of 30,000 patients, 70 participants is considered 
a reasonable assumption for the yearly representational event rate in the group. Assuming 
recruitment over a 16 month period, and a total study duration of 24 months, 70 participants per 
group has been historically signiﬁcant for prior trials designed to illustrate clear efﬁcacy of a 
device as it relates to the United States CMS for this category of device.
13.3 Study Patient Description  
No speciﬁcs other than the trial inclusion parameters.
 
13.3.1 Disposition of Participants  
The number of randomized participants will be summarized by county and center using counts 
and percentages. The number of participants either completing or permanently discontinuing the 
study medical device period will be summarized using counts and percentages.  
13.3.2 Clinical Trial Protocol Deviations  
All the following deviations will be summarized on the all randomized patient population:  

 • 
Inclusion or exclusion criteria not satisfied.  
 • 
Deviations related to the study medical device administration  
 • 
Not permitted concomitant medications.  
13.4 Data Analysis Considerations  
 
13.4.1 Dataset Analyzed 
 
13.4.1.1 Treatment Group Considered for Statistical Analysis  
 
For all efﬁcacy and safety analyses, participants will be included in the treatment group to which 
they were originally allocated by the PI.
13.4.1.2 Populations to be Analyzed  
The intent-to-treat (ITT) population will be used for all efﬁcacy and safety analyses. This will 
consist of all randomized participants irrespective of whether the patient actually received study 
medical device or the participant's compliance with the study protocol, in the treatment group 
assigned by the software system. A patient will be considered randomized as soon as they are 
assigned to the group, after proper consent.
13.4.1.3 General Statistical Approach  
All statistical tests will be two-sided.  
All summary tables for quantitative parameters will display mean, standard deviation, median, 
range (minimum and maximum), as well as number of missing data (if relevant). All summary 
tables for qualitative parameters will display counts, percentages and number of missing data if 
relevant.  

Baseline data are deﬁned as the last measurement performed before the ﬁrst study medical 
device intake. 
 
13.4.2 General Convention  
 
13.4.2.1 General Rules for Handling of Missing, Unused or Inconsistent Data 
  
In general, missing values will remain as missing, i.e., no attempt will be made to impute 
missing values and only observed values will be used in data analyses and presentations. 
Speciﬁc rules for handling missing efﬁcacy data are described in Section 13.7.1.2.1.  
13.4.2.2 Other Specific Conventions 
 
13.5 Demographic and Baseline Characteristics 
No specifics other than the trial inclusion parameters. 
 
13.5.1 Patient Demographic Characteristics, Medical History and Diagnoses  
Baseline characteristics will be described using the ITT population. Demographics, medical 
history and other baseline variables will be summarized as appropriate to the type of data.  
13.5.2 Previous Medications  
In order to further characterize the study population, the incidence of the use of selected 
medications should be disclosed by the participant to include: Any current or passed drugs 
directly prescribed or used to treat cystic fibrosis (CF). 
13.6 Investigational Product and Concomitant Therapy  
Not applicable to this Clinical Trial. 

13.6.1 Investigational Product 
13.6.1.1 Extent of Exposure  
The duration of study medical device treatment (accounting for permanent discontinuation) will 
be summarized. The number of participants on treatment over time will be summarized. The 
total patient years on study medical device will also be calculated  
13.6.1.2 Measurement of Treatment Compliance  
Treatment compliance for each patient will be calculated as the number of days study medical 
device was actually used (ie, number of days on treatment minus days of temporary 
discontinuation) divided by the number of days of follow-up, allowing for early permanent 
discontinuation of study medical device when applicable. Study medical device discontinuation 
is defined as a minimum of 3 consecutive days without study medical device intake. The 
percentage of participants at least 80% compliant will also be reported.  
13.6.2 Concomitant Medication/Therapy  
Not recommended for this Clinical Trial - however, if deemed medical necessary then the 
appropriate treatment should be administered as ordered by the physician. 
13.7 Efficacy/Activity Analysis 
The main efﬁcacy measurement shall be a reduction the appearance of cystic ﬁbrosis (CF).
 
13.7.1 Primary Efficacy Variable(s) 
A reduction in the appearance of cystic ﬁbrosis (CF).
 
13.7.1.1 Description of the Primary Variable(s)  
The primary efﬁcacy endpoint is the composite cluster of the ﬁrst occurrence, over the duration 
of study (randomization to study end date inclusive), of the following adjudicated events: 

•
Any skin conditions caused by the device to include irritations,  
•
Any allergic reactions, 
•
Any new medical conditions during the study.
13.7.1.2 Primary Analysis  
 
13.7.1.2.1 Handling of Dropouts or Missing Data 
All randomized participants will be included in the primary ITT efﬁcacy analysis. Participants not 
reaching the primary efﬁcacy endpoint by the study end date, or before their last assessment for 
participants lost to follow-up, will be censored at the date of their last assessment visit.
 
13.7.1.2.2 Data Transformation Before Analysis, If Any 
 
No data transformation will be applied to raw data. 
 
13.7.1.2.3 Main Statistical Model and Adjustment for Covariates  
 
For the primary analysis, all adjudicated events occurring from randomization to the study end 
date (inclusive) will be counted, including events occurring after early permanent discontinuation 
of study medical device. The proportion of participants remaining event-free over time will be 
displayed in the form of survival curves using the Kaplan-Meier method and analyzed (primary 
analysis) using a two-sided log-rank test. Statistical signiﬁcance will be claimed if the computed 
p-value is equal to or less than 0.05. 
 
The number and percentage (crude rate) of participants experiencing a primary endpoint will be 
summarized. 

 
13.7.1.2.4 Multiple Comparisons/Multiplicity 
If the primary efﬁcacy reaches statistical signiﬁcance, then the two secondary endpoints will be 
formally tested at the 5% level in a hierarchical (step-down) procedure. 
13.7.1.2.5 Other Analyses for Primary Variable(s)  
In order to further investigate the primary endpoint the following analysis will be done: 
Subgroup Analysis: The incidence of the primary efﬁcacy endpoint will be summarized by a 
number of covariates including age, gender, and race to examine their potential effects. Each of 
these factors will be analyzed statistically using a Cox proportional hazards model incorporating 
terms for treatment, the covariate and the treatment-by covariate interaction. The number of 
participants with outcomes, estimated hazard ratios, and associated 95% conﬁdence intervals 
will be calculated within each of the subgroups generated by these analyses. 
13.7.2 Secondary/Other Efficacy Variables  
13.7.2.1 Description of Secondary/Other Variables  
Secondary endpoint: The composite cluster of the ﬁrst occurrence, over the duration of study 
(randomization to study end date inclusive), of the following cluster of events: 
 
 
 
13.7.2.2 Statistical Analysis of Secondary/Other Variables  
The secondary and other endpoints will be analyzed using the same statistical methodology as 
for the primary efﬁcacy endpoint (except for weight and waist circumference).  
13.8 Safety Analysis  
For this morbidity/mortality trial, a benefit risk assessment is important. For this purpose safety 
analyses will be conducted on the same population (ITT) and using the same evaluation period 
as for efficacy analyses. (ie, from randomization until study end date)  

13.8.1 Adverse Events  
13.8.1.1 Definitions  
All adverse events recorded during the study will be coded according to Medical Dictionary for 
Regulatory Activities. 
13.8.1.2 Adverse Events  
Summaries will be done for the following types of AE: 
•
Number (%) of participants with any AE,
•          Number (%) of participants with any new pulmonary condition,     
•
Number (%) of participants with any  cardiology and neurologic  
•
Number (%) of participants permanently withdrawn from treatment.
 
All summaries will display, by treatment group, the overall frequency of participants with events, 
the frequency of participants with events within each primary system organ class and by 
preferred terms. For each preferred term and each system organ class a patient will be counted 
only once. For summaries on severe or medical device-related AE, for a given patient, the 
highest severity or relationship for a speciﬁc preferred term will be considered. 
 
13.8.1.3 Deaths and Serious Adverse Events  
Serious adverse events and events leading to death will be summarized overall and by primary 
system organ class and preferred term. 
 
13.8.1.4 Adverse Events Leading to Treatment Discontinuation 
Adverse events leading to treatment discontinuation will be summarized overall and by primary 
system organ class and preferred term.
 
13.8.2 Clinical Laboratory Evaluations 

Not Applicable in this Clinical Trial. 
Descriptive statistics will also be used to summarize the values and changes from baseline for 
each treatment group across time. 
13.8.3 Vital Signs  
Vital signs need to be within normal parameters for age of participant and remain so for the 21 
day period of the trial.  Vitals shall be taken before trial enrollment by prescribing physician.
14. SUBSTUDIES  
Not Applicable in this Clinical Trial. 
15. ETHICAL AND REGULATORY STANDARDS  
15.1 Ethical Principles  
This Clinical Trial will be conducted in accordance with the principles laid down by the 18th 
World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World 
Medical Assemblies, and the ICH guidelines for Good Clinical Practice (GCP). Those 
Investigators participating as leaders in this trial, including members of the Executive and 
Operations Committees and National Coordinators, will receive compensation for their time but 
will receive no ﬁnancial proﬁt from their activities related to the trial. 
15.2 Laws and Regulations  
This Clinical Trial will be conducted in compliance with all international laws and regulations, 
and national laws and regulations of the countries in which the clinical trial is performed, as well 
as any applicable guidelines. The trial will be registered on www.clintrials.gov and on other sites, 
as appropriate.  

15.3 Informed Consent  
The Investigator (according to applicable regulatory requirements), or a person designated by 
the Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial, including the written information given approval/favorable 
opinion by the Institutional Review Board/Ethics Committee (IRB/EC).  
Prior to a participant's participation in the clinical trial, the written Informed Consent Form should 
be signed, name filled in and personally dated by the patient or by the participant's legally 
acceptable representative, and by the person who conducted the informed consent discussion. 
A copy of the signed and dated written Informed Consent Form will be provided to the patient.  
If informed consent is obtained under special circumstances (emergency, from a guardian, 
minor, etc.), the method should be specified following the ICH requirements. The first part of the 
section should be adapted, keeping the point as appropriate.  
The Informed Consent Form used by the Investigator for obtaining the participant's informed 
consent must be reviewed and approved by the Sponsor prior to submission to the appropriate 
IRB/EC for approval/favorable opinion.  
15.4 Institutional Review Board/Independent Ethics Committee (IRB/EC)  
In this Phase IV, clinical trial for efficacy of previously cleared device under current FDA 510k 
indications and no new indications being investigated the need for an IRB/EC is not required by 
law or by ICH GCP guidelines. 
If the Sponsor chooses to enlist the services of an IRB/EC then: 
The Investigator must submit this Clinical Trial Protocol to the appropriate IRB/EC, and is 
required to forward to the Sponsor a copy of the written and dated approval/favorable opinion 
signed by the Chairman with IRB/EC composition.  
The Clinical Trial (study number, Clinical Trial Protocol title and version number), the documents 
reviewed (Clinical Trial Protocol, Informed Consent Form, Investigator’s Brochure, Investigator’s 
CV, etc.) and the date of the review should be clearly stated on the written IRB/EC approval/
favorable opinion.  

Investigational Product will not be released at the study site and the Clinical Trial will not start 
until a copy of this written and dated approval/favorable opinion has been received by the 
Sponsor.  
During the Clinical Trial, any amendment or modification to the Clinical Trial Protocol should be 
submitted to the IRB/EC. It should also be informed of any event likely to affect the safety of 
participants or the continued conduct of the Clinical Trial, in particular any change in safety. All 
updates to the Investigator’s Brochure will be sent to the IRB/EC.  
If requested, a progress report is sent to the IRB/EC annually and a summary of the Clinical 
Trial’s outcome at the end of the Clinical Trial.  
16. STUDY MONITORING 
  
16.1 Responsibilities of the Investigator(s)  
The Investigator(s) undertake(s) to perform the Clinical Trial in accordance with this Clinical Trial 
Protocol, ICH guidelines for Good Clinical Practice and the applicable regulatory requirements.  
The Investigator is required to ensure compliance with all procedures required by the Clinical 
Trial Protocol and by study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the Clinical Trial 
Protocol (with the help of the Case Report Form [CRF], Discrepancy Resolution Form [DRF] or 
other appropriate instrument) in an accurate and legible manner according to the instructions 
provided and to ensure direct access to source documents to Sponsor representatives.  
If any particular circuits have to be defined (e.g., e-CRF, Email), particular attention should be 
paid to the confidentiality of the participant's data to be transferred.  
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub-
Investigators to assist in the conduct of the Clinical Trial in accordance with the Clinical Trial 
Protocol. All Sub-Investigators shall be timely appointed and listed. The Sub-Investigators will 
be supervised by and under the responsibility of the Investigator. The Investigator will provide 
them with a Clinical Trial Protocol and all necessary information.  

16.2 Responsibilities of the Sponsor  
The Sponsor of this Clinical Trial is responsible to Health Authorities for taking all reasonable 
steps to ensure the proper conduct of the Clinical Trial Protocol as regards ethics, Clinical Trial 
Protocol compliance, integrity and validity of the data recorded on the Case Report Forms. 
Thus, the main duty of the Monitoring Team is to help the Investigator and the Sponsor maintain 
a high level of ethical, scientific, technical and regulatory quality in all aspects of the Clinical 
Trial.  
At regular intervals during the Clinical Trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the Monitoring Team to review study progress, 
Investigator and patient compliance with Clinical Trial Protocol requirements, and any emergent 
problems. During these monitoring visits, the following but not exhaustive list of points will be 
scrutinized with the Investigator: patient informed consent, patient recruitment and follow-up, 
Serious Adverse Event documentation and reporting, outcome events documentation and 
reporting, Investigational Product allocation, patient compliance with the Investigational Product 
regimen, Investigational Product accountability, concomitant therapy use and quality of data.  
16.3 Source Document Requirements  
According to the ICH guidelines for Good Clinical Practice, the Monitoring Team must check the 
Case Report Form entries against the source documents, except for the pre-identified source 
data directly recorded in the Case Report Form. The Informed Consent Form will include a 
statement by which the patient allows the Sponsor’s duly authorized personnel, the Ethics 
Committee (IRB/EC), and the regulatory authorities to have direct access to source data which 
supports the data on the Case Report Forms (e.g., participant's medical file, appointment books, 
original laboratory records, etc.). These personnel, bound by professional secrecy, must keep 
confidential all personal identity or personal medical information (according to confidentiality 
rules).  
16.4 Use and Completion of Case Report Forms and Additional Requests  
It is the responsibility of the Investigator to maintain adequate and accurate CRFs designed by 
the Sponsor to record all observations and other data pertinent to the clinical investigation. All 
CRFs should be completed in their entirety in a neat, legible manner to ensure accurate 

interpretation of data; a black ball point pen should be used to ensure the clarity of the 
reproduced copy of all CRFs, which should be emailed within 48 hours of completion or any 
modification to the Central Database number.  
Should a correction be made, the information to be modified must not be overwritten. The 
corrected information will be transcribed by the authorized person next to the previous value, 
initialed and dated, and the corrected CRF should be emailed again to the Central Database 
number.  
The computerized handling of the data by the Sponsor after receipt of the CRFs may generate 
additional requests (DRF) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. Unresolved requests will be emailed to the Investigator at least 
every 2 weeks. Modified CRFs following resolution of the queries should be emailed again to 
the Central Database number.  
17. ADMINISTRATIVE RULES  
17.1 Curriculum Vitae  
An updated copy of the curriculum vitae limited to the experience, qualification and training for 
each Investigator and Sub-Investigator will be provided to the Sponsor prior to the beginning of 
the Clinical Trial.  
17.2 Record Retention at Study Site(s)  
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. All data and information shall 
be kept in secure digital format with no paper files stored.  Data drives shall all be taken offline 
and physically retained in triple level secure vault.  These data records shall be available for 
inspection by any and all Federal regulatory agencies, State agencies or parties legally 
designated by the Sponsor within two (2) business days.  Records shall be available during 
normal business hours, during normal business days with the exception of weekends or any 
bank holidays. 
It is recommended that the Investigator retain the study documents at least fifteen (15) years 
after the completion or discontinuation of the Clinical Trial.  

However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required.  
The Investigator must notify the Sponsor prior to destroying any study essential documents 
within the fifteen (15) year period following the Clinical Trial completion or discontinuation.  
If the Investigator's personal situation is such that archiving can no longer be ensured by him/
her, the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
18. CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the Clinical Trial, including, but not limited to, the Clinical Trial 
Protocol, the CRFs, the Investigator's Brochure and the results obtained during the course of 
the Clinical Trial, is confidential. The Investigator or any person under his/her authority agrees to 
undertake to keep confidential and not to disclose the information to any third party without the 
prior written approval of the Sponsor.  
However, the submission of this Clinical Trial Protocol and other necessary documentation to 
the Ethics Committee (IRB/EC) is expressly permitted, the IRB/EC members having the same 
obligation of confidentiality.  
The Sub-Investigators shall be bound by the same obligation as the Investigator. The 
Investigator shall inform the Sub-Investigators of the confidential nature of the Clinical Trial.  
The Investigator and the Sub-Investigators shall use the information solely for the purposes of 
the Clinical Trial, to the exclusion of any use for their own or for a third party's account.  
19. PROPERTY RIGHTS  
All information, documents and Investigational Product provided by the Sponsor or its designee 
are and remain the sole property of the Sponsor. 

 
The Investigator shall not mention any information or the Product in any application for a patent 
or for any other intellectual property rights.  
All the results, data, documents and inventions, which arise directly or indirectly from the Clinical 
Trial in any form, shall be the immediate and exclusive property of the Sponsor. The complete 
verified database will be shared with the Operations Committee, which shall have full access to 
all data.  
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the Clinical Trial. 
 
As the case may be, the Investigator and/or the Sub-Investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents.  
20. DATA PROTECTION  
 • 
The participant's personal data and Investigator's personal data which may be included 
in the Sponsor database shall be treated in compliance with all applicable laws and 
regulations;  
 • 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party.  
21. INSURANCE COMPENSATION  
 
The Sponsor certiﬁes that it has taken out a liability insurance policy that covers the liability of 
the medical device. This insurance policy is in accordance with local laws and requirements.  
An insurance certiﬁcate will be provided to the Investigator in countries requiring this document.  
The insurance of the Sponsor does not relieve the Investigator and the collaborators of any 

obligation to maintain their own liability insurance policy as required by applicable law.  
22. SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
 
For the purpose of ensuring compliance with the Clinical Trial Protocol, Good Clinical Practice 
and applicable regulatory requirements, the Investigator should permit auditing by or on the 
behalf of the Sponsor and inspection by applicable regulatory authorities.  
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that this personnel is bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information.  
The Investigator will make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data, and documents.  
As soon as the Investigator is notiﬁed of a future inspection by the authorities, he will inform the 
Sponsor and authorize the Sponsor to participate in this inspection.  
The conﬁdentiality of the data veriﬁed and the protection of the should be respected during 
these inspections.  
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor.  
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
23. PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT SITE  
23.1 Decided by the Sponsor in the Following Cases:  
 • 
In the event the results of the Clinical Trial do not appear to be scientifically convincing to 
the Sponsor;  
 • 
If the aim of the Clinical Trial has become outdated or is no longer of interest;  
 • 
If the information on the product leads to doubt as to the benefit/risk ratio;  

 • 
If the Investigator has received from the Sponsor all Investigational Product, means and  
information necessary to perform the Clinical Trial and has not included any patient  
after a reasonable period of time mutually agreed upon;  
 • 
In the event of breach by the Investigator of a fundamental obligation under this  
agreement, including but not limited to breach of the Clinical Trial Protocol, breach of  
the applicable laws and regulations or breach of the ICH guidelines for GCP;  
 • 
If the total number of participants are included earlier than expected; 
In any case the Sponsor will notify the Investigator of its decision by written notice.  
23.2 Decided by the Investigator  
 
The Investigator must notify (30 days' prior notice) the Sponsor of his/her decision and give the 
reason in writing. 
 
In all cases (decided by the sponsor or by the Investigator), the appropriate Ethics Committee(s) 
(IRB/EC) and Health Authorities should be informed.  
24. CLINICAL TRIAL RESULTS  
 • 
The Sponsor will be responsible for preparing a Clinical Study Report;  
 • 
When the data from all investigational sites have been fully analyzed by the Sponsor,  
the latter will communicate the results of the Clinical Trial to the Investigator(s).  
25. PUBLICATIONS AND COMMUNICATIONS  
 
It is the policy of the Sponsor to encourage the presentation and/or publication of the results of 

their studies, using only clean, checked and validated data in order to ensure the accuracy of 
the results.  
At least thirty (30) days in advance of proposed submission, the primary author should forward a 
copy of the manuscript or abstract for review by the Sponsor, and, if necessary,  
delay publication or communication for a limited time in order to protect the conﬁdentiality or 
proprietary nature of any information contained therein. 
The Sponsor may also request that the Sponsor’s name and/or names of one or several of its 
employees appear or not appear in such publication. 
In multi-center studies conducted by an Executive Committee, with an Operations Committee, it 
is those bodies that are responsible for presentations and/or publications. The Committee must 
send a copy of the manuscript or abstract to the Sponsor for review at least thirty (30) days 
before submission. 
All study participants (Investigators and Committee members) give full authority to the Executive 
Committee for primary presentation and/or primary publication of the results in the name of 
wholehearted collaborators. No other publication is allowed before the primary publication. Any 
subsequent presentation or publication by a study participant (including for sub-studies) must be 
approved by the Operations Committee and make reference to the study and the primary 
publication. The ﬁnal decision to publish articles and their content will be made by the 
Operations Committee after prior notice to the Sponsor, allowing their review and comments on 
all manuscripts (at least thirty days in advance of submission, unless a mutual agreement allows 
a shorter notice). 
26. CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this Clinical Trial 
Protocol.  
The Investigator should not implement any deviation from, or changes of the Clinical Trial 
Protocol without agreement by the sponsor and prior review and documented approval/
favorable opinion from the IRB/EC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to clinical trial participants, or when the change(s) involves only logistical 

or administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this Clinical Trial Protocol.  
Any amendment to the Clinical Trial Protocol requires written approval/favorable opinion by the 
IRB/EC prior to its implementation, unless there are overriding safety reasons.  
In some instances, an amendment may require a change to the Informed Consent Form. The 
Investigator must receive an IRB/EC approval/favorable opinion concerning the revised 
Informed Consent Form prior to implementation of the change.  
27. BIBLIOGRAPHIC REFERENCES  
Please see User Manual 
28. APPENDICES  
Appendix 1: The Optional Study Group Coordinating Center and Study Sponsor 
Responsibilities 
1. Optional Study Group Project Team responsibilities  
The Optional Study Group 2, is independent of the Sponsor and its primary function is to 
facilitate and oversee the execution of the study in collaboration with the Sponsor. The Optional 
Study Group Project Office will keep the Operations Committee appraised of the progress and 
conduct of the trial and will provide ongoing administrative support to the Clinical Events 
Committee and other committees.  
Key members of the Optional Study Group Project Team are:   
• Oversight activities of the Optional Study Group Project Team include the 
following:  
• Coordination of protocol and CRF review at the Optional Study Group Site 
Management for US sites.  
• Review of monitoring visit reports (selection, initiation and interim reports)  

• Direct communication with the sites regarding the trial and any relevant issues 
(calls documented in a database)  
• Re-training of sites staff in case of turnover  
• Distribution of a monthly newsletter 
• Maintenance of a hot-line service for medical questions, including medical 
advice if unblinding is considered  
Clinical Events Committee (CEC):  
• Development of CEC review forms and CEC review instructions  
• Appointment of medical reviewers blinded to treatment at Optional Study Group 
for  
validation of events reported in English (approximately 50% of  
adjudicated events)  
• Appointment of decentralized physician reviewers in each of the non-  
English languages  
• Coordination of the ongoing medical review of adjudicated endpoints  
• Reviews contracts and payments  
Executive Committee, Operations Committee and National Coordinators:  
• Coordination, organization of meetings, distribution of documents and minutes  
• Contracts and honorarium payments  
DMC:  
• Support for organization of DMC meetings 
• Contracts and honorarium payments Prepare final study manuscript for 
publication  

2. Study Sponsor responsibilities  
The Study is being sponsored by Med Systems, Inc., LTD., and monitored by Med Systems, 
Inc., LTD.. As such, they will share legal and regulatory responsibilities for the conduct of the 
study and control and distribution of the investigational device, Electro Flo 5000 . In fulfilling 
these responsibilities according to Med Systems, Inc., LTD. standard operating procedures, the 
Sponsor's activities include the following:  
 • 
Medical Input 
• Participate at the Operations Committee and the Executive Committee meetings 
or teleconferences  
• Update the Clinical Investigator’s Brochure at least annually  
•  
Medical Device Supplies 
• Manufacture and ship medical devices and matching-placebos 
• Release medical device supplies to individual Clinical Centers after receipt of 
documentation at the Sponsor's regional centers 
 • 
Funding  
• Provide indemnification letters as required  
• Provide funding and contracting with Investigators for the conduct of the study.  
 • 
Regulatory  
• Obtain all necessary documents from Investigators for regulatory filings  

• Ensure initial, and then annual (when applicable) IRB/EC approval is obtained by 
Investigators  
• Monitor compliance with all applicable national and local law 
maintain and coordinate contact with national regulatory authorities 
• Submit all necessary regulatory filings oversee all communication between DMC 
and regulatory authorities to make certain it occurs in a timely manner 
• Perform all statistical analysis and medical writing of clinical reports for  
• Registration applications 
•   Study Monitoring  
• Develop a study monitoring plan 
• Monitor clinical centers 
• Ensure protocol adherence 
• Assess timely completion and submission of Case Report Forms (CRFs) and support 
documents 
• Monitor quality and homogeneity of all data processing activities 
• Quality Assurance audits of the study as needed 
• Monitoring and overseeing the maintenance of study conduct according to ICH, 
GCPs, and all country-specific regulations 
• Clarify queries or missing documents, including assisting Optional Study Group 
Project Team to  
• Clarify queries or missing documents from US sites maintain necessary 
communication with all National Coordinators, Investigators and study personnel 
 
• Data Management and Study Medical device Allocation Procedure  

• Develop and manage the Central Study Database, perform data entry and validate 
records in the email acquisition system   
• Implement appropriate measures for data quality control   
• Implement and manage the central randomization system  
• Generate patient visit schedules for all centers compile and  
• Generate weekly study status reports for general distribution to all  
personnel involved in the study, centrally and locally Study Archives  
• Maintain study archives Study Reporting provide support to the Executive Committee 
for the primary scientific publication of the study  
• Develop a clinical study report for registration purpose  
Responsibilities  
Membership  
Expert members:  Function Chairman  Member/International PI Member/Investigator  
Appendix 2: The Executive Committee  
The Executive Committee is composed of university-based and Sponsor-based scientists with 
clinical and methodological expertise. The committee has the overall responsibility for producing 
and conducting a scientifically sound study and ensuring accurate reporting of the study. In that 
capacity, the Executive Committee must address and resolve scientific issues encountered 
during the study. This committee will meet at least twice a year.  
All proposed ancillary research investigations on participants enrolled must be approved by the 
Executive Committee. The primary scientific publication reporting the study results is the 
responsibility of the Executive Committee. Collaborating Investigators or members of the 
various study committees wishing to prepare secondary publications must submit proposals and 
manuscripts to the Executive for approval. The Sponsor reserves the right to review 
manuscripts prior to submission for publication in a scientific journal. The final decision on all 
publications will be the responsibility of the Operations Committee.  

Responsibilities  
Appendix 3: The Operations Committee  
The Operations Committee is responsible for ensuring that study execution and management 
are of the highest quality. Issues relating to regulatory reporting are the responsibility of the 
Sponsor, although the Operations Committee is to be kept informed of these activities. The 
Operations Committee will determine its own guidelines and approve the criteria and guidelines 
of the other committees prior to commencement of the study. The Operations Committee will be 
responsible for publications.  
The Operations Committee will convene regularly to discuss and report on the ongoing 
supervision of the study.  
Membership  
Working procedure  
The Operations Committee will need to determine its own working guidelines, especially 
regarding the decision-making process on specific aspects of the study conduct.  
Appendix 4: The Clinical Events Committee (CEC)  
Responsibilities  
The Clinical Events Committee is charged with the responsibility for validating all reported 
primary efficacy outcomes and validating the classification of the cause of all deaths. The event 
adjudication process will be coordinated by C5.  
Members of the Clinical Event Committee will be chosen based on their clinical expertise and 
language skills. Adjudicators will be trained at a preliminary meeting where study definitions will 
be reviewed and test cases performed to ensure uniform application of study definitions. 
Reported events will be adjudicated by at least one committee member. Dossiers of reported 
events will be prepared and distributed to committee members on a regular basis to ensure that 
events are adjudicated in a timely fashion. Each committee member will be requested to review 
the dossiers sent to him/her and acknowledge in writing his/her agreement/disagreement with 
the investigator’s interpretation of events.  
Definitions for Validation of Reported Outcome Events  

Reported outcome events are all defined in the protocol. 
 
Review Process for Reported Efficacy Outcome Events  
 
•  First adjudicator agrees with Investigator’s report of outcome event:  
  
-  Agreement acknowledged in writing and filed at Optional Study Group 
  
-  Event Adjudication database updated accordingly  
  
-  Investigator’ s report of outcome event accepted  
  
-  Adjudication complete  
 • 
First adjudicator disagrees with Investigator’s report of outcome event:  
 
 
-  Disagreement or uncertainty acknowledged in writing  
 
 
-  Event Adjudication database updated accordingly  
 
 
-  Outcome event forwarded for review to second adjudicator who is unaware of  
prior adjudication  
 • 
If second adjudicator agrees with Investigator’s report of outcome event:  

 
 
-  Agreement acknowledged in writing and adjudication report filed at Optional 
Study Group 
 
 
-  Event Adjudication database updated accordingly  
 
 
-  Investigator’ s report of outcome event accepted  
 
 
-  Adjudication complete  
 • 
If second adjudicator disagrees with Investigator’s report of outcome event and agrees 
with first adjudicator:  
 
 
-  Disagreement acknowledged in writing and adjudication report filed at Optional 
Study Group 
 
 
-  Event Adjudication database updated accordingly  
 
 
-  Adjudicator’ s report of outcome event accepted  
 
 
-  Adjudication complete  
 • 
If second adjudicator is uncertain:  

• Stalemate acknowledged in writing 
• Event Adjudication database updated accordingly  
• Outcome event forwarded to Chairman of Clinical Events Committee for  
resolution. Final decision mandatory at this stage 
  
• Chairman’s decision acknowledged in writing and reports filed at Optional 
Study Group 
Adjudication complete  
 
 
The Clinical Events Committee and Optional Study Group will establish detailed 
written guidelines for the event adjudication process. The CEC will prepare a 
manual that will describe the quality assurance procedures.  
The Clinical Events Committee will meet initially for orientation and training. 
Afterwards, meetings will be held as required to address and resolve committee 
policy issues.  
Membership  
Chairman : 
Members will be supplemented as necessary in order to ensure that two 
cardiologists and two neurologists are available to represent most languages of 
study participant countries.  
General Overview  
Appendix 5: The Data Monitoring Committee (DMC) 
The Study will be conducted in a double-blind manner in which participants and treating 
physicians are blinded. The trial management team, including Operations Committee, Executive 
Committee, Clinical Events Committee, the Optional Study Group Project Team and the 
Sponsor will also be blinded with respect to treatment allocation.  
To facilitate its responsibilities, the DMC will have an Associated Statistician who will receive 
study data directly from the Central Database and who will remain independent of the trial 

management team. The DMC Associated Statistician is not a member of the DMC, but presents 
data to the committee and is responsible to the Chairman.  
The DMC Associated Statistician, being unblinded, will not be able to edit/alter any part of the 
Central Database.  
Other than the Associated Statistician, routine access to the treatment code will be restricted to 
the Chairman of the DMC, except for emergency unblinding on a case-by- case basis, if 
required for regulatory purpose.  
DMC Responsibilities  
Primary:  
1. Regular review of safety data including serious adverse events, as defined in the DMC 
Charter  
2. Feedback to the Chairman of the Operations Committee Secondary:  
 A. 
Respond to special requests from regulatory authorities or IRB/ECs  
 B. 
Recommendations for protocol amendments  
Verification of final analysis of the study will be done by the DMC Associated Statistician.  
Safety Review  
Recommendation to stop a trial early for safety reasons is, by definition, a subjective judgment. 
The DMC is composed of eminent clinicians and methodologists who are experienced with 
clinical trials and can be relied upon to exercise good judgment in weighing the potential risks 
and benefits to participants as data accumulate in this trial.  
The DMC will fulfill its responsibility to monitor the safety of participants by conducting formal 
reviews of accumulated safety and efficacy data. These reviews will normally occur at regular 
intervals as defined in the DMC charter, however, in case of specific concerns, ad-hoc meetings 
can be set up. The DMC Associated Statistician will prepare a report of aggregate data 

summaries and other data, where appropriate, for each treatment group. This report will be 
circulated to each member of the DMC at least one week prior to their collective review. The 
committee will then convene, either by face-to-face meeting or by telephone conference call, to 
make its recommendation to the Operations Committee with respect to continuance of the trial 
or any changes to the conduct of the trial. A formal written communication to the Chairman of 
the Operations Committee will then follow. Minutes of all official meetings of the DMC and any 
recommendations will ultimately be part of the Sponsor's master files after the study is over and 
the results are known (archives).  
The report of data summaries and listings will include information on both safety and efficacy 
parameters, together with status reports designed to show the extent to which the trial is being 
executed according to protocol. Included among the safety data will be (a) all deaths (b) SAEs 
and (c) other adverse events as requested by the DMC. Efficacy summaries will provide 
information on the occurrence of all study outcomes. The outcome events are considered as 
distinct from adverse events and summarized separately. At each review by the DMC, 
consideration of a decision to stop the trial on grounds of patient safety will weigh the current 
evidence of differences between treatments regarding adverse effects (as expressed by 
mortality, adverse event reports, etc) against emerging trends in efficacy. Providing efficacy data 
at each of these routine safety reviews does not constitute a formal interim analysis of efficacy, 
and these analyses will not, in and of themselves, be used for stopping the trial (see next 
section).  
Data for the safety review will be made available from the Central Database on a quarterly basis 
(roughly three weeks prior to DMC meetings). Serious adverse events are required to be 
reported rapidly to the Sponsor and will be entered into a separate Pharmacovigilance database 
that will also be transferred to the DMC Associated Statistician, in addition to the Central 
Database. Primary outcome events will be reviewed by the Clinical Events Committee on an 
ongoing basis to determine if each reported event meets the defined criteria for a study outcome 
event. The DMC will review data on all reported outcome events. Additional summaries will 
show the results of the Clinical Event Committee's judgments on the subset of reports that has 
been reviewed by this committee.  
Feedback From the DMC  
a) To the Operations Committee  
All communications between the Operations Committee and the DMC will be through the office 
of the Chairman of the Operations Committee and be documented in writing.  

Information provided by the DMC may be confidential and must be kept so within the Operations 
Committee.  
The Operations Committee may request supplementary information from the DMC, if necessary. 
The DMC Chairman will consider all such requests.  
b) To/From the Sponsor  
Special requests from any national regulatory authority requiring DMC input will be forwarded by 
the Sponsor to the Chairman of the Operations Committee. Any requests that cannot be 
performed by the Chairman of the Operations Committee will be forwarded to the Chairman of 
the DMC to be done by the DMC Associated Statistician. New preclinical and clinical information 
from other trials will be provided to the DMC in an updated Investigator's Brochure.  
Representatives of the study organization will discuss the content and timing of such feedback 
with the agencies concerned. All necessary analyses and reports will be sent in a timely fashion. 
The Chairman of the Operations Committee and the Sponsor's regulatory department will be 
copied on the covering letter to any reports provided to individual regulatory agencies. However, 
no unblinded reports will be sent to any organization other than the regulatory agency that 
requested it.  
Protocol Change Recommendations  
It is possible that the DMC might suggest changes in the protocol as a result of their reviews. 
Any suggestions will be provided in writing to the Chairman of the Operations Committee, 
including a detailed rationale with the anticipated consequences in terms of study bias.  
Confidentiality  
Information provided to the DMC is strictly confidential and must not be disclosed other than 
through the mechanisms described above. In particular, members of the DMC cannot publish 
any information derived from its privileged access to the study data without the approval of the 
Operations Committee.  
Membership  
Chairman Members  
Independent Statistician