A Prospective, Randomized, Multi-center, Double-Blinded, Placebo-Controlled, 3-Arm Clinical Study to Assess the Efficacy and Safety of Vibrant Capsule, for the Treatment of Chronic Idiopathic Constipation
Phase: NA
Conditions: Chronic Idiopathic Constipation
Sponsor: Vibrant Ltd.

 
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NCT number: NCT03879239 
 
Vibrant Ltd. 
Study Protocol 
 
 
 
Study number: V-270 
Protocol number: 270CLD  
Protocol Date: Jan 24th, 2019  
Rev. 01 
 
A Prospective, Randomized, Multi-center, double-
Blinded, Placebo-Controlled, 3-Arm Clinical Study 
to Assess the Efficacy and Safety of Vibrant 
Capsule, for the Treatment of Chronic Idiopathic 
Constipation 
 
Confidentiality statement: 
The following confidential information is the property of Vibrant Ltd.  As long as the information 
contained in this protocol has not been published, it may only be used when permission has been 
obtained from Vibrant Ltd. in writing.  It is not permitted to make reproductions of all or sections 
of this protocol.  Commercial use of the information is only possible with the permission of the 
proprietor and is subject to a license fee. 
 
 

 
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1. Sponsor Statement of compliance 
 
The sponsor of this study, Vibrant Ltd., manufacturer of the investigational device, legally 
represented by Lior Ben-Tsur, Chief Executive Officer, states the following: 
 
a. to assume responsibility related to the clinical investigation; 
b. that the treatments used to perform the clinical study are adequate for the device under 
investigation; 
c. that the clinical study, as for the responsibility of the manufacturer, will be conducted in 
conformance with: 
 
The Federal Food, Drug, and Cosmetic Act, as amended, and regulations promulgated thereunder 
(“the Act”) and the United States Food and Drug Administration (“FDA”) regulations governing 
the protection of human subjects and regulations governing clinical investigators, The World 
Medical Association Declaration of Helsinki, titled “Ethical Principles for Medical Research 
Involving Human Subjects”, ICH/GCP guidelines, Applicable relevant national legislation, 
HIPAA as defined in 45. C.F.R. section 164.501 or relevant national equivalent and following 
revisions or other analogous internationally recognized standards, to be specified, and only after 
the approval, by the competent Ethics Committee, of the investigational protocol, the informed 
consent and the documentation required by the above mentioned standards; 
  
 
 
Print Name: 
 
Signature:  
 
Date: 
 
  
          
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2. Investigator Agreement: 
 
Prior to participation in this study, a written approval must be obtained from the Institutional 
Review Board, and copy should be provided to the Sponsor, Vibrant Ltd., or their authorized 
representatives, along with the Institutional Review Board approved Informed Consent Form.   
 
The Principal Investigator must also: 
 
Conduct the study in accordance with the study protocol, the Investigator Agreement, 
Declaration of Helsinki, Good Clinical Practices, international harmonized standards for 
clinical investigation of medical devices (Title 21 of the Code of Federal Regulations (21 
CFR), part 812 (Investigational Device Exemptions), the laws and regulations of the 
countries where the study will take place, indemnity/insurance requirements and any other 
applicable regulations.   
 
Agree to participate in an appropriate training program as part of the study initiation. 
 
Assure that informed consent is obtained from each subject prior to enrollment, using the 
Institutional Review Board approved form.   
 
Assure that the study is not commenced until Institutional Review Board approval has 
been obtained. 
 
Provide all required data and agree to source document verification of study data with 
subject’s medical records.   
 
Allow staff of the Sponsor and its authorized representatives, as well as representatives 
from regulatory agencies, to review, inspect and copy any documents pertaining to this 
clinical investigation.  
 
The Principal Investigator (PI) may delegate one or more of the above functions to an associate 
or sub-investigator.  However, the PI retains overall responsibility for proper conduct of the 
study, including obtaining and documenting subject informed consent, compliance with the study 
protocol, and the collection of all required data. 
 
Principal Investigator Statement: 
I the undersigned, have reviewed this protocol and agree to conduct this study in adherence to the 
study protocol, GCP (Good Clinical Practice) compliance, Ethical principles set forth in the 
declaration of Helsinki and authority regulations for the protection of human subjects 
participating in clinical trials. 
 
Print Name: 
 
Signature:  
 
Date: 
 
----------------- 
 
 ----------------------- 
 
--------------- 

 
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Table of Contents 
 
1. 
Sponsor Statement of compliance .................................................................................. 2 
2. 
Investigator Agreement: ................................................................................................. 3 
3. 
List of Abbreviations ....................................................................................................... 7 
4. 
Protocol Synopsis ............................................................................................................ 9 
5. 
INTRODUCTION ............................................................................................................. 19 
6. 
BACKGROUND ............................................................................................................... 19 
7. 
DEVICE NAME AND INTENDED USE ............................................................................... 22 
7.1 
Device Name ................................................................................................................. 22 
7.2 
Intended Use ................................................................................................................ 22 
8. 
DEVICE DESCRIPTION .................................................................................................... 22 
8.1 
Capsule ......................................................................................................................... 23 
8.1.1 Vibrant Active: .............................................................................................................. 23 
8.1.2 Vibrant Placebo: ........................................................................................................... 24 
8.1.3 Accessory: activation base unit ..................................................................................... 25 
8.2 
Capsules Activation ....................................................................................................... 26 
9. 
RISKS & BENEFITS .......................................................................................................... 27 
9.1 
Risks .............................................................................................................................. 28 
9.2 
Benefits ......................................................................................................................... 30 
10. 
ANIMAL INVESTIGATIONS ......................................................................................... 31 
11. 
HUMAN CLINICAL INVESTIGATIONS .................................................................. 32 
12. 
STUDY OBJECTIVE ......................................................................................................... 41 
13. 
STUDY ENDPOINTS ........................................................................................................ 41 
13.1 Primary endpoint .......................................................................................................... 41 
13.2 Secondary endpoints .................................................................................................... 42 
14. 
STUDY CONDUCT & POPULATION ................................................................................. 43 
14.1 Inclusion Criteria ........................................................................................................... 43 
14.2 Exclusion Criteria .......................................................................................................... 44 
14.3 Duration of Study .......................................................................................................... 45 
15. 
STUDY TREATMENT ...................................................................................................... 45 
15.1 Study Design ................................................................................................................. 45 
15.2 Medical History ............................................................................................................. 47 
15.3 Constipation History ..................................................................................................... 47 
15.4 Physical Examination .................................................................................................... 47 

 
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15.5 Assessment of pelvic floor dysfunction (defecatory disorder) ...................................... 48 
15.6 Blood and urine tests .................................................................................................... 48 
15.7 Screening visit (day -21 to -14) ..................................................................................... 48 
15.8 Run-in period (day -21 or -14, to -1) ............................................................................. 49 
15.9 Baseline / randomization visit (day 0) ........................................................................... 50 
15.10 4 weeks visit (day 28 ± 2) .............................................................................................. 51 
15.11 8 weeks visit / Termination (day 56 ± 2) ....................................................................... 52 
15.12 Rescue Treatment ......................................................................................................... 52 
15.13 Concomitant medication .............................................................................................. 53 
15.14 Prohibited medication .................................................................................................. 53 
15.15 Recording ...................................................................................................................... 54 
15.16 Study Schedule ............................................................................................................. 55 
15.17 Deviations from study protocol .................................................................................... 56 
15.18 Investigative Center Selection Criteria .......................................................................... 57 
16. 
ADVERSE EVENTS RECORDING ...................................................................................... 58 
16.1 Reporting Requirements ............................................................................................... 58 
16.2 Definitions .................................................................................................................... 58 
16.3 Anticipated Adverse Events .......................................................................................... 60 
16.4 Adverse Event Reporting .............................................................................................. 61 
16.4.1 Intensity or Severity ...................................................................................................... 61 
16.4.2 Relatedness................................................................................................................... 62 
16.4.3 Outcome ....................................................................................................................... 62 
16.4.4 Treatment or Action taken ............................................................................................ 62 
16.5 Expedited Reporting of Serious Adverse Events ........................................................... 63 
16.6 Follow- Up of Unresolved Events .................................................................................. 64 
17. 
STATISTICAL CONSIDERATIONS ..................................................................................... 64 
17.1 Study Design and Objectives ......................................................................................... 64 
17.2 Study Endpoints ............................................................................................................ 64 
17.2.1 Primary Efficacy Endpoint ............................................................................................. 64 
17.2.2 Secondary Efficacy Endpoints ....................................................................................... 65 
17.2.3 Additional Efficacy Endpoints ....................................................................................... 65 
17.2.4 Safety Endpoints ........................................................................................................... 66 
17.3 Statistical Hypothesis .................................................................................................... 66 
17.4 Sample size ................................................................................................................... 66 
17.5 Interim Analyses ........................................................................................................... 67 
17.5.1      Procedure ................................................................................................................ 67 
17.5.2 Blinding ......................................................................................................................... 67 
17.5.3 Decision Rules ............................................................................................................... 67 
17.5.4 Controlling the Alpha level for the primary endpoint ................................................... 69 
17.6 Randomization .............................................................................................................. 69 
17.7 Blinding ......................................................................................................................... 69 
17.8 Data Analysis Sets ......................................................................................................... 69 

 
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17.8.1 Intent to Treat (ITT) ...................................................................................................... 69 
17.8.2 Modified Intent to Treat (mITT) .................................................................................... 69 
17.8.3 Per-Protocol (PP) .......................................................................................................... 70 
17.8.4 Statistical Analysis of Analysis Sets ............................................................................... 70 
17.9 Statistical Analysis ......................................................................................................... 70 
17.9.1 General Considerations................................................................................................. 70 
17.9.2 Significance levels and handling of type I error ............................................................ 71 
17.9.2.1 
Type I Error ............................................................................................................ 71 
17.9.2.2 
Primary Endpoints ................................................................................................. 71 
17.9.2.3 
Hierarchy Approach for Secondary Endpoints Analysis ......................................... 71 
17.9.3 Demographic and Other Baseline Variables .................................................................. 71 
17.9.4 Disposition of Subjects .................................................................................................. 72 
17.9.5 Efficacy Analysis ............................................................................................................ 72 
17.9.6 Treatment by Center Interaction .................................................................................. 73 
17.9.7 Safety Analysis .............................................................................................................. 73 
17.9.8 Handling of Missing Data .............................................................................................. 73 
18. 
DATA MONITORING PLAN ............................................................................................. 74 
19. 
DATA CONFIDENTIALITY................................................................................................ 76 
20. 
FUNDING....................................................................................................................... 76 
21. 
ETHICS ........................................................................................................................... 76 
22. 
INFORMED CONSENT .................................................................................................... 77 
23. 
REGULATORY AND HEALTH AUTHORITY AUDITS .......................................................... 78 
24. 
ELECTRONIC REPORTING OF DATA ............................................................................... 78 
25. 
RECORD RETENTION ..................................................................................................... 79 
26. 
PROTOCOL MODIFICATIONS ......................................................................................... 79 
27. 
PUBLICATION POLICY .................................................................................................... 79 
28. 
SUBJECT / STUDY DISCONTINUATION ........................................................................... 80 
29. 
DEVICE ACCOUNTABILITY ............................................................................................. 81 
30. 
APPENDICES .................................................................................................................. 82 
31. 
REFERENCES .................................................................................................................. 82 
 
 

 
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3. List of Abbreviations 
 
% 
Percent 
AE 
ADE 
AGA 
AR 
Adverse Event 
Adverse Device Effect 
American Gastroenterological Association 
Authorized Representative 
BMI 
BUN 
CSBM 
Body Mass Index 
Blood Urea Nitrogen 
Complete Spontaneous Bowel Movement 
eCRF 
CI 
Electronic Case Report Form 
Confidence Interval 
CIC 
Chronic Idiopathic Constipation 
DSMB 
Data and Safety Monitoring Committee 
EC 
Ethics Committee 
ECG 
EDC 
FA 
FC 
Electrocardiogram 
Electronic Data Capture 
Full Analysis Set 
Functional Constipation 
GCP 
Good Clinical Practice 
FDA 
Food and Drug Administration 
IBS-C 
ICF 
Irritable Bowel Syndrome with Constipation 
Informed Consent Form  
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IFU 
Instruction for Use 
IRB 
ISF 
Institutional Review Board 
Investigator Site Files 
ITT 
Intent To Treat 
Mg 
Milligram 
g 
Microgram 
Min 
MFR 
NCAs 
NSAIDs 
minute(s) 
Manufacturer 
National Competent Authorities 
Non-Steroidal Anti-Inflammatory Drugs 
mITT 
Modified Intent to Treat 
OTC 
PAC-QOL 
PEG 
Over The Counter 
Patient Assessment of Constipation Quality of Life questionnaire 
Polyethylene glycol 

 
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PI 
PP 
QOL 
Principal Investigator 
Per Protocol 
Quality of life 
SAE 
SADE 
SBM 
US 
USADE 
 
Serious Adverse Event 
Serious Adverse Device Effect 
Spontaneous Bowel Movement 
United States 
Unanticipated Serious Adverse Device Effect 
  

 
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4. Protocol Synopsis 
Title 
A Prospective, Randomized, Multi-center, double-Blinded, Placebo-
Controlled, 3 Arm Clinical Study to Assess the Efficacy and Safety of 
Vibrant Capsule, for the Treatment of Chronic Idiopathic Constipation  
Indication 
The Vibrant Capsule is intended for the treatment of adult subjects with 
Chronic Idiopathic Constipation. 
Objectives 
The objectives are to assess the efficacy and safety of Vibrant capsule 
administered 5 times per week  
Number of 
Subjects 
About 168 enrolled subjects including 10% drop-outs. 
 
Number of 
centers 
The study will be performed in about 30 centers   
 
 
Study 
Duration 
Study duration is 10 to 11 weeks 
- 
2 to 3 weeks of run-in 
- 
8 weeks of treatment 
Design 
The study is a prospective, randomized, multicenter, adaptive design, double 
blinded, placebo-controlled study, to evaluate the efficacy and safety of 
Vibrant Capsule vs. placebo in relieving constipation in subjects with 
Chronic Idiopathic Constipation. 
 
Three arms will be assessed:  
- 
Vibrant Capsule mode A administered 5 times per week 
- 
Vibrant Capsule mode B administered 5 times per week 
- 
Placebo Capsule administered 5 times per week 
The difference between the 2 operating modes is in the vibrating sequence 
during the capsule's operating time. 

 
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An interim analysis will be performed after about 90 evaluable subjects will 
complete 8 weeks of treatment. The following parameters will be assessed: 
primary endpoint, and main safety parameters.  
 
 Depending on the results of the interim analyis: 
 
 The study will be stopped, 
 The study will continue as planned 
 The sample size will be increased, 
 
In addition, the less promising treatment arm will be stopped (Drop-the-
losers design) and continue with the more promising treatment arm on 
1:1 randomization of Vibrant Treatment VS placebo 
 
Method  
Subjects will come for 4 visits: Screening (visit 1), baseline (visit 2), after 4 
treatment weeks from baseline (visit 3) and after 8 treatment weeks from 
baseline (Final visit , visit 4). A total of 8 treatment weeks. 
 
Visit 1 - Screening: Subjects will be screened to the study at the screening 
visit, PAC-QOL questionnaire will be completed. Following this visit,  
subjects will have a run-in time for a period of 2-3 weeks, in which they will 
be instructed to complete a simple subject eDiary each day  which includes 
questions on:  
 Daily BM, SBM, CSBM  
 Change of subject’s diet, if applicable (NOTE: the protocol will not 
ask/require the subjects to change anything in his/her diet)  
 Change in sympotms as: brisol stool consistency, straining, bloating, 
and the other questions in the eDiary    
 Medication 

 
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 AE / change in general health condition  
 
Assessment of subject’s eligibility will be based on 14 consecutive days of 
this eDiary with an average of ≥1 SBM and ≤ 2.5 SBM per week. 
 
Visit 2 - Baseline: After the run-in period, the subjects will return and 
eligibility will be re-assessed. Subjects will be randomized to either Vibrant 
mode A or B  or Vibrant placebo for a treatment period of 8 weeks. Subjects 
will have their first capsule administration on site and will be trained on 
their treatment administration as well as on the usage of the base unit.  
 
Subjects will be instructed to continue completion of the eDiary each day 
until the end of the study. 
 
The first 2 weeks of treatment will be considered as a subjects’ training 
period. 
 
Visit 3 – after 4 weeks of treatment - an on site visit will take place to 
evaluate subject's treatment efficacy and safety. Capsules for additional 4 
weeks of treatment will be dispensed to the subjects. 
  
Visit 4 - Final visit –after another 4  weeks of treatment - an on site visit will 
take place to evaluate subject's treatment efficacy and safety. The base units 
and remaining capsules will be collected.  
PAC-QOL, Ease of use and TSQM questionnaires will be completed. 
During the entire study period, data reporting will be done on an electronic 
Case Report Form (eCRF) and an eDiary. 
 

 
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During the entire study period subjects will be asked to refrain from taking 
any medication or supplement to relieve their constipation. Subjects will 
receive phone calls at least once a week and subject’s compliance will be 
monitored throughout the 8 weeks of the study. 
Subjects will be authorized to use rescue medication after 3 consecutive 
days without a bowel movement. 
 
Endpoints 
Primary endpoints: 
 
Efficacy Endpoints: 
The two primary efficacy endpoints are the CSBM1 success rate, defined as 
an increase from the run-in period of at least one weekly Complete 
Spontaneous Bowel Movement (CSBM) during at least 6 of the 8 weeks of 
treatment, and CSBM2 success rate, defined as an increase from the run-in 
period of at least two weekly Complete Spontaneous Bowel Movement 
(CSBM) during at least 6 of the 8 weeks of treatment. 
 
The study will be deemed successful if either the CSBM1 or the CSBM2 
success rate is statistically significantly higher in the active arm that was 
continued after the interim analysis, than in the placebo arm. 
 
NOTE:  
• 
A spontaneous bowel movement (SBM) is defined as a bowel 
movement that occurs at least 48h after laxative/rescue intake and 
without digital maneuver. 

 
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• 
A complete spontaneous bowel movement (CSBM) is defined as a 
spontaneous bowel movement associated with a feeling of complete 
evacuation by the subject. 
  
 
 
 
Safety Endpoints: 
Safety endpoints include all adverse events related and unrelated to the 
study treatment 
Secondary Efficacy Endpoints: 
 
Secondary efficacy endpoints include:  
• 
Change from baseline in average straining. 
• 
Change from baseline in average stool consistency, using the Bristol 
Stool Scale 
• 
Change from baseline in average bloating. 
 
Additional Secondary Efficacy Endpoints: 
Additional secondary efficacy endpoints include: 
• 
CSBM1 success rate when using the data from the two active arms 
together. 
• 
CSBM2 success rate when using the data from the two active arms 
together. 
• 
SBM success rate, defined as an increase from baseline period of at 
least one weekly Spontaneous Bowel Movement (SBM) during at 
least 6 of the  8 weeks of treatment. 

 
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• 
Incidence of Rescue Medication use during the treatment period 
• 
Change from baseline in weekly number of Spontaneous Bowel 
Movement (SBM). 
• 
Change from baseline in weekly number of Complete Spontaneous 
Bowel Movement (CSBM). 
• 
Rate of SBM ≤ 24 hours after first dose 
• 
Change from baseline in average abdominal gas. 
• 
Change from baseline in average abdominal pain. 
• 
Change from baseline in abdominal discomfort. 
• 
Time to occurrence of spontaneous bowel movement after first 
capsule activation. 
• 
Treatment satisfaction score using the TSQM (Treatment 
Satisfaction Questionnaire for Medication) 
• 
Change from baseline in quality of life using the PAC-QOL (Patient 
Assessment of Constipation Quality of Life) questionnaire.  
 
Subject 
Population 
Subjects with Chronic Idiopathic Constipation refractory to existing 
treatments.  
Inclusion 
criteria 
1. Subjects aged 22 years and older 
2. Subjects with Chronic Idiopathic Constipation (CIC) according to 
Rome III criteria and who have not experienced relief of their 
symptoms from available therapies (osmotic and stimulant laxatives 
used for at least one month at recommended dose) 
3. Subjects with an average of ≤2.5 Spontaneous Bowel Movements 
(SBM) per week and ≥1 SBM per week  
4. Normal colonoscopy performed within 5 years prior to study 
participation, unless the subjects are <50 years old and without alarm 
signs and/or symptoms 

 
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5. Subject signed the Informed Consent Form (ICF) 
6. Female subjects must have a negative blood pregnancy test during 
screening, confirmed by a negative urine pregnancy test during 
baseline and must not be lactating prior to receiving study 
medication. For females of child-bearing potential, a hormonal (i.e., 
oral, implantable, or injectable) and single-barrier method, or a 
double-barrier method of birth control must be used throughout the 
study. All other female subjects must have the reason for their 
inability to bear children documented in the medical record [i.e., 
tubal ligation, hysterectomy, or post-menopausal (defined as a 
minimum of one year since the last menstrual period)]; in these 
circumstances, a pregnancy test will not be necessary.  
 
Exclusion 
criteria 
1. History of complicated/obstructive diverticular disease 
2. History of intestinal or colonic obstruction, or suspected intestinal 
obstruction. 
3. History of significant gastrointestinal disorder, including any form of 
inflammatory bowel disease or gastrointestinal malignancy (celiac 
disease is accepted if the subject has been treated and is in remission) 
4. History of gastroparesis 
5. Use of any of the following medications:  
o Medications that may affect intestinal motility, prokinetics, 
anti-Parkinsonian medications, opiates, opioids, calcium-
channel blockers, aluminum/magnesium hydroxide 
o With the exception of antidepressants, thyroid or hormonal 
replacement therapy, when the subject has been on a stable 
dose for at least 3 months prior to enrollment. 

 
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6. Clinical evidence of significant respiratory, cardiovascular, renal, 
hepatic, biliary, endocrine, psychiatric or neurologic disease. 
7. Presence of cardiac pacemaker or gastric electrical stimulator. 
8. History of, or current eating disorders, such as anorexia, bulimia, or 
compulsory overeating. 
9. Diagnosis 
of 
mega-rectum 
or 
colon, 
congenital 
anorectal 
malformation, clinically significant rectocele, history of intestinal 
resection (with an exception for appendectomy, cholecystectomy and 
inguinal hernia repair), history of bariatric surgery or evidence of any 
structural abnormality of the gastrointestinal tract that might affect 
transit 
10. History of Zenker’s diverticulum, dysphagia, Barrett's esophagus, 
esophageal stricture or achalasia 
11. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs): 
chronic use is defined as taking full dose NSAIDs more than three 
times a week for at least six months. Subjects on cardiac doses of 
aspirin may be enrolled in the study  
12. Subjects with pelvic floor dysfunction/defecatory disorder, based on 
subject history 
13. Participation in another clinical study within one month prior to 
screening. 
14. Women who are pregnant or lactating 
15. Use of any medication for constipation relief during the study, except 
as rescue medication, as indicated by study rules 
16. Inability to use an electronic daily Diary (on a computer, phone 
application, tablet or other electronic device) to report bowel 
movements, symptoms and medication usage 
17. Subject participated in a previous Vibrant study 

 
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18. Subjects planning to undergo MRI during the study 
19. Any known allergy to soybean or beeswax or Calcium Carbonate  
20. Any other condition which in the opinion of the investigator may 
adversely affect the safety of the subject or would limit the subject's 
ability to complete the study 
Statistical 
analysis  
Study Hypotheses: 
In this study, we will test the following hypotheses: 
 
H0 : Pa1-Ps1=0 
 
H1: Pa1-Ps1≠0 
Where Pa1 is the CSBM1 success rate in the selected active arm, 
and Ps1, the CSBM1 success rate in the placebo arm. 
AND: 
 
H0 : Pa2-Ps2=0 
 
H1: Pa2-Ps2≠0 
Where Pa2 is the CSBM2 success rate in the selected active 
arm, and Ps2, the CSBM2 success rate in the placebo arm. 
 
Sample size: 
A sample size is calculated to test the null hypothesis. Calculations (using 
SAS® proc power) show that a sample size of 150 subjects (60 in the 2 
study arms that will be continued till the end of the study, and 30 for the 
study arm that will be dropped at the interim analysis), would provide 80% 
power at  a study wise 5% level of significance (two-sided), i.e. 2.5% for 
each one of the primary endpoints to detect a difference of 25% in the 
success rate, assuming a success rate of 15% in the placebo arm.  

 
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The sample size will be increased to at least 168 subjects (67 in the 2 study 
arms that will be continued till the end of the study, and 34 for the study 
arm that will be dropped at the interim analysis) to account for a potential 
10% of drop-out rate. 
 
Main Efficacy Analysis: 
 
The subject’s CSBM1 success status (i.e. if the subjects achieve an increase 
from baseline of at least 1 weekly CSBM during at least 6 out of the 8 
treatment weeks will be presented in tabular form by study arm, along with 
95% Wilson score Confidence Intervals (CI) and will be compared between 
the study arms with a Cochran-Mantel-Haenszel test controlling for center. 
 
The CSBM2 success rate will be analyzed in the same manner.  
 
 
 

 
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5. 
INTRODUCTION 
 
This document is a clinical research protocol and the described study will be conducted in compliance with the protocol, standards of 
Good Clinical Practices and associated regulations, and all applicable research requirements. 
 
6. 
BACKGROUND 
 
Chronic constipation is a common gastrointestinal disorder in the general population. It is estimated that chronic constipation affects 
between 2 and 27% of the population. A majority of chronic constipation sufferers are women, who represent three-fourths of those 
affected1. 
Constipation may be primary (Chronic Idiopathic Constipation (CIC), Irritable Bowel Syndrome with Constipation (IBS-C)) or 
secondary to other factors (such as drugs like opioids, colorectal cancer, diabetes, Parkinson’s disease or spinal cord injury). It is 
estimated that 100 million adults in the United States (US) have chronic pain2.  
There is no widely accepted definition of chronic constipation. Although physicians often define constipation based on stool 
frequency, subjects experience constipation as a multi-symptom disorder that includes infrequent bowel movements, hard or lumpy 
stools, straining, bloating, a feeling of incomplete evacuation after a bowel movement and abdominal discomfort3. The Rome 
Foundation has created symptom-based diagnostic criteria for chronic constipation. To meet the definition of chronic constipation, the 
criteria must be fulfilled for the prior 3 months with symptom onset at least 6 months prior to diagnosis4.  
Chronic constipation impacts quality of life and is perceived by subjects as a severe disease3.  Adding to the burden of disease, 
constipation is among the ten most expensive gastrointestinal diseases in terms of direct and indirect healthcare costs5. A recent 
systematic review of the disease burden of IBS and CIC found the attributable direct costs of IBS to range from approximately $1,600 
to $7,500 per subject-year, whereas the attributable direct costs of CIC range from approximately $1,900 to $7,500 per subject-year6. 

 
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Although a variety of treatment options are available for chronic constipation, subjects have reported low satisfaction with current 
treatment alternatives in multiple published studies.  Thus, there is a need for additional therapeutic options that address subject 
symptoms and preferences. 
Constipation Management  
The American Gastroenterological Association (AGA) has established a treatment algorithm for constipation that provides multiple 
therapeutic steps depending on severity of symptoms.  See http://www.gastrojournal.org/article/S0016-5085(12)01545-4/pdf. The first 
step in the treatment of constipation focuses on lifestyle modification with three main parameters: adequate fluid intake, a high fiber 
diet and regular physical activity. 
Fiber absorbs water, increases stool bulk, and in doing so stimulates the bowel to decrease stool transit time and ease evacuation.  
Medicinal and dietary fiber supplements, such as psyllium, can be added to the high fiber diet or used as primary therapy. 
If lifestyle modification does not produce satisfactory results, subjects have access to a number of FDA-approved products (Food and 
Drug Administration), available both over the counter (OTC) and by prescription. Stool softeners (docusate sodium, docusate calcium) 
act by decreasing surface tension to allow water to enter the bowel more readily, making the stool softer, which makes it easier and 
less painful to pass. However, there is currently limited data on the efficacy of stool softeners in subjects with constipation1.  
Osmotic laxatives are also available, including polyethylene glycol (PEG), lactulose, magnesium hydroxide, magnesium citrate, 
magnesium sulfate, and sodium phosphate. PEG and lactulose have been shown to improve stool frequency and stool consistency1,6,7.   
Osmotic laxatives contain poorly absorbed ions or molecules that retain water in the intestinal lumen. Although effective, they can 
cause bloating and cramping.  In addition, due to their mechanism of action, they should be used with caution in older adults and in 
subjects with renal impairment because of the risk of dehydration and electrolyte disturbances. 
Stimulant laxatives include senna, bisacodyl or sodium picosulphate. They induce fluid and electrolyte secretion by the colon or 
induce peristalsis in the colon, thereby producing a bowel movement.  
Recent advances in research have resulted in new classes of medication for the treatment of constipation, available on prescription. 
For example, linaclotide is an agonist of guanylate cyclase-C receptors, and increases chloride, bicarbonate and fluid secretion into the 

 
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intestinal lumen, lubricating the stool and accelerating gastrointestinal transit. Linaclotide was FDA-approved in 2012 for CIC and 
IBS-C. Adverse events include diarrhea, which leads to discontinuation of the medication in approximately 5% of subjects8.  In total, 
8% of subjects in linaclotide clinical trials discontinued due to adverse events, and 27% had their dose reduced or suspended 
secondary to adverse reactions, the majority of which were diarrhea or other gastrointestinal adverse reactions.  See 
http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2014/202811s004lbl.pdf 
 
Lubiprostone is approved for use in women with IBS-C and in men and women with CIC, as well as opioid-induced constipation in 
subjects with non-cancer pain. It is a selective chloride channel activator, increasing ion and fluid secretion. The main adverse events 
associated with lubiprostone are mild to moderate nausea and diarrhea2,9.  Approximately 29% of subjects who received lubiprostone 
24 mcg twice daily in clinical trials experienced nausea; 4% of subjects had severe nausea while 9% of subjects discontinued 
treatment due to nausea. Approximately 12% of subjects who received lubiprostone 24 mcg twice daily experienced diarrhea; 2% had 
severe diarrhea while 2% discontinued treatment due to diarrhea.  In addition, it has been reported to cause dyspnea, which was 
reported in 2.5% of the treated chronic idiopathic constipation population and 0.4% in the treated IBS-C population. Although not 
classified as serious adverse events, some subjects discontinued treatment because of this event. These events have usually been 
described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within 30-60 minutes 
after taking the first dose. They generally resolve within a few hours after taking the dose, but recurrence has been frequently reported 
with subsequent doses.  See http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2008/021908s005lbl.pdf.   
In subjects with severe chronic constipation, surgery may be considered; however, it is generally limited to use in the most severe 
cases after medical management has failed to provide adequate relief.  In subjects with severe incapacitating slow transit constipation, 
colectomy with ileorectal anastomosis can improve constipation and related symptoms10,11. 
In summary, while there are a variety of treatments available for constipation, there is currently no satisfactory treatment for many 
constipated subjects:  a US study showed that 47% of constipated subjects are not completely satisfied with their current constipation 
treatment3, while a European study showed that only 27% of European subjects are satisfied with current treatment options5. 
Furthermore, many subjects become refractory to one or more OTC laxatives with chronic use, which may cause frustration for both 
the clinician and the subject, and ultimately leads many subjects to abandon therapy and remain dissatisfied with their condition2. 
Nearly 90% of subjects express interest in new therapies12.   

 
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7. 
DEVICE NAME AND INTENDED USE 
7.1 
Device Name 
 
 
Vibrant Capsule 
 
7.2 
Intended Use 
 
 
The Vibrant Capsule is an orally administered non-biodegradable vibrating capsule intended to be prescribed for the treatment of adult 
chronic idiopathic constipation in patients who have not experienced relief of their symptoms from available therapies (osmotic and 
stimulant laxatives used for at least 1 month at recommended dosage). The capsule achieves its purpose by mechanically inducing a 
bowel movement in the large intestine. 
 
 
 
8. 
DEVICE DESCRIPTION 
 

 
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The Vibrant Capsule is designed to mechanically induce a peristaltic wave in the large intestine, thus aiding in relieving constipated 
subjects. Constipation relief is achieved by the capsule’s vibrations impinging on the gastrointestinal wall, consequently inducing 
peristaltic activity which promotes transit and facilitates defecation. 
 
The Vibrant Capsule has several important features: 
 Small Dimensions. 
 Easy to swallow (smooth shell). 
 Mode of Operations - defines the vibration start time, vibration duration, sequence, and force and rest time between the 
vibration cycles. In this study 2 different Modes of Operations will be evaluated. 
The capsule is activated by an electromagnetic signal which carries an Activation Code using the activation base unit prior to 
swallowing the capsule. 
 
8.1 
Capsule 
8.1.1 
Vibrant Active:  
The Vibrant non-biodegradable capsule is comprised of a flat motor, electronic card and batteries, all encapsulated in a 2-piece shell 
(please refer to Figure 1 below). The capsule is activated by an electromagnetic signal which carries the Activation Code using the 
activation base unit, prior to swallowing the capsule. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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The capsule dimensions are: 
 
Length: 24.2 ± 0.1 mm 
 
Diameter: 11.3± 0.1 mm 
 
The capsule shell is made of a well-known biocompatible material: PC MAKROLON 2458. 
Shell is hard & non-biodegradable.  
Before starting the vibrating action and to ensure the capsule has arrived at the large intestine, the company has integrated a tightly 
controlled vibrating algorithm, i.e. multi vibration sessions.  
 
 
 
The capsules are packaged in a blister (cf. Fig. 2 below).  
 
 
 
Figure 2.  The blister  
 
8.1.2 
Vibrant Placebo:  
The placebo capsule is a white colored, softgel biodegradable capsule filled with soybean oil, beeswax and Calcium Carbonate, which 
is visually similar to the Vibrant active capsule. 
 
 
Figure 1. The capsule and components 

 
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8.1.3 
 Accessory: activation base unit 
 
A user friendly activation base was developed by the company for subject use 
(please refer to Fig 3 below). The activation base (or base unit) is meant to be used at home by subjects. The base unit is easy to use 
and requires a simple training before taking it home. Subjects will activate the capsule themselves at home.  
 
 
 
The activation base is composed of: 

An electronic circuit board  

Electromagnetic antenna bedding the capsule.  
The Activation base is provided in a protective package containing the following (see Fig.3): 
- 
Base Unit 
- 
USB cable  
- 
AC/DC USB adapter  
- 
Instructions for use 
 
 
 
 
 
1. Base Unit 
2. USB cable  
3. AC/DC USB adapter  
 
 
 
 

 
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1. Base Unit Cover 
2. The "Ready" Green Light Indicator 
3. The Designated Groove for Capsule 
4. The "X" Red Light Indicator 
5. The "ON" Green Light Indicator 
 
 
 
 
Figure 3. Activation base: description of components and image 
 
 
 
 
Setting up the base unit 
First, the user connects the base unit to an electricity outlet, with the USB cable and AC/DC adapter. The green “ON” light on the base 
unit turns on indicating, that the base unit is connected to electricity  
 
 
 
8.2 
Capsules Activation 
1. The capsule will be placed in the designated groove in the center 

 
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2. The capsule is ready to be swallowed by the subject after it stops to vibrate in the groove  
3. Capsule will reach the large intestine and start predefined vibrating program, inducing peristaltic activity.  
4. Capsule will be extracted from the body during normal bowel movement. 
 
Additional details can be found within the Investigator's Brochure (Document # 114CLD,) the Instruction For Use (IFU) for the 
vibrating capsule (Document # 117LAB) and User Manual (Document # 113CLD). 
 
9. 
RISKS & BENEFITS 
 
The Vibrant Capsule is designed according to international standards for medical devices. Compliance with these standards ensures 
that the device can be used safely in human beings.  
Biocompatible materials are used for the vibrating capsule components. The use of biocompatible materials should protect the subject 
of any hazardous from possible adverse events.  
 
The device classification according to ISO10993-1 and FDA’s guidance Use of International Standard ISO-10993-1:2009, 
"Biological Evaluation of Medical Devices Part 1: Evaluation and Testing" :  Draft Guidance for Industry and Food and Drug 
Administration Staff (“FDA Biocompatibility Guidance”) is as follows: 
Category:  Surface device. 
Contact duration: permanent contact (>30 days) 
Contact:  breached or compromised surfaces. 
 
According to this classification, the following tests were performed, all of which had passing results: Cytotoxicity Study Using the 
ISO Elution Method, Bacterial Reverse Mutation Study, ISO Intracutaneous Study in Rabbits, ISO Systemic Toxicity Study in Mice, 
ISO Guinea Pig Maximization Sensitization Test, Mouse Peripheral Blood Micronucleus Study, Genotoxicity: Mouse Lymphoma 
Assay, ISO 10993-18 - Chemical Characterization 
 

 
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A biological risk assessment of the Vibrant Capsule has also been performed by NAMSA in accordance with ISO 10993-1:2009 
requirements. The purpose of this study is to use information from biological safety studies of the materials used to manufacture the 
Vibrant Capsule, chemical characterization data, and biological safety test results on the device to support and demonstrate the overall 
biological safety of the Vibrant Capsule. This assessment focuses on the requirements of ISO 10993-1:2009, EN ISO 14971:2012, 
FDA General Program Memorandum #G95-1 and the 2013 Draft Biocompatibility Guidance, and the European Union Medical 
Device Directive 93/42/EEC. 
 
The company also evaluated the mechanical, structural integrity, electrical safety, shelf life and other characteristics of the Vibrant 
Capsule when subjected to clinical use conditions.  
 
Testing performed included the following:  
a. Visual inspection 
b. Dimensional verification of the capsule 
c. Mode of Operation test 
d. pH Resistance test 
e. Mechanical integrity test  
f. Electrical safety and EMC  
g. Environmental and transportation test. 
 
   
9.1 
Risks 
 
The Vibrant capsule has been designed to mechanically induce a normal peristaltic wave in the large intestine, thus aiding in relieving 
constipated subjects.  
 

 
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The capsule moves through the gastrointestinal system, without interacting with any other body system and does not deliver 
medication of any kind. The Vibrant capsule targets basic pathophysiological factors contributing to chronic constipation by inducing 
intrinsic contractile activity without using chemical supplements. The capsule operates without any biological interference. 
 
The capsule has been sealed up by using a biocompatible shell and will remain sealed up until it has been excreted out of the human 
body, thus ensuring that, as it transits the gastrointestinal tract, there will be no unwanted outputs of energy or substance. This has 
been evaluated and confirmed in preclinical testing (please refer to the study investigational brochure). 
 
The capsule coating (a biocompatible and widely used shell) protects the subject from any potential hazards that might be associated 
with its contents. The energy of the batteries is harmless and cannot leak while the capsule remains intact (break force was tested up to 
60 Kgf/cm²). The capsule was tested for Safety and EMC 60601 trials. No ionizing radiation is emitted and no thermal energy 
generated. 
 
Device manufacturing and assembly is done in an ISO 13485:2003 facility. 
 
 
Adverse events 
Potential adverse events associated with the use of this device may include abdominal pain, blood in stool and diarrhea. In rare cases 
obstruction may occur  
 
Warnings: 
 The Vibrant Capsule has not been evaluated for safety and compatibility in the MR (magnetic resonance) environment. It has 
not been tested for heating, migration, or image artifact in the MR (magnetic resonance) environment. The safety of the 
Vibrant Capsule in the MR (magnetic resonance) environment is unknown. Scanning a subject who has this device may result 
in patient injury  
 before using this product  please read the clinical applications and risks associated listed in the Instruction for Use (IFU)  
 If you have reasonable doubt concerning the integrity of a Vibrant capsule, it should not be used and discarded 
 A Vibrant capsule should not be ingested after its expiration date 
 Avoid biting the Vibrant capsule prior to swallowing 

 
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 After ingesting a Vibrant capsule and until it is excreted, you should not be near any source of powerful electromagnetic fields 
such as one created near an MRI device 
 The capsule should be kept away from implants such as pacemakers, defibrillators, nerve stimulators, and other devices that 
could be affected by proximity to a DC (direct current) magnetic field 
 
If after ingesting a Vibrant capsule you experience any abnormal abdominal pain, nausea or vomiting, you should contact a 
physician immediately  
 
Vibrant capsules must be stored in a safe place, out of the reach of children and/or infants  
 
If a child has accidentally swallowed an unused Vibrant capsule, he/she should be brought immediately to a hospital  
 
Undergoing an MRI while the capsule is inside your body may result in serious damage to your intestinal tract or abdominal 
cavity. If you require an MRI instruct your physician to verify capsule expulsion via abdominal X-ray before undergoing an 
MRI examination  
 
The safety of this device has not been established in pregnancy and/or lactation  
 
The safety of this device in subjects with significant gastrointestinal diverticular disease is unknown  
 
The safety of this device has not been established in adolescents  
 
 
Safety in Animal and Human Clinical Investigations 
 
No safety concern was raised during animal and human clinical investigations. 
 
The animal studies and human investigation studies demonstrated safety of the capsule to support subsequent studies in the 
target population. All capsules were extracted safely with no related serious adverse events and all clinical and laboratory 
results were within normal values. For more details see section 11: Human Clinical Investigations. 
 
9.2 
Benefits 
 
Human Clinical Investigations 

 
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Phase 1, 2a and 3 studies showed clinical benefits with the Vibrant Capsule: the capsule increased the number of weekly SBM / 
CSBM among subjects with constipation and improved constipation symptoms, such as straining, bloating and stool consistency. For 
more details see section 11: Human Clinical Investigations. 
 
 
10. 
ANIMAL INVESTIGATIONS 
 
Two animal studies were conducted using the Vibrant Capsule: 
The initial study was approved by Helsinki committee for animal studies (approval no. IL-089-09-2008), and performed at the 
Technion – Israel Institute of Technology. The study was overseen by the committee for the supervision of animal experiments. Study 
objectives were to evaluate the safety and physiological effect of the vibrating capsule in 3 dogs. On study initiation the dogs were 
given sham capsules to evaluate defecation time, clear passage of the capsule and safety. After approximately 1 week each animal 
swallowed a vibrating capsule in different intervals starting from 3 days to two week intervals during a 6-month period. 
 
Final analysis showed that the capsules were safe for use – they were not damaged even when bitten by the dogs. There was no 
evidence of any discomfort or adverse effects on the dog’s health. Evidence of effectiveness of the capsule was indicated by reduced 
defecation time with the vibrating capsule compared to the Sham, without creating artificial constipation conditions in the dog's 
gastrointestinal tract.  
 
The second study was conducted at the Rambam Hospital in Haifa, Israel.  The study was approved by the Helsinki committee for 
animal trials (approval no. IL-130-11-2009).  
Study objectives were to evaluate the safety and physiological effect of vibrating capsule in 2 dogs. On study initiation the dogs were 
given sham capsules to evaluate defection time, clear passage of the capsule and safety. After approximately 2 days each animal 
ingested a vibrating capsule every second day for two weeks' time and was followed for an additional month. Capsule delay time was 
adjusted for the animal model (8 hours for a smaller dog and 16 hours for a bigger dog). Clinical observations were recorded by lab 
personnel to ensure no signs of distress, pain, vomiting or irregular behavior. In addition X-ray was used to verify capsule location and 

 
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vibrating movement. The time of defecation and stool consistency were recorded. The capsules were retrieved from the dog 
stools. Capsule integrity was confirmed; capsules were whole with no defects in seal, no ruptures, no shell cracks or any other 
damage.   
 
In all the animals the capsule were passed by the dogs without any adverse effects to the dog and/or any damage to the capsules. There 
was no evidence that the capsule's colon transit or its vibration caused any adverse effect to the dog's physical health and behavior.  
Evidence of effectiveness of the capsule was indicated by reduced defecation time with the vibrating capsule compared to the Sham. 
Moreover, one dog suffered from constipation for 4 days (not induced by the study), which was relieved by the vibrating capsule.  
 
11. 
HUMAN CLINICAL INVESTIGATIONS 
 
Vibrant Ltd. has completed five human clinical investigations. 
 
Total Exposure – Human Clinical Investigations 
The human clinical investigations performed by Vibrant exposed a total of 449 participants, healthy or constipated, to either the 
Vibrant Capsule or the Sham Capsule. 
In total, 259 subjects received the Vibrant Capsule.   
 
The remaining 190 subjects who participated in clinical investigations received the Sham Capsule. 
 
Phase 1 clinical investigation – healthy volunteers 
 
An initial clinical study was approved and initiated in 2 sites in Israel (Tel-Aviv Sourasky Medical Center and The Holy Family 
Hospital, Nazareth), from March 8 to 24th, 2011. The study was initially approved for use in 6 healthy volunteers in order to evaluate 
the safety of the Vibrant Capsule in a prospective, open-label, single group study. 
Six consecutive healthy volunteers (3 men and 3 women) ages 21 to 41 years, all fulfilling the exclusion/exclusion criteria, were 
enrolled in the study. During the Baseline study visit, subjects were evaluated for eligibility and went through physical examination, 

 
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vital sign measurements, ECG measurements and blood tests, which were all within the normal values. Eligible subjects were asked to 
take 1 vibrating capsule by the study personnel.  Subjects were followed for 7 days on their normal bowel movements and excretion of 
the capsule.  One week following the baseline visit, subjects returned for a visit and repeated the physical examination, vital sign 
measurements, ECG measurements and blood tests.  
All capsules were evacuated from the body, along with stool, safely with no adverse events. Average time for capsule excretion was 
2.2 days (2 days for 4 subjects, 1 day for 1 subject, and 6 days for 1 subject). All clinical and laboratory results were within normal 
values.  Thus, this preliminary study demonstrated safety of the capsule to support subsequent studies in the target population. 
 
Phase 2a clinical investigation  
 
V-111: "A Prospective, open-label, safety evaluation of the Vibrating capsule in aiding reliving constipated individuals" 
The study was conducted in the Departments of Gastroenterology and Hepatology at the Tel-Aviv Sourasky Medical Center and at The 
Nazareth Holy Family Hospital, beginning in July 2011.  
Study design: Prospective, Open Label, Single Group Assignment, Safety pilot Study.  
Objective: safety  
Study population: 26 Subjects with Chronic Constipation or Irritable Bowel Syndrome With Constipation 
Endpoints: The primary endpoint was safety, assessed descriptively by summarizing adverse events (AEs), clinical laboratory test 
results, vital sign measurements, and ECG measurements.  
The secondary endpoint was efficacy, determined as an increase of more than one spontaneous bowel movement (SBM)/week during 
the 7.5 weeks of treatment compared to the 2-week run-in period.  The number of spontaneous bowel movements was calculated as a 
weekly average. 
Methods: 2 capsules/ week for 8 weeks of treatment 
Each capsule was collected from the stool by subject, before the next capsule was administrated.  
Results: Safety - 15 AEs were observed during the study for 8 subjects (36.4% of the subjects), none of them was serious. 8 AEs were 
possibly related to study device for 5 subjects (22.7% of the subjects) 
Efficacy - Mean increase of SBM =1.78, Std=1.09, p<0.001 
Conclusion: The Vibrant capsule found to be safe.  
 

 
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The next study was conducted to evaluate safety and efficacy (V-179) 
 
 
 
Comparative clinical investigation  
 
V-179: "A multinational, multicenter, prospective double-blind, sham controlled, randomized study to assess the performance, efficacy 
and safety of Vibrating Capsule medical device in aiding relieving Constipated Individuals" 
 
The study was conducted in 16 sites (10 in the USA and 6 in Israel) from Aug 2014 until Jan 2016. 
Study design: The study was a multinational, multicenter, prospective, randomized, double-blind, sham controlled trial. Identical 
capsules were used in the sham arm, eliminating only the activation of the capsule in the large intestine, for the sham group.  
Study objectives: The purpose of the investigation was to evaluate the efficacy and safety of the Vibrant Capsule compared to a sham 
non-vibrating capsule on spontaneous bowel movements 
Study population: 154 (77 in each group) Subjects with Chronic Idiopathic Constipation according to Rome III criteria who failed 
currently available therapy (osmotic and stimulant laxatives which was used for at least one month at recommended dose).  
 
Endpoints: the primary endpoints were safety and efficacy.  
Safety: related AE's/SAE's 
Efficacy: an increase of at least 1 weekly SBM from baseline in at least 6 (of 8) weeks during the treatment period and 
improvement of at least 1 point in PAC-QOL from baseline.  
 
The secondary endpoints were:  
1. Change from baseline in weekly SBM 
2. Time from fist Vibrant pill intake (either active or sham) to first SBM 
3. Number of rescue therapy uses during the treatment period 
4. Change from baseline in PAQ-QOL score 
5. Change from baseline in stool consistency as classified with the Bristol stool chart 

 
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Methods: 2 capsules/ week for 8 weeks of treatment 
Results: A total of 252 Adverse Events (AE’s) were reported in the active arm and 183 in the sham arm. 2 AE’s were considered serious: 
1 in the active arm - a fractured nose considered not related and 1 in the sham arm - a viral syndrome considered not related 
 
A summary of adverse events severity is provided below. 
 
 
 
 
  
  
Vibrant Group 
Sham Group 
Number 
of reports 
Number of 
subjects 
IncidenceŦ 
Number of 
reports 
Number of 
subjects 
IncidenceŦ 
Any Adverse Event 
252 
51 
62.20% 
183 
44 
54.32% 
Mild 
203 
42 
51.22% 
136 
34 
41.98% 
Moderate 
47 
21 
25.61% 
44 
18 
22.22% 
Severe 
1 
1 
1.22% 
1 
1 
1.23% 
Adverse Event Leading 
to Discontinuation 
0 
0 
0% 
0 
0 
0% 
Ŧ The incidence is defined as the percent of subject’s reporting a specific AE at least once, out of the total number of subjects in that group. 
 
The primary efficacy endpoints results are:  
1. SBM: 45.45% vs. 46.75% in Vibrant and Sham respectively (p= 0.8552).  
2. In a sub-group analysis 50% of the population (N=77) (Pts who have avg of 1-2.5 SBM at baseline): SBM: 59.5% vs. 47.5% in 
Vibrant and Sham respectively (p=0.2933). CSBM: 35.1% vs. 15.0% in Vibrant and Sham respectively (p=0.0406) 
3. Improvement of QOL from baseline: 26.1% vs. 32.0% in Vibrant and Sham respectively (p= 0.4409) 
 
The secondary endpoints results are: 

 
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1. Change from baseline in stool consistency: Average change from baseline in Bristol score: 0.9 vs. 0.6 Vibrant and Sham respectively 
(p=0.1303) Sub-group analysis - Average change from baseline in Bristol score: 1.1 vs 0.6 Vibrant and Sham respectively (p=0.0428) 
2. Change from baseline in bloating: Average change from baseline in Bristol score: -1.8 vs. -0.8 Vibrant and Sham respectively 
(p=0.0345) Sub-group analysis - Average change from baseline in bloating: -2.0 vs -0.5 Vibrant and Sham respectively (p=0.0043) 
3. Change from baseline in straining: Average change from baseline in Bristol score: -2.3 vs. -1.5 Vibrant and Sham respectively 
(p=0.0824) Sub-group analysis - Average change from baseline in straining: -2.8 vs -1.3 Vibrant and Sham respectively (p=0.0082) 
4. Responders from both arms used significantly less rescue medication than patients who were not responders (p<0.0001 for Vibrant 
group, p=0.0002 for Sham): in the Vibrant group, responders took a total of 40 days of rescue medication, and non-responders took 
a total of 272 days. This confirms that responders were positively affected by the Capsule and needed less medication use. When 
comparing the Vibrant and Sham groups, there was no overall significant difference in rescue usage (p=0.5626).  
 
 
Summary results of Subgroup Analysis: 
For the moderate to severe patients, when using the endpoint CSBM (increase of at least 1 CSBM/week for at least 6 out of 8 weeks of 
treatment), the sham response rate is significantly reduced, and the results reach significance (35.1% vs. 15.0%, p=0.0307). Multiple 
symptoms were significantly improved in the Vibrant arm, compared to sham: the Bristol Stool Score, straining and bloating. The 
Vibrant Capsule showed two to three times the magnitude of effect of the sham on each of these endpoints. Other subgroups (mild 
constipation and very severe constipation) were moderately improved for endpoints but were never negatively impacted by the Vibrant 
Capsule 
 
Conclusions: The Vibrant capsule found to be safe and effective in sub-group (average weekly SBM _1.1 and <2.5 at baseline) compared 
to sham.  
 
Additional study was planned for assess safety and efficacy in an increased administration (V-240) 
 
V-240: "A prospective, multicenter, randomized, double-blind, Sham-controlled study to assess the efficacy and safety of the Vibrant 
capsule administered 5 times per week" 
The study was conducted in 25 sites in the USA from Feb 2017 until Jan Dec 2017. 
 
Study design: This study is a prospective, adaptive, multicenter, randomized, double-blind, Sham-controlled study  

 
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Study objectives: the purpose of this study is to assess the efficacy and safety of the Vibrant capsule administered 5 times per week. 
Study population: 182 Subjects with Functional Constipation refractory to existing treatments with an average of ≥1 and <3 
SBMs/week at baseline 
Endpoints: the primary endpoint were safety and efficacy.  
Safety: related AE's/SAE's 
Efficacy: an increase of at least 1 and 2 weekly CSBM from baseline in at least 6 (of 8) weeks during the treatment period  
The secondary endpoints were:  
1. Change from baseline (run-in period) in average straining. 
2. Change from baseline (run-in period) in average stool consistency, using the Bristol Stool Scale 
3. Change from baseline (run-in period) in average bloating. 
4. SBM success rate, defined as an increase from the run-in period of at least one weekly Spontaneous Bowel Movement (SBM) 
during at least 6 of the 8 weeks of treatment. 
 
Methods: 5 capsules / week for 8 weeks of treatment 
Results: A total of 88 Adverse Events (AE’s) were reported in the active arm and 50 in the sham arm. 2 AE’s were considered serious, 
1 in the Active arm - a traumatic fracture of pelvis considered not related and 1 in the Sham arm - anxiety attack considered not related. 
 
A summary of adverse events severity is provided below. 
 
  
  
Vibrant Group 
Sham Group 
Number of 
reports 
Number of 
subjects 
IncidenceŦ 
Number of 
reports 
Number of 
subjects 
IncidenceŦ 
Any Adverse Event 
88 
37 
41.57% 
50 
23 
24.73% 
Mild 
44 
21 
23.60% 
26 
16 
17.20% 
Moderate 
43 
19 
21.35% 
24 
14 
15.05% 
Severe 
1 
1 
1.12% 
. 
. 
. 
 
 
The primary efficacy endpoints results are: –  

 
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1. At least 1 additional CSMB from baseline: 26.4% vs. 35.8% in the active arm and sham arm, respectively (ITT).  
2. At least 2 additional CSMB from baseline: 17.9% vs. 28.2% in the active arm and sham arm, respectively (ITT). 
 
According to the response rate of additional 1CSBM in this study, the increase of the administration frequency to 5 capsules per week 
contribute to the sham group (35.9%) while the active group shows 26.9 % of responder's rate (ITT). The data indicates that the 
Vibrant sham (i.e., Vibrant capsule without vibrations) is an active control, not a placebo. The Vibrant sham performs better than 
would be expected for a passive control. The capsule shape, size, and persistence in the GI tract is part of the Vibrant therapeutic 
effect in addition to the vibration  
 
An important pattern was found between Frequency of CSBM and the actual time of vibration during the day. The pattern is important 
to understand the mechanism of action of the Vibrant capsule and its effect on SBM/CSBM. A clinical correlation was found in this 
study between the time of vibration and CSBM (graph 1).  CSBM frequency is higher in the active arm compared to the sham arm 
during vibrating time as shown in the graph, and exactly correlated to the time of vibration as preprogrammed for the capsule (1st 
peak) around 8-12 hours from administration. In addition, the active capsule effect is shown again 24 hours after activation of same 
capsule (2nd peak around hour 34-36) and suggest that there is a residual effect of the capsule vibration, (graph 1). 
 
Subjects in the sham group can be clearly identified in their behavior, as they report CSBM immediately after capsule swallowed (time 
0 in the above graph). In addition, the sham response drops dramatically the next morning, (hours 34-36), as no additional capsule was 
administrated that morning, while Vibrant active arm is showing superiority during that time (24 hours from last vibration). 
The benefit to subjects during vibration time is clearly shown in the graph below. The percentage of CSBM is higher in the active group 
than in the sham group, during vibration time (see Vibrant edge in graph 2) 
 
Graph 2 Correlation between vibration and CSBM 
 
Conclusions: 

 
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 Clean safety profile was maintained as in the previous studies. 
 Minimal AEs were reported during the 8 weeks of treatment, and all those reported were either mild or moderate. 
 A clinical correlation was found in this study between the time of vibration and Frequency of CSBM.   
 CSBM frequency during the capsule's vibrating time is higher for active arm compared to the sham arm, and exactly correlated 
to the time of vibration and near vibration time, as preprogrammed for the capsule around 8-12 hours from administration. 
 
An additional study (V-300) was planned to assess safety with active capsules in 2 different operation modes. The total vibration time 
of the active capsules will be increased compared to the previous study and the vibration occurs in various areas of the colon (multi 
vibration sessions)  
 
 
 
 
 
 
V-300: " A prospective, multicenter, randomized, double-blind, sham-controlled pilot study to assess the efficacy and safety of various 
vibrating capsule modes" 
 
The study was conducted in 2017- 2018. The enrollment period started on 14/Nov/2017 and the follow-up period was completed for 
the last subject on 14/March/2018.  
Study design: the study is a prospective, adaptive, multicenter, randomized, double-blind, Sham-controlled pilot study. This is a 3- 
arm study: 2 active capsule arms (mode 1 and 2) vs. a sham capsule arm. 
Study objectives: to assess Safety and efficacy of the Vibrant capsule administered 5 times per week 
Study population: 63 Subjects with Functional Constipation refractory to existing treatments with an average of ≥1 and <3 
SBMs/week at baseline. 
Endpoints: the primary endpoint were safety and efficacy.  
Safety: related AE's/SAE's 
Efficacy: an increase of at least 1 and 2 weekly CSBM from baseline in at least 6 (of 8) weeks during the treatment period  

 
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Methods: The administration was 5 capsules/week.  The administration regimen was 1 capsule/day on Mondays, Tuesdays, Thursday, 
Fridays and Saturdays and 2 days off (Sundays and Wednesdays). On Jan 11th 2018 an amendment was approved and the weekly 
capsule administration regimen was changed from 5 per/week to 2 per/week. 
 
Results: The results presented are from subjects treated with 5 capsules/week.  
Safety: A total of 8 and Adverse Events (AE’s) in mode 1 and 2, and 4  in the sham arm. None of the subjects experienced 
SAE's or adverse events related to the Vibrant Capsule that required discontinuation.  
Efficacy: In this study, the active capsule used has multiple vibration sessions compared to single vibration session in the V240 
study and the vibration occurs in various areas of the colon. The results in V300 demonstrate the effect of multiple vibration 
sessions on the responder's rate. Improvement by at least 1 CSBM - 75% of treatment weeks: 71.43% and 33.33% vs. 50% in 
Active mode 1, mode 2 and sham respectively. The improvement form baseline by at least 1 CSBM is higher in the vibrant 
capsule mode 1 than in sham capsule. 
 
A final analysis performed at the end of the study on 61 subject. The improvement form baseline in SBM/CSBM by at least 1 is higher 
in the vibrant capsule (mode 1 and 2) than in sham capsule for administration of 5 capsules/week:  
a. SBM - 50% vs. 47.6% vs. 36.3% in Mode 1, mode 2 and sham, respectively for 5 capsules/week.  
b. CSBM - 50% vs. 38.1% vs. 31.8% in Mode 1, mode 2 and sham, respectively for 5 capsules/week.  
 
In this study the expected correlation between vibration and near vibration time and frequency of CSBM repeated itself, as in the previous 
study (V-240). The capsule used was pre-programmed with multiple vibration session. Hence, 2 peaks are shown: 1st peak around 8-12 
hours from administration followed, a 2nd peak is shown around evening time (graph 3) 
 
 
Graph 3 - Correlation between vibration and frequency of CSBM – multiple vibration sessions 
 
Conclusions: 
 

 
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1. The active capsule found to be safe, even with an increased frequency of vibration (in the 2 different modes), the treatment 
does not result with side effects and retains a very strong safety profile. 
2. The results indicate that multiple vibration sessions improves efficacy and thus the percentage of CSBM was higher in the 
active arm (mode 1) than in the sham arm. 
3. Vibration dose, as an active ingredient to treat CIC patients, is shown to be more effective with patients in V-300 study, 
compared to administration of 5 cap/ week with a single vibration session (lower dose of vibration), in V-240 study.  
4. Mechanism of action is well indicated in V-300 study (capsule with multiple vibration sessions. Hence, 2 peaks are shown 
around vibration time), whereby higher frequency of CSBM is shown during and near vibration time, compared to sham arm. 
5.  The Vibrant capsule stimulates the existing natural mechanism of the GI tract, in a mechanical stimulation fashion only, which 
is different from a drugs, thus no related side-effects are found for the treatment with vibrating capsule 
 
 
12. 
STUDY OBJECTIVE 
 
The objectives are to assess the efficacy and safety of Vibrant capsule administered 5 times per week. 
 
13. 
STUDY ENDPOINTS  
 
13.1 
Primary endpoint 
Efficacy:  
The two primary efficacy endpoints are the CSBM1 success rate, defined as an increase from the run-in period of at least one weekly 
Complete Spontaneous Bowel Movement (CSBM) during at least 6 of the 8 weeks of treatment, and CSBM2 success rate, defined as 
an increase from the run-in period of at least two weekly Complete Spontaneous Bowel Movement (CSBM) during at least 6 of the 8 
weeks of treatment. 
 

 
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The study will be deemed successful if either the CSBM1 or the CSBM2 success rate is statistically significantly higher in the active 
arm that was continued after the interim analysis, than in the placebo arm. 
 
 
NOTE:  
• 
A spontaneous bowel movement (SBM) is defined as a bowel movement that occurs at least 48h after laxative/rescue intake and without 
digital maneuver. 
• 
A complete spontaneous bowel movement (CSBM) is defined as a spontaneous bowel movement associated with a feeling of complete 
evacuation by the subject. 
 
 
Safety Endpoints: 
• 
Safety endpoints include all adverse events related and unrelated to the study treatment 
 
13.2 
Secondary endpoints 
Secondary efficacy endpoints include:  
• 
Change from baseline  in average straining. 
• 
Change from baseline in average stool consistency, using the Bristol Stool Scale 
• 
Change from baseline in average bloating. 
 
Additional secondary efficacy endpoints include:  
• 
CSBM1 success rate when using the data from the two active arms together. 
• 
CSBM2 success rate when using the data from the two active arms together. 
• 
SBM success rate, defined as an increase from baseline of at least one weekly Spontaneous Bowel Movement (SBM) during at 
least 6 of the  8 weeks of treatment. 
• 
Incidence of Rescue Medication use during the treatment period 

 
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• 
Change from baseline period in weekly number of Spontaneous Bowel Movement (SBM). 
• 
Change from baseline period in weekly number of Complete Spontaneous Bowel Movement (CSBM). 
• 
Rate of SBM ≤ 24 hours after first dose 
• 
Change from baseline period in average abdominal gas. 
• 
Change from baseline period in average abdominal pain. 
• 
Change from baseline period in abdominal discomfort. 
• 
Time to occurrence of spontaneous bowel movement after first capsule activation. 
• 
Treatment satisfaction score using the TSQM (Treatment Satisfaction Questionnaire for Medication) 
• 
Change from baseline in quality of life using the PAC-QOL (Patient Assessment of Constipation Quality of Life) 
questionnaire.  
 
 
14. 
STUDY CONDUCT & POPULATION  
 
This study will be performed in accordance with the design and specific provisions of this protocol, in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, that are consistent with Good Clinical Practice (GCP), Title 21 of the 
Code of Federal Regulations (21 CFR), part 812 (Investigational Device Exemptions),  and the applicable regulatory requirements. 
 
14.1 
Inclusion Criteria 
1. 
Subjects aged 22 years and older 
2. 
Subjects with Chronic Idiopathic Constipation (CIC) according to Rome III criteria and who have not experienced relief of 
their symptoms from available therapies (osmotic and stimulant laxatives used for at least one month at recommended dose) 
3. 
Subjects with an average of ≤2.5 Spontaneous Bowel Movements (SBM) per week and ≥1 SBM per week  
4. 
Normal colonoscopy performed within 5 years prior to study participation, unless the subjects are <50 years old and 
without alarm signs and/or symptoms 

 
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5. 
Subject signed the Informed Consent Form (ICF) 
6. 
Female subjects must have a negative blood pregnancy test during screening, confirmed by a negative urine pregnancy test 
during baseline and must not be lactating prior to receiving study medication. For females of child-bearing potential, a 
hormonal (i.e., oral, implantable, or injectable) and single-barrier method, or a double-barrier method of birth control must 
be used throughout the study. All other female subjects must have the reason for their inability to bear children 
documented in the medical record [i.e., tubal ligation, hysterectomy, or post-menopausal (defined as a minimum of one 
year since the last menstrual period)]; in these circumstances, a pregnancy test will not be necessary 
 
 
14.2 
Exclusion Criteria 
1. 
History of complicated/obstructive diverticular disease 
2. 
History of intestinal or colonic obstruction, or suspected intestinal obstruction. 
3. 
History of significant gastrointestinal disorder, including any form of inflammatory bowel disease or gastrointestinal 
malignancy (celiac disease is accepted if the subject has been treated and is in remission) 
4. 
History of gastroparesis 
5. 
Use of any of the following medications:  
 
Medications that may affect intestinal motility, prokinetics, anti-Parkinsonian medications, opiates, opioids, 
calcium-channel blockers, aluminum/magnesium hydroxide 
 
With the exception of antidepressants, thyroid or hormonal replacement therapy, when the subject has been on 
a stable dose for at least 3 months prior to enrollment. 
6. 
Clinical evidence of significant respiratory, cardiovascular, renal, hepatic, biliary, endocrine, psychiatric or neurologic 
disease. 
7. 
Presence of cardiac pacemaker or gastric electrical stimulator. 
8. 
History of, or current eating disorders, such as anorexia, bulimia, or compulsory overeating. 
9. 
Diagnosis of mega-rectum or colon, congenital anorectal malformation, clinically significant rectocele, history of intestinal 
resection (with an exception for appendectomy, cholecystectomy and inguinal hernia repair), history of bariatric surgery or 
evidence of any structural abnormality of the gastrointestinal tract that might affect transit 
10. 
History of Zenker’s diverticulum, dysphagia, Barrett's esophagus, esophageal stricture or achalasia 

 
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11. 
Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs): chronic use is defined as taking full dose NSAIDs more 
than three times a week for at least six months. Subjects on cardiac doses of aspirin may be enrolled in the study  
12. 
Subjects with pelvic floor dysfunction/defecatory disorder, based on subject history 
13. 
Participation in another clinical study within one month prior to screening. 
14. 
Women who are pregnant or lactating 
15. 
Use of any medication for constipation relief during the study, except as rescue medication, as indicated by study rules 
16. 
Inability to use an electronic daily Diary (on a computer, phone application, tablet or other electronic device) to report bowel 
movements, symptoms and medication usage 
17. 
Subject participated in a previous Vibrant study 
18. 
Subjects planning to undergo MRI during the study 
19. 
Any known allergy to soybean or beeswax or Calcium Carbonate 
20. 
Any other condition which in the opinion of the investigator may adversely affect the safety of the subject or would limit 
the subject's ability to complete the study 
 
14.3 
Duration of Study  
 
Study duration includes at least 2-3 consecutive weeks of run-in, followed by 8 weeks of treatment - Total of at least 10-11 weeks. 
The sample size is calculated for about 168 enrolled subjects (depending of the results of the sample size adaptation) including 10% 
drop-outs. 
Actual point of enrollment for the subject is considered the day of first capsule intake. 
 
 
15. 
STUDY TREATMENT 
15.1 
Study Design 
 

 
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The study is a prospective, randomized, multi-center, double-blinded, placebo-controlled, 3- arm clinical study to assess the efficacy 
and safety of the Vibrant capsule, for the treatment of Chronic Idiopathic Constipation. 
 
The objectives are to assess the efficacy and safety of Vibrant capsule administered 5 times a week vs. Placebo in subjects with chronic 
idiopathic constipation. 
 
The study will be performed in about 30 centers in the USA. 
 
Data reporting will be done on an electronic Case Report Form (eCRF). In addition, subjects will fill in daily information about their 
bowel movements, clinical symptoms and medication usage on an electronic Diary (eDiary). The eDiary will be accessed via a computer, 
smartphone, tablet or other suitable device, through a designated website.  
Information about time of activation of the Vibrant Capsules will be recorded automatically by the base unit and automatically 
transferred to a designated website. 
 
 
Subjects with Chronic Idiopathic Constipation (CIC) according to Rome III criteria who failed currently available therapy (defined as 
osmotic and stimulant laxatives used for at least one month at recommended dose) and meet the study inclusion and exclusion criteria 
will be offered participation in this study. The background of the proposed study and its risks and benefits will be explained to the 
subject and the informed consent form will be signed prior to any study related procedures.  
 
Subject will come for 4 visits: Screening, baseline, after 4 weeks and after 8 weeks of treatment. 
 
During the visits, an interview will be conducted, where the following topics will be discussed: occurrence of adverse events, 
compliance to filling in the daily information on the eDiary and to the treatment, concomitant medication/rescue taken, evolution of 
constipation symptoms, subject’s perceptions about the treatment, motivation of the subject, or any other relevant topic. 
 
Subjects will take either Vibrant or Placebo capsule during 8 weeks: 
 

 
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Three arms will be assessed:  
- 
Vibrant Capsule mode A administered 5 times per week  
- 
Vibrant Capsule mode B administered 5 times per week 
- 
Placebo Capsule administered 5 times per week  
 
One capsule will be taken each day, except Sunday and Wednesday. 
The first capsule will be administrated on site at the baseline visit and the next capsules will be swallowed at subject's home (for more 
details see section 15.9).  
 
 
15.2 
Medical History 
Subject’s demographic and medical information acquired from the subject or the subject's medical chart, including age, gender, 
weight, height, body mass index (BMI), number of natural childbirth and previous medical history and medications will be recorded, 
including: a history of clinically significant abnormalities of all body systems; concurrent diseases; relevant past medical history.  
The information will be recorded in the eCRF for all subjects participating in this study.  
15.3 
Constipation History 
Full history of constipation will be recorded on the eCRF, including duration of constipation, full history and habits of medication 
(over the counter and prescription) and supplements use, frequency of spontaneous bowel, current medication/supplements use, 
description of current diet (with focus on water intake and fiber intake), physical activity (number of hours of physical activity per 
week), recent change in bowel movements. 
15.4 
Physical Examination 
During the screening visit all subjects will undergo a conventional physical examination by an authorized physician. The physical 
examination will include diagnosis and documentation of any significant abnormalities or diseases. The physical examination will 
include a digital rectal examination. 

 
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15.5 
Assessment of pelvic floor dysfunction (defecatory disorder) 
Assessment of pelvic floor dysfunction will be based on subject history. Subjects with suspicion of pelvic floor dysfunction will be 
excluded. 
If subjects have been previously diagnosed with pelvic floor dysfunction following anorectal manometry, a balloon expulsion test, or 
other examinations, documented results from these tests can be used to exclude subjects.   
 
15.6 
Blood and urine tests 
During the screening visit all subjects will undergo the following blood tests: blood count, calcium, creatinine, Blood Urea Nitrogen 
(BUN), sodium, potassium and TSH. Blood pregnancy test will be performed during the screening visit. A pregnancy urine test will be 
performed during the baseline visit. 
 
15.7 
Screening visit (day -21 to -14) 
Subjects will be asked to sign a consent form and will be screened for study eligibility according to inclusion and exclusion criteria. The 
daily bowel movements frequency, history of constipation, etiology of constipation and medication use (including prescription 
medication) will be thoroughly assessed. Subject demographic and medical information acquired from the subject or the subject's 
medical chart, including age, gender, previous medical history, concomitant medications, risk factors etc. will be also recorded on the 
eCRF.  
 
The Bristol Stool Scale and Rome III questionnaire (see Appendix A, B) will be completed by the investigator to confirm the diagnosis 
of Chronic Idiopathic Constipation.  Findings will be recorded on the eCRF. 
 
In addition, subjects will undergo a physical examination including digital rectal examination, vital sign measurements and blood tests. 
PAC-QOL (see Appendix D) be completed by the subject at screening visit. 
 
The investigator will confirm their eligibility and their physical and mental suitability to participate in this study.  
 

 
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Eligible subjects will then be asked to refrain from taking any medication or supplement they are using to relieve their constipation 
during the entire study period except as allowed under the protocol (rescue treatment is allowed as per section 15.12).  
 
Following the screening visit, subjects will enter the run-in period, in which an e-diary will be completed (on a daily basis) for 14 
consecutive days  (run-in period). On the day of screening, the coordinator should determine with the subject the last day of intake of 
constipation medication/aid and ensure that the last intake of constipation medication/aid has been taken more than 48 hours before the 
first diary entry.  
 
The subject will define his/her preferred device to use the eDiary. The subject and study coordinator will define together the time of the 
day during which the subject will fill in the eDiary and a daily alert will be set up on the phone of the subject.  
 
Subjects exiting the trial at this stage will be considered screening failure subjects and will be replaced with new subjects. 
 
15.8 
Run-in period (day -21 or -14, to -1) 
Eligible subjects after screening, will be observed and monitored for the first 2 weeks, in which they will be asked to refrain from taking 
any medication or supplement to relieve their constipation.  
Subjects will complete the eDiary every day and there should be a period of at least 14 consecutive days between the first day the subject 
fills in the diary and the last day of run-in period.  
 
In the eDiary the subjects will be asked to report on their:  
• 
Daily BM,   
• 
Change of diet, if applicable (NOTE: the protocol will not ask the pt to change anything in his/her diet. any change of diet will 
be recorded in the eDiary)   
• 
Change in symptoms as: Bristol stool consistency, straining, bloating, and the other questions in the eDiary     
• 
Medication 
• 
AE/ change in general health condition  
 

 
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The information will be transferred to the eCRF every day.  
 
 
The run-in period may be extended by a few days in case of technical issue (difficulty to access eDiary), to allow for a wash-out period, 
or other. The run-in period may be extended by up to 7 days. 
The last 14 consecutive days of the eDiary will be monitored to determine eligibility of the subjects. Subjects need to have an average 
of ≥1 SBM and ≤2.5 SBM per week during the two weeks of run-in for eligibility. 
 
The subjects will receive at least 1 short phone call/week from the study coordinator.  
The phone calls will be about 5-10 minutes long and will check subject compliance with the eDiary, occurrence of adverse events, use 
of rescue medication, subject understanding of what he/she needs to do in the context of the study and discuss any issue or difficulty 
that the subject might have. Confirmation of date and time of the phone call will be reported on the eCRF. 
 
If a subject does not fill in his/her eDiary, the sponsor/investigator will be alerted and the subject will be contacted by phone call in 
order to receive more information and gather the missing information. Compliance of the subject will be closely monitored. 
3 times or more of missing diary (not due to technical issues) during the run-in period, may be considered as screening failures due to 
lack of compliance. 
15.9 
Baseline / randomization visit (day 0) 
 
After the run-in period, if subject is found eligibile for randomization,  he/she will be invited to the medical center for the baseline visit 
for further assessment. Eligibility will be re-assessed and confirmed based on Rome III questionnaire and the subject's eDiary. 
 
Eligible subjects will be randomized to either Vibrant mode A or Vibrant mode B or Placebo arm (1:1:1 ratio), for a treatment period of 
8 weeks.  
 
The subjects will be trained in the medical center how to use the base unit. He/she will activate the first capsule and will ingest it in front 
of the medical staff. All other capsules will be ingested at the subject' home.  

 
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During the 8 weeks treatment period, subjects will ingest the capsules 5 days per week: one capsule on Mondays, Tuesdays, Thursdays, 
Fridays and Saturdays (total of 40 capsules for the whole study). Subjects will not ingest any capsule onWednesdays, and Sundays.  
If the visit falls on a Sunday or Wednesday, the subject should ingest the first capsule on site and skip the next day.  
 
Actual point of enrollment for the subject is considered the day of first capsule intake. 
The first 2 weeks of treatment will be considered as a subjects’ training period. 
 
During the visit, an interview will be conducted, where the following topics will be discussed: occurrence of adverse events, 
compliance to filling in the daily information on the eDiary and to the treatment, concomitant medication/rescue taken, evolution of 
constipation symptoms, subject’s perceptions about the treatment, motivation of the subject, or any other relevant topic. In addition, 
the subject will receive capsules supply for Treatment period 1 (period of 4 weeks between baseline and next visit).  
 
During treatment period 1, Subjects will be instructed to continue filling a daily eDiary. This will include daily recordings of capsule 
intake, number and time of bowel movements, clinical symptoms score, AEs/ change in their health condition , and 
medication/supplements usage, including rescue medication. 
 
 
15.10 
4 weeks visit (day 28 ± 2) 
 
Four weeks after baseline visit, an on-site visit will be conducted to evaluate subject's treatment efficacy and safety.  
 
During the visit, the following topics will be discussed to evaluate the following: 
 
 subject's safety (including AE/ change in general health condition) 
 eDiary completion  
 compliance with capsules intake 

 
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 concomitant medication/rescue administration 
 evolution of constipation symptoms 
 device accountability: at 4 weeks visit, subject must bring back to the site all remaining capsules (including spare capsule) in 
his/her possession and the capsules must be counted and accounted for. 
 
motivation of the subject, or any other relevant topic. 
 
In this visit the subject will receive capsules supply for Treatment period 2 (period of 4 weeks between this visit and termination visit).  
 
During treatment period 2, Subjects will be instructed to continue  filling a daily eDiary. This will include daily recordings of capsule 
intake, number and time of bowel movements, clinical symptoms score, AEs/ change in their health condition , and 
medication/supplements usage, including rescue medication 
   
 
15.11 
8 weeks visit / Termination (day 56 ± 2) 
Eight weeks after baseline visit, an on-site visit (final visit) will be conducted to evaluate the following: 
 subject's safety (including AE/ change in general health condition).  
 eDiary completion  
 concomitant medication/rescue administration 
 evolution of constipation symptoms 
 device accountability: At 8W visit, subject must bring back to the site the base unit and the router as well as all remaining 
capsules in his/her possession and the capsules must be counted and accounted for. 
 PAC-QOL ,TSQM and ease of use questionnaires 
 
 
15.12 
Rescue Treatment 
 

 
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Subjects will stop using all medication or supplement to relieve constipation during the entire study period and comply to use 
constipation aid only for rescue.  
Using one rescue medication is authorized only after 3 consecutive days without a bowel movement and under the rules described 
below. The subjects will not be required to contact the investigator prior to taking any medication/supplement but they will be 
required to declare all the rescue medication on their eDiary. The following treatment is recommended (not by order): 
1. Dulcolax® (bisacodyl) suppository 
2. Fleet Enema® 
3. Dulcolax® (bisacodyl) tablet (1x5mg) 
 
The subject is allowed to take a rescue medication/supplement that is not in the above list, without contacting the investigator. The 
subject must declare all rescue intake in the eDiary. 
 
Subjects who take rescue medication three times or more during the run-in period will be considered as screening failures. 
 
 
15.13 
Concomitant medication 
All medications taken by the subject in addition to the investigational device is termed concomitant medications.  All concomitant 
medications taken during the study must be documented in the case report form (name of drug, date of intake, dosage, number of takes 
per day, reason for medication). The subject will fill in all the information in the eDiary on a daily basis.  
 
 
15.14 
Prohibited medication 
The medications listed below will be prohibited during the entire study:  
- 
Medications that may affect intestinal motility  
- 
Prokinetics 
- 
Opiates 

 
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- 
Opioids 
- 
Calcium-channel blockers 
- 
Aluminum/magnesium hydroxide. 
 
 
Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is also prohibited. Chronic use is defined as taking full dose NSAIDs 
on a regular basis (i.e. more than three times a week) for at least six months.  
Subjects on cardiac doses of aspirin may be enrolled in the study.  
 
The following medications are equally prohibited, but with an exception when the subject has been on a stable dose of the medication 
for at least 3 months: 
- 
Antidepressants 
- 
Thyroid or hormonal replacement therapy. 
 
 
 
15.15 
Recording 
All tests will be performed prior to procedure in case where not already done per routine hospital protocol. Device handling and 
function will be recorded.  
The standard treatment and care provided to all subjects, alongside the Vibrant capsule and other treatments will be performed and 
recorded on the appropriate study eCRF.  
The subject will be questioned on his/her clinical status, the presence of any medical intervention performed since the last visit and 
any adverse events or discomforts. When necessary, the subject will be asked to arrive for a follow-up visit at the clinic. 
 
 
 
 

 
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15.16 
Study Schedule   
Table 1 summarizes the required data collection from assessments and tests performed during the study. 
 
 
Procedures 
Screening 
Baseline 
4w visit  
8w visit 
(Termination) 
  
  
Visit No. 
1 
2 
3 
4 
  
Day 
-21 to -14 
0 
28 (±2 days) 
56 (±2 days) 
  
IC 
+ 
 
 
 
  
Eligibility Criteria 
+ 
+ 
 
 
  
Physical Exam 
+ 
 
 
 
  
Digital Rectal Exam 
+ 
 
 
 
  
Vital Signs 
+ 
 
 
 
  

 
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Blood test 
+ 
 
 
 
  
Urine Pregnancy test (if 
applicable) 
 
+ 
 
 
  
Administration of 
capsule 
 
+ 
 
 
  
Rome III 
+ 
+ 
 
 
  
Bristol Stool 
+ 
 
 
 
  
PAC-QOL 
+ 
 
 
+ 
 
TSQM & Ease of use 
 
 
 
+ 
 
Subject eDiary 
+ 
+ 
+ 
+ 
  
Adverse Events 
 
+ 
+ 
+ 
  
Device accountability 
 
 
+ 
+ 
 
Concomitant Medication 
+ 
+ 
+ 
+ 
  
Table 1 – Study Schedule of Assessments 
 
15.17 
Deviations from study protocol 
 
Any deviation from the study protocol should be notified to the sponsor, documented on study deviation forms and reported to the Ethics 
Committee as required. 
 
Protocol deviations related to treatment compliance (e.g. missed capsule, capsule taken on a non-capsule administration day, etc.) will 
not be declared on the protocol deviation form accessible via the EDC (Electronic Data Capture). Protocol deviations related to treatment 
compliance will be monitored and declared by the Sponsor, CRO and sites using a platform external to the EDC. This external platform 
will use the information transmitted from the base units about activations (base unit serial number, date and time of activation, 
success/failure) as a basis to monitor treatment compliance. 

 
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Additional information transmitted by the subject from the eDiary about number of capsules taken out of the blister and swallowed for 
each day, as well as direct information given by the subject to the study coordinator by phone, email or SMS, will be used by the Sponsor 
and CRO to make a final decision about treatment compliance, for each day of treatment, for all subjects. 
A final list of protocol deviations related to treatment compliance will be issued at the end of the study, from the external platform, and 
signed by the site. This list will be considered equivalent as protocol deviations forms. The site will not manually enter these protocol 
deviations in the EDC. 
 
15.18 
Investigative Center Selection Criteria 
 
The investigative site will meet the following selection criteria prior to inclusion in this study: 
 Clinical research study experience and resources that demonstrate good compliance with study requirements and timely, 
complete documentation of subject follow-up.   
 Sufficient subject volume to meet enrollment timeframe. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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16. 
ADVERSE EVENTS RECORDING 
 
At each evaluation, the investigator will determine whether any adverse events (AE’s) have occurred. All adverse events occurring 
during the study will be recorded on the appropriate case report form page and signed by the investigator.  The nature, severity and 
relation of the adverse event to the study device will be documented. 
16.1 
Reporting Requirements 
Timely and complete reporting of Adverse Events (AE) and safety assessment allows: 
 Protection of safety and study subjects. 
 Greater understanding of the overall safety profile of the study treatment. 
 Appropriate modification of study protocols and improvement in study design and procedures. 
 Adherence to regulatory requirements. 
The definitions and reporting requirements adopted in this study are derived from the current International standard on clinical 
investigations: Title 21 of the Code of Federal Regulations (21 CFR), part 312 (Investigational New Drug Application), Section 32 (IND 
Safety Reporting) and part 812 (Investigational Device Exemptions), Section 150 (Reports). 
16.2 
Definitions  
Adverse Events (AE) 
AE is defined as any untoward medical occurrence in a subject. This definition does not imply that there is a relationship between the 
adverse event and the device under investigation.  An AE can therefore be any unintended sign, symptom, disease or injury or any 
untoward clinical signs (including an abnormal laboratory findings) in subjects, users or other persons whether or not related to the 
investigational medical device. The following should be reported as AE: 
 Untoward medical conditions or signs or symptoms that were absent before starting study treatment. 
 Untoward medical conditions or signs or symptoms present before starting study treatment and worsen (increase severity or 
frequency) after starting study treatment. 
 Abnormal laboratory findings. 
 Clinical signs or symptoms that require therapy. 

 
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Adverse Device Effect (ADE) 
ADE is adverse event, related to the use of an investigational medical device. This includes any adverse event resulting from 
insufficiencies or inadequacies in the instructions for use or the deployment of the device, the operation, or any malfunction of the 
investigational medical device, device failure or misuse, and any event that is a result of a user error. 
 
Device failures, Malfunctions and Misuse 
Investigators are instructed to report all possible device failures or misuse observed during the course of the trial. These incidents will 
be documented in the case report form provided as follows: 
 
 Device Failure - A device failure has occurred when the device is used in compliance with the Instructions for Use, but does 
not perform as described in the Instructions for Use. A device failure occurs when  
o A capsule fails to activate.  
o The transmission about the first capsule activation cannot be performed (during the baseline visit) by the base unit. 
This event must lead to the replacement of the base unit.  
o The base unit loses its ability to transmit information permanently. This event must lead to the replacement of the base 
unit. 
Device Misuse - Any use of the investigational device by an investigator or subject that is contradictory to the application 
described in the Instructions for Use will be categorized as device misuse.  
 
 
Serious Adverse Events (SAE) 
A SAE is an adverse event that: 
1.     Led to a death, 
2.     Led to a serious deterioration in the health of the subject that: 
a. Resulted in a life-threatening illness or injury 
b. Resulted in a permanent impairment of a body structure or a body function 

 
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c. Required in-subject hospitalization or prolongation of existing hospitalization  
d. Resulted in medical or surgical intervention to prevent permanent impairment to body structure or a body function. 
  3.    Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Device Deficiency  
Device Deficiency is defined as Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or 
performance, such as malfunction, misuse or use error and inadequate labeling. A final list of device deficiency will be issued at the end 
of the study, from the external platform, and signed by the site.  
 
 
Device deficiencies that might have led to a SAE if a suitable action had not been taken or intervention had not been made or if 
circumstances had been less opportune are also handled under the SAE reporting system.  
However, planned hospitalization for pre-existing condition and/or procedure required by the clinical trial protocol, without serious 
deterioration in health, is not considered to be a SAE. 
 
Serious Adverse Device Effect (SADE) 
A Serious Adverse Device Effect is an adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
USADE is defined as serious adverse device effect which by its nature, incidence, severity or outcome has not been identified in the 
current version of the risk analysis report or other study related documents.  
 
16.3 
Anticipated Adverse Events 
The Vibrant Capsule targets pathophysiological parameters of chronic constipation by inducing natural bowel activity without using 
chemical supplements. 

 
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Anticipated Adverse Events include those that are reasonably expected to occur in association with a clinical investigation assessing a 
treatment for Chronic Idiopathic Constipation. Events can occur as a result of the disease or as a result of the treatment (including 
usage of the home base unit). They may include but are not limited to the following (in alphabetical order): 
 
Abdominal pain/discomfort/cramping 
 
Blood in the stool may develop or increase 
 
Bloating/Flatulence 
 
Diarrhea  
 
Nausea may develop or increase 
 
Rectal pain may develop or increase 
 
Sensation of vibration in the abdomen 
 
Uncontrolled leakage of stool may occur 
 
Vomiting may develop 
 
All events listed above, and additional events that the investigator will evaluate will fit the definition of ‘anticipated event’, will be 
categorized as such in the study. 
16.4 
Adverse Event Reporting 
All adverse events and adverse device effects occurring during the clinical trial must be recorded on the appropriate AE form in the 
eCRF, within a reasonable time (up to 5 calendar days from investigator's awareness of the event). All AEs will be characterized by 
the following criteria: 
 Intensity or Severity 
 Relatedness 
 Outcome 
 Treatment or Action Taken. 
 
16.4.1 
Intensity or Severity 
The following categories of the intensity of an adverse event are to be used:  

 
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Mild – Awareness of a sign or symptom that does not interfere with the subject’s usual activity or is transient, resolved without 
treatment and with no sequelae. 
Moderate – Interferes with the subject’s usual activity and/or requires symptomatic treatment. 
Severe – Symptom(s) causing severe discomfort and significant impact of the subject’s usual activity and requires treatment. 
16.4.2 
Relatedness 
The investigator will use the following definitions to assess the relationship of the AE to the investigational medical device: 
Not related - The cause of the AE is known and the event is not related to the investigational medical device. 
Possibly related - There is a reasonable possibility that the event may have been caused by the investigational medical device. 
The AE has a timely relationship to the study procedure(s); however, follows no known pattern of response, and an alternative cause 
seems more likely or there is significant uncertainty about the cause of the event.  
Probably related - It is likely that the event was caused by the investigational medical device. 
The AE has a timely relationship to the study procedure(s) and follows a known pattern of response; a potential alternative cause, 
however, may explain the event. 
Related - A related event has a strong temporal relationship and an alternative cause is unlikely. 
 
16.4.3 
Outcome 
The clinical outcome of the AE or SAE will be characterized as follows: 
Death - The SAE CRF must be completed for this outcome (see section 16.5 Expedited Reporting of Serious Adverse Events). 
Recovered without sequelae - The subject has recovered with no sequelae from the event 
Ongoing - Subject did not recover and symptoms continue 
Recovered with sequelae - The subject has recovered but with clinical sequelae from the event 
Unknown - The subject outcome is unknown 
 
16.4.4 
Treatment or Action taken 
The treatment or action taken after the occurrence of an AE or SAE will be reported as: 

 
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Interventional Treatment - Surgical, percutaneous or other procedure 
Medical Treatment - Medication frequency of administration reduction/interruption or discontinuation, or medication initiated for 
event 
None - No action is taken 
 
16.5 
Expedited Reporting of Serious Adverse Events 
Any Serious Adverse Event, and device deficiencies should be reported to Vibrant Ltd. within 24 hours of investigators' knowledge of 
the event. Investigator should report these events on the appropriate SAE form / Device Deficiencies Form in the eCRF and send the 
form by fax or e-mail, to the following safety contact person: 
 
Lior Ben Tsur 
Vibrant 
Hakochav 
Yokneam 2069206 
P.O.Box 516, Israel 
Tel: +972-46-663322 
Cell: + 972-54-6950001 
Lior.b@vibrantgastro.com 
 
If applicable, the investigator should also inform the representative of the appropriate local Ethics Committee, within 24 hours of 
investigator's awareness of the event. A copy of the report cover letter should be filed within the study file.  
  
The sponsor is responsible for the ongoing safety evaluation of the investigational medical device. The sponsor will promptly notify 
all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of 
subjects, impact the conduct of the trial, or alter the Medical Ethics Committee approval/favorable opinion to continue the trial. 
 

 
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The sponsor will expedite the reporting to all concerned investigator(s)/institutions(s), to the EC(s), where required, and to the 
regulatory authority(ies) of the occurrence of Unanticipated Serious Adverse Device Effects.  
 
16.6 
Follow- Up of Unresolved Events 
All adverse events should be followed until they are resolved or the subject’s participation in the study ends.  
 
17. 
STATISTICAL CONSIDERATIONS  
17.1 
Study Design and Objectives 
 
The study is planned as a prospective, randomized, multi-center, double-blinded, placebo-controlled, 3- arm study, designed to assess 
the efficacy and safety of Vibrant capsule vs. placebo, for the treatment of chronic idiopathic constipation. 
  
After a run-in period of 14-21 days, subjects will be randomized with a ratio of 1:1:1 to either Vibrant capsule mode A, or Vibrant 
capsule mode B or placebo capsule. The subjects will then be treated with the active Vibrant or placebo capsule for 8 weeks. The first 
2 weeks of treatment will be considered as a subjects’ training period. One interim analysis will be conducted after about 90 evaluable 
subjects will complete 8 weeks of treatment.  
 
17.2 
Study Endpoints 
17.2.1 
Primary Efficacy Endpoint 
 The two primary efficacy endpoints are the CSBM1 success rate, defined as an increase from the run-in period of at least one weekly 
Complete Spontaneous Bowel Movement (CSBM) during at least 6 of the 8 weeks of treatment, and CSBM2 success rate, defined as 

 
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an increase from the run-in period of at least two weekly Complete Spontaneous Bowel Movement (CSBM) during at least 6 of the 8 
weeks of treatment. 
 
The study will be deemed successful if either the CSBM1 or the CSBM2 success rate is statistically significantly higher in the active 
arm that was continued after the interim analysis, than in the placebo arm. 
 
17.2.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include:  
1. Change from baseline in average straining 
2. Change from baseline in average stool consistency, using the Bristol Stool Scale 
3. Change from baseline in average bloating. 
17.2.3 
Additional Efficacy Endpoints 
Additional secondary efficacy endpoints include: 
- 
CSBM1 success rate when using the data from the two active arms together . 
- 
CSBM2 success rate when using the data from the two active arms together.  
- 
SBM success rate, defined as an increase from baseline at least one weekly spontanuous Bowel Movement (SBM) during at 
lease 6 out of 8 weeks of treatment.  
- 
Incidence of Rescue Medication use during the treatment period. 
- 
Change from baseline in weekly number of Spontaneous Bowel Movement (SBM). 
- 
Change from baseline in weekly number of Complete Spontaneous Bowel Movement (CSBM). 
- 
Rate of SBM ≤ 24 hours after first dose  
- 
Change from baseline in average abdominal gas. 
- 
Change from baseline in average abdominal pain. 
- 
Change from baseline in abdominal discomfort. 
- 
Time to occurrence of spontaneous bowel movement after first  capsule activation. 
- 
Treatment satisfaction score using the TSQM (Treatment Satisfaction Questionnaire for Medication) 
- 
Change from baseline in quality of life using the PAC-QOL (Patient Assessment of Constipation Quality of Life) 
questionnaire.  

 
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17.2.4 
Safety Endpoints 
Safety endpoints include all adverse events related and unrelated to the study treatment. 
17.3 
Statistical Hypothesis 
 
  
In this study, we will test the following hypotheses: 
 
H0 : Pa1-Ps1=0 
 
H1: Pa1-Ps1≠0 
Where Pa1 is the CSBM1 success rate in the selected active arm, and Ps1, the CSBM1 success rate in the placebo arm. 
AND: 
 
H0 : Pa2-Ps2=0 
 
H1: Pa2-Ps2≠0 
Where Pa2 is the CSBM2 success rate in the selected active arm, and Ps2, the CSBM2 success rate in the placebo arm 
17.4 
Sample size 
A sample size is calculated to test the null hypothesis. Calculations (using SAS® proc power) show that a sample size of 150 subjects 
(60 in the 2 study arms that will be continued till the end of the study, and 30 for the study arm that will be dropped at the interim 
analysis), would provide 80% power at  a study wise 5% level of significance (two-sided), i.e. 2.5% for each one of the primary 
endpoints to detect a difference of 25% in the success rate, assuming a success rate of 15% in the placebo arm.  
The sample size will be increased to at least 168 subjects (67 in the 2 study arms that will be continued till the end of the study, and 34 
for the study arm that will be dropped at the interim analysis to account for a potential 10% of drop-out rate. 
 
 

 
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17.5 
Interim Analyses 
One interim analysis will be performed, after about 90 evaluable subjects will complete 8 weeks of treatment. Planning an interim 
analysis that permits an increase in the sample size as described below does not additionally inflate the type I error according to 
references 26-28. In addition, the final analysis is performed using the conventional test as appropriate for the statistical hypothesis. 
ONLY the un-blinded statistician and members of the DSMB committee will be exposed to the report. Investigators and company 
directors will only be informed of a decision to continue or to discontinue the trial, or to implement modifications in sample size 
increase. 
 
17.5.1      Procedure 
After all the relevant data will be entered into the database, and the database cleaned, a soft lock to the database will be performed. An 
independent un-blinded statistician (not the study statistician) will perform the assessments described below. 
At the interim analysis, the data of the evaluable subjects will be analyzed.  
 
17.5.2 
Blinding 
ONLY the un-blinded statistician will be exposed to the subjects’ treatment allocation. Investigators and company directors will only 
be exposed to the interim report. 
The members of the DSMB (Data and Safety Monitoring Committee) may also have access to the unmasked information of the 
interim analysis. Investigators and company directors will only be informed of a decision to continue or to discontinue the trial, or to 
implement modifications in sample size of the trial. The un-blinded statistician who is responsible for conducting the interim analyses 
should ensure that the unmasked data is not available to any unauthorized person within or outside the company. 
17.5.3 
Decision Rules 
The purposes of the interim analysis are: 
 to select the most promising vibrations regimen (drop-the-loser design), and 
 
to re-assess the sample size based on conditional power. 

 
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The selection of the active study arm that will be continued till the end of the study is the one with the higher difference in CSBM1 or 
CSBM2 rate versus the ones in the placebo arm. 
First the most promising vibrations regimen will be selected, and then the following will be performed for this study arm. 
The study will either continue to the originally planned sample size if the result is “favorable”, stop for futility if the result is 
“unfavorable”, or an increase will be made to the sample size if the result is “promising”. These decisions will be made based on the 
conditional power (CP), defined as the conditional probability that the result will exceed a critical value at the interim given the 
observed effect size  𝛿ଵ
෢  = difference between CSBM success rates active versus placebo at the interim look.  
Notation: 
n1= sample size at interim analysis (30 subjects in each study arm). 
n2= original sample size calculated based on assumed effect size (168). 
nmax = the highest sample size the company is willing to use, nmax = 600 (including allowance for drop-out). 
CPmin=is the calculated minimum CP based on the ratios nmax/n2, n1/n2 and the target study power (80%). 
The following are the decision rules for the interim analysis. These depend on the zone into which CP falls at the interim, the 
calculated CPmin, the maximum sample size designated for the study and the % of the originally planned sample size at which the 
interim analysis will be performed. Following this principle does not inflate the Type I error. 
1. If the respective conditional power for each of the primary endpoints is < 26.97% or if the difference between the success rate 
(treatment –placebo) for both primary endpoints is less than 10%, then stop the trial for futility. 
2. a. If the conditional power for both primary endpoints is 26.97% ≤ CP < 80% then recalculate the sample size to recover the targeted 
80% for both endpoints, the maximum sample size selected will be the larger of the two. 
b. If the CP of only one of the primary endpoints is 26.97% ≤ CP < 80% then recalculate the sample size to recover the targeted 
80% for that endpoint alone.  
In both cases a and b, the maximum sample size for the study will be 600 subjects 
3. If the respective conditional power for each of the primary endpoints is ≥ 80% then continue to the originally planned sample size. 
Note that the interim analysis will be conducted on both the ITT and mITT analysis sets, and the study will be stopped due to futility 
only if the interim effects in both populations fall below the threshold. 

 
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17.5.4 
 Controlling the Alpha level for the primary endpoint 
The overall alpha level for this study is 5%. According to references 26-28, planning an interim analysis that permits an increase in the 
sample size as described above does not inflate the type I error. 
 
17.6 
Randomization 
 
After a subject meets the eligibility criteria, he/she will be equally allocated (with a 1:1:1 ratio) to one of the following treatment groups 
based on a randomization scheme with randomized blocks’ size stratified by center:  
 Vibrant capsule mode A administered 5 times per week 
 Vibrant capsule mode B administered 5 times per week 
 Placebo capsule administered 5 times per week 
The randomization scheme will be prepared by BioStats using the SAS® (version 9.4.) random number generating procedure. 
17.7 
Blinding 
This is a double-blind study. The subjects and the evaluators will be blinded to the treatment allocated to each subject. 
17.8 
Data Analysis Sets 
17.8.1 
Intent to Treat (ITT) 
The ITT analysis set will consist of all subjects randomized. In accordance with the ITT principle, all subjects randomized will be kept 
in their originally assigned treatment group for analysis. Subjects with no valid post baseline assessment will not be part of the 
relevant analysis. 
17.8.2 
Modified Intent to Treat (mITT) 
The mITT analysis set will consist of all randomized subjects who met the inclusion criteria of the protocol. In accordance with the 
ITT principle, all subjects randomized will be kept in their originally assigned treatment group. Subjects with no valid post baseline 

 
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assessment will not be part of the relevant analysis. Subjects with less than 2 weeks (with at least 5 days per week) of valid diary 
during the treatment period will be considered as non-evaluable 
17.8.3 
Per-Protocol (PP) 
The per-protocol analysis set will consist of all subjects from the mITT analysis set without major protocol violations and successfully 
completed the study, with treatment group analyzed as treated. 
17.8.4 
Statistical Analysis of Analysis Sets 
The ITT analysis set will serve as the main set for safety assessments . 
The mITT analysis set will serve as the main set for efficacy assessments . 
 
The efficacy assessment will be presented on the ITT and PP analysis sets . 
17.9 
Statistical Analysis 
17.9.1 
General Considerations 
Statistical analyses will be performed using SAS® v9.4 or higher (SAS Institute, Cary NC, USA). 
Baseline demographic and other baseline characteristics, together with safety analyses will be performed on all enrolled subjects. 
Baseline values are defined as the last valid value prior to treatment . 
All statistical tests will be two-sided.  If statistical tests are performed nominal p-values will be presented. Where confidence limits are 
appropriate, non-adjusted two-sided 95% confidence interval will be constructed . 
For comparison of means (continuous variables), the two-sample t-test or the Wilcoxon rank sum test will be used as appropriate.  For 
comparison of proportions (categorical variables), the Chi-squared test or Fisher’s exact test will be used as appropriate . 

 
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17.9.2 
Significance levels and handling of type I error 
17.9.2.1 Type I Error 
The overall significance level for this study is 5% using two-tailed tests. According to references 26-28, planning an interim analysis 
that permits an increase in the sample size as described in section 17.5 does not inflate the type I error. The treatment by site 
interaction will be tested at a significance level of 10%.  
17.9.2.2 Primary Endpoints 
The primary endpoints for the dropped study arm will not be analyzed. 
The Benjamini and Hochberg technique for controlling the false discovery rate will be implanted for the two primary endpoints. 
17.9.2.3 Hierarchy Approach for Secondary Endpoints Analysis 
The hierarchy approach will be adopted for the primary and secondary endpoints to control type I error due to multiple endpoints 
testing. Thus, the primary endpoint will first be analyzed and only if one of them is found statistically significant, will the secondary 
endpoints be analyzed.  
The first secondary endpoint will be tested, first, for statistical significance and only if found significant (versus an alpha level of 5%), 
the next in line will be tested. Only if the first and second secondary endpoints are found statistically significant, then the third one 
will be tested, and so on. 
The order of the secondary endpoints is as listed in paragraph 17.2.2. 
  
17.9.3 
Demographic and Other Baseline Variables 
Demographic and baseline condition related characteristics will be tabulated. Continuous variables will be summarized by a mean, 
standard deviation, minimum, median and maximum, and categorical variables by a count and percentage . 

 
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17.9.4 
Disposition of Subjects 
Treatment tolerability will be presented by treatment groups, the number and percent of subjects who fail to complete the study and 
the number and percent of subjects who fail to complete the study because of Adverse Events will be presented. Time to withdrawal 
will also be assessed and presented by Kaplan-Meier curves and will be compared using the Log-Rank test if relevant. 
17.9.5 
Efficacy Analysis 
    
The subject’s CSBM1 success status (i.e. if the subjects achieve an increase from baseline of at least 1 weekly CSBM during at least 6 
out of the 8 treatment weeks) will be presented in tabular form by study arm, along with 95% Wilson score Confidence Intervals (CI) 
and will be compared between the study arms with a Cochran-Mantel-Haenszel test controlling for center. 
 
The CSBM2 and SBM success rates will be analyzed in a similar manner. 
 
The incidence of rescue medication and the rate of SBM within 24 hours from the first study dose use will be analyzed in a similar 
manner. 
 
The change from baseline in average straining will be modeled with an Analysis of Covariance (ANCOVA) model, with baseline 
average straining and site entered as covariates. The adjusted means of the change from baseline per study arm, and the difference 
between the groups will be presented along with respective 95% CI. The change from baseline in average stool consistency, in average 
bloating, in weekly number of SBM and CSBM, and in symptoms will be analyzed with similar ANCOVA models. 
 
Time to occurrence of SBM after intake of the first Vibrant capsule (either active or placebo) will be assessed and presented by 
Kaplan-Meier curves and will be compared between the study arms using the Log-Rank test if relevant. 
 
Treatment satisfaction, and incidence of use of rescue medication will be presented in tabular form. 
The PAC-QoL, the rescue medication use, and the rate of SBM during the first 24 hours after the first dose will be presented in tabular 
form. 

 
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17.9.6 
Treatment by Center Interaction 
 Poolability will be tested in the primary analysis at a significance level of 10%. 
Poolability across centers, for the primary endpoints, will be assessed using a logistic regression model.  
Centers will be grouped together by geographical area, a table of the sites and their geographical area within and without the USA will 
be presented. If found significant, the reason for the significance would be further explored and rationalized. This evaluation may 
include demographic features, symptoms at presentation, clinical and treatment history, and site comparability in the features found to 
be associated with the primary performance variable. 
Pooling analysis will be repeated with US centers combined, and Out of US (OUS) centers combined. 
 
17.9.7 
Safety Analysis 
Adverse events (AE) will be presented by seriousness, severity and relation to treatment by treatment group. The number of reports, 
the number of subjects, and the incidence (percent of subjects) will be tabulated by study arm. 
17.9.8 
Handling of Missing Data 
 
Subjects with less than 6 weeks of diary data will be considered as failures for the CSBM and SBM success rates. 
Multiple imputation for binary data will be used as the primary imputation method in the case of missing data for the primary 
performance end-point, baseline variable to be used in the analysis: BMI, sex, Age, duration of historical symptoms, straining and 
Bristol stool scale at baseline. Once the data is finalized if this method is deemed inappropriate a more appropriate analysis may be 
performed.  
Additional sensitivity analysis of the primary end-point will be performed to assess the impact of missing data on the study outcome 
using possible imputation methods for binary data:  
• 
Tipping point analysis. 
• 
Observed Data: Use only subjects with 8 weeks of non-missing diary data and who did not withdraw early from study. 
• 
Best Case Scenario: Assume all subjects with missing data in study group are successes; Assume all subjects in the 
placebo group with missing data are failures. 

 
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• 
Worst Case Scenario: Assume all subjects with missing data in study group are failures; Assume all subjects in the 
placebo group with missing data are successes. 
 
In addition, for missing diary day, the number of bowel movement will be imputed to “0”, and the intake of rescue medicine to “No”. 
For the time to first SBM analysis, subjects with no known SBM will be considered left censored. 
For the analyses of the other endpoints, no imputations for missing values will be performed. 
18. 
DATA MONITORING PLAN  
The Principal Investigator and his study staff will monitor all data accrual. In addition a data monitor will visit the study site during 
the study and review the progress of the clinical trial including safety data and ensure as possible that it is conducted, recorded, and 
reported in accordance with the protocol, Good Clinical Practice (GCP), and the applicable regulatory requirement(s). A written report 
form will be issued after each monitoring visit (including initiation and close out visits). The monitoring visit report will include a 
summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and 
deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance. The investigator/institution 
should provide direct access to source data/documents for trial-related monitoring and auditing, IRB/IEC review and inspection by the 
appropriate regulatory authority/ies.  
 
NOTE: e-Source may be used. 
 
Verification during monitoring visit will include: 
 
1. That the investigator has adequate qualifications and resources and remains adequate throughout the trial period, that facility, 
including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout 
the trial period. 
2. Verifying for the investigational product(s): 
a. That storage conditions are acceptable. 
b. That the investigational product(s) are supplied only to subjects who are eligible to receive it according to protocol and 
no other use is being done with the Vibrant devices. 

 
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c. That the receipt, use, and return of the investigational product(s) at site are controlled and documented adequately and 
that supplies delivery notes are confirmed upon reception throughout the trial. 
d. That the unused investigational product(s) at sites will be returned. 
3. Verifying that the investigator follows the approved protocol and all approved amendment(s), if any. 
4. Verifying that written informed consent was obtained before each subject's participation in the trial. 
5. Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct 
the trial properly and to comply with the applicable regulatory requirement(s). 
6. Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial. 
7. Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the 
protocol and any other written agreements, and have not delegated these functions to unauthorized individuals. 
8. Verifying that the investigator is enrolling only eligible subjects and at sufficient recruitment rate. 
9. Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained. 
10. Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these 
documents are accurate, complete, timely, legible, dated, and identify the trial. 
11. Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other.  
12. The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents. 
13. Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs. 
14. Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as 
such on the CRFs. 
15. All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs. 
16. Verifying that the investigator had answered all of the queries that came up from inspection of the CRFs or other trial material. 
17. That the investigator is maintaining the essential documents.  
18. Verifying that deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements are reported by the 
investigator to the IRB/IEC and that appropriate actions were taken to prevent recurrence of the detected deviations. 
 
Should there be an unexpected number of device failures or related complications that increase the risks to the participants, or critical 
efficacy endpoints at intervals that are not satisfying, the study will be halted and analysis performed to determine whether to 
continue, modify the protocol, or close the study. 

 
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19. 
DATA CONFIDENTIALITY  
 
Each subject will be identified by his/ her initials and a unique subject identification number. Source data will be stored with source 
documents. The Investigator Site Files (ISF) will be held in a secure area. The subject’s name and personal data will remain 
confidential and will not be published in any way. However, the sponsor’s monitor or representative and regulatory representatives, 
auditors and inspectors may have access to medical files in order to verify authenticity of data collected. 
 
20. 
FUNDING  
 
The study is funded by Vibrant Ltd.  
21. 
ETHICS  
 
Prior to study initiation the site shall obtain EC or IRB approval of the study. A copy of the written EC approval must be provided to 
the sponsor prior to the start of the study. 
Any changes in the study protocol, informed consent forms, or investigator must be re-approved by the EC or IRB and the approval 
documented. All subjects screened in the study will provide their consent prior to entering the study. An informed consent form shall 
be signed and dated by the subject. The investigator will retain the forms as part of the study records.  
This study will be executed in accordance with the Declaration of Helsinki, in agreement with the guidelines for conducting a clinical 
investigation in accordance with the principles of ICH GCP outlined in the E6 document. By signing the present protocol, the 
investigator commits to carry it out in accordance with local legal requirements. 
 
Other investigator responsibilities relative to the EC/IRB include the following: 

 
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1. During the conduct of the study, the investigator will submit progress reports to the EC/IRB as required, and request re-review and 
approval of the study at least once a year; 
2. The investigator will report immediately to the EC/IRB of any unexpected serious adverse events that occur during the study, and 
provide the sponsor with a copy of the correspondence; 
3. If the sponsor notifies about serious adverse events reported in other studies using this device, the investigator must report that 
information to the EC/IRB; 
4. As required, the investigator must obtain approval from the EC for protocol amendments and for revisions to the consent form or 
subject recruitment advertisements; 
5. The investigator should provide the EC/IRB with any other information it requests before or during conduct the study; 
6. The investigator must maintain a file of study-related information that includes all correspondence with the EC/IRB; 
7. The investigator must notify EC/IRB when study is completed (i.e. after the last study visit of the final study subject); 
8. After study completion (within 12 months is recommended) the investigator should provide the EC/IRB with a final report on the 
study. The recommended components of a final report are as follows; dates of study start and completion, number of subjects 
enrolled/treated, number of subjects who discontinued participation early and reason why, itemization and discussion of any 
serious adverse event. 
  
22. 
INFORMED CONSENT  
 
Written informed consent must be obtained from each study subject. The subject will be asked to read the informed consent form and 
to sign the form to indicate consent to participate in the study.  
The investigator will explain carefully to the subject the research nature of the study. The scope and aims of the research will be 
described together with known or foreseeable benefits, risks and discomforts that subjects may experience. Appropriate alternative 
treatments will be discussed so that the subject may determine whether or not he or she wishes to participate in the study.  The subject 
must understand that throughout the study his or her participation remains voluntary and protected by the Declaration of Helsinki.  
The investigator is responsible for obtaining written (or witnessed) informed consent from potential subjects prior to study entry.  
Subjects will be given time to read the informed consent and ask any questions before being asked to sign the form.  The informed 
consent (approved by the sponsor and the Ethics Committee) must be signed and dated by the subject and the investigator. One copy 

 
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of the signed consent will be given to the subject, a second copy will be sent to the referral investigator and the original will be 
retained by the investigator.  
Subjects may withdraw their consent to participate in the study at any time without prejudice. The investigator may withdraw a subject 
if, in his clinical judgment, it is in the best interest of the subject or if the subject cannot comply with the protocol. Attempts should be 
made to complete any examinations and the sponsor must be notified of all withdrawals.  
Should a protocol amendment be made, the subject's consent form may be revised to reflect the changes of the protocol. It is the 
responsibility of the investigator to ensure that an amended informed consent is approved or reviewed by the EC/IRB, and that it is 
signed by all subjects subsequently entered in the study and those currently in the study, if affected by the amendment. 
 
23. 
REGULATORY AND HEALTH AUTHORITY AUDITS 
The European Union’s authorities and/or the Food and Drug Administration (FDA) and/or the local state health authorities may 
request access to all study records, including source documents for inspection. The investigator and hospital staff are requested to 
cooperate with these audits. The investigator must notify the sponsor of any health authority audit as soon as notification of such audit 
is made. A representative or designee of the sponsor may also conduct similar audits and may be present during health authority audit. 
 
24. 
ELECTRONIC REPORTING OF DATA 
 
All medical data in this trial are to be recorded directly in the EDC (Electronic Data Capture) system. Documentation on paper will be 
restricted to exceptional circumstances only. 
The investigator must ensure the accuracy, completeness and timeliness (and legibility in 
case of documentation on paper) of data. 
 
Sites will get trained on how to access and use the EDC and will be foreseen with a personal user login and password.  
Subjects will access and complete their diaries online via a website specifically created for the purposes of the study. Subjects will be 
trained on how to access and use this website and will be foreseen with a personal user login and password. 
 

 
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25. 
RECORD RETENTION 
It is required that a copy of all records (e.g., informed consent documents, source documents, safety reports, study device dispensing 
record, etc.) which support case report forms for this study, be retained in the files of the responsible investigator for a minimum of 
fifteen (15) years following notification by the sponsor that all investigations (not merely the investigator's portion) are completed, 
terminated and/or discontinued.  If the principal investigator retires, relocates, or for other reasons withdraws from the responsibility 
of keeping the study records, custody must be transferred to a person who will accept the responsibility. Vibrant Ltd. must be notified 
in writing of the name and address of the new custodian. 
26. 
PROTOCOL MODIFICATIONS 
An amendment to the protocol may be proposed by an investigator or the sponsor. The amendment will be prepared and approved by 
the sponsor according to the sponsor’s relevant SOP. The amendment must be submitted to the EC/IRB. When applicable, the 
amendment’s implementation will take place only once approved by the EC/IRB. 
If for any unexpected reasons, there is any requirement to deviate from the treatments stated above, the protocol deviation should be 
discussed in advance with a Vibrant Ltd. representative.  
 
27. 
PUBLICATION POLICY 
All information concerning this study that was not previously published is considered confidential information. This confidential 
information shall remain the sole property of Vibrant Ltd.; it shall not be disclosed to others without written consent of Vibrant Ltd. 
and shall not be used except in the performance of this study. 
Any investigator involved with this study is obligated to provide the Sponsor with complete test results and all data derived from the 
study. 
 

 
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28. 
SUBJECT / STUDY DISCONTINUATION 
 
Subjects should be removed from the study whenever considered necessary for their welfare or when the subject expresses a desire to 
withdraw from the study. Non-compliance with the protocol, the occurrence of a Serious Adverse Event or any medical condition that, 
in the opinion of the investigator, warrants discontinuation from the study for the safety of the subject, may necessitate discontinuing a 
subject. If a subject is discontinued, the reason must be entered on the case report form and signed by the investigator. In case of any 
questionable situation, the study monitor or Vibrant Ltd. personnel should be consulted. When a subject is removed from the study as 
a result of Serious Adverse Event, a final physical examination must be performed. Subjects removed from the study because of an 
adverse event will be followed-up until the adverse event has been resolved. 
 
In the case that the occurrence of adverse events is greater than anticipated, the clinical investigation will be suspended; in such a case, 
a safety committee will be arranged to decide if the study could be continued. The Ethics Committee will be notified and the results of 
the safety committee discussions will be brought for the EC/IRB review and decision. 
 
Early termination could be a result of: 
1. Withdrawal of informed consent by the subject. 
2. Subjects who after inclusion develop medical diseases which may affect the function and interpretation of study results. 
3. Serious protocol deviation. 
4. Non-compliance with medical device administration or study procedures as determined by the sponsor. 
5. Change in subject's condition. 
6. Subject is Lost to follow-up. 
7. Confirmed pregnancy. 
8. Regulatory authorities stop the trial. 
 
During the study, subjects exiting the trial will be replaced with new subjects, up to 10%  
 

 
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Vibrant Ltd., reserves the right to discontinue any study for administrative reasons at any time, such as, but not limited to a decision to 
discontinue further clinical investigation with the device, improper conduct of the study by the investigator, inability to obtain the 
number of subjects required by the protocol, etc.  Reimbursements for reasonable expenses will be made if such an action is necessary. 
 
 
 
 
29. 
DEVICE ACCOUNTABILITY  
 
Complete traceability records will be kept of all devices during the study. Vibrant devices and relevant accessories will be provided by 
Vibrant Ltd., bearing required labeling. Device identification and accessory identification will be documented in subject medical records, 
CRF and in center log. 
 
Each clinical investigator will be responsible for the safe storage with restricted access of the investigational materials in their possession, 
thereby preventing use of any materials by any persons not participating in the study. 
All base units and remaining capsules (untouched or taken out of the blister package) must be brought back by the subjects to the site 
by the time they exit the study. The number of remaining capsules must match the information transmitted by the base unit about capsule 
activations and the information gathered about the subject’s treatment compliance throughout the study. In order to perform this task, 
the Sponsor, CRO and study coordinator will rely on the same platform used to monitor protocol deviations related to treatment 
compliance.  A final account, and the whereabouts of each capsule provided to the subject will be documented in the EDC by the study 
coordinator. Capsule failures will not be documented in the EDC but on the external platform, using the base unit information. 
 
After completion of the study, all unused or remaining devices must be returned in their original package to Vibrant Ltd. Hakochav, 
Yokneam 2069206 P.O.Box 516, Israel. 
All investigators will be responsible for using the products according to the IFU and protocol and maintaining product inventory and 
records. 
 

 
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30. 
APPENDICES 
Appendix A – Bristol Stool Scale 
Appendix B - Rome III questionnaire and instructions for completion 
Appendix C – Ease of use questionnaire 
Appendix D – Patient Assessment of Constipation Quality of Life (PAC-QOL) Questionnaire 
Appendix E – TSQM questionnaire 
 
 
 
 
31. 
REFERENCES  
 
1. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of 
chronic constipation in North America. Am J Gastroenterol. 2005;100 Suppl 1:S1–4. 
2. Wilson N, Schey R. Lubiprostone in constipation: clinical evidence and place in therapy. Ther Adv Chronic Dis. 2015 
Mar;6(2):40–50. 
3. Johanson JF, Kralstein J. Chronic constipation: a survey of the subject perspective. Aliment Pharmacol Ther. 2007 Mar 
1;25(5):599–608. 
4. Rome III Diagnostic Criteria [Internet]. [Accessed 2015 Nov 3]. Available from: http://www.romecriteria.org/criteria/ 
5. Only 27% of European subjects with chronic constipation are satisfied with current treatment options [Internet]. [Accessed 2015 
Nov 
3]. 
Available 
from: 
https://www.ueg.eu/education/document-
detail/?name=only_27_of_european_subjects_with_chronic_constipation_are_satisfied_with_current_treatment_options&file=
89240 

 
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6. Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. American College of Gastroenterology monograph on 
the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014 Aug;109 Suppl 
1:S2–26; quiz S27. 
7. Paré P, Fedorak RN. Systematic review of stimulant and nonstimulant laxatives for the treatment of functional constipation. Can 
J Gastroenterol Hepatol. 2014 Nov;28(10):549–57. 
8. Lembo AJ, Schneier HA, Shiff SJ, Kurtz CB, MacDougall JE, Jia XD, et al. Two randomized trials of linaclotide for chronic 
constipation. N Engl J Med. 2011 Aug 11;365(6):527–36. 
9. Soubra M, Schey R. Lubiprostone for the treatment of adult women with irritable bowel syndrome with constipation. Clin Med 
Insights Gastroenterol. 2012;5:23–30.  
10. Wald A. Severe constipation. Clin Gastroenterol Hepatol 2005; 3: 432–5. 
11. Cheung O, Wald A. Management of pelvic floor disorders. Aliment Pharmacol Ther 2004; 19: 481–95. 
12. Tack J, Müller-Lissner S, Stanghellini V, Boeckxstaens G, Kamm MA, Simren M, et al. Diagnosis and treatment of chronic 
constipation--a European perspective. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc. 2011 Aug;23(8):697–710.  
13. Do Stool Form and Frequency Correlate With Whole-Gut and Colonic Transit ?  Results From a Multicenter Study in 
Constipated 
Individuals 
and 
Healthy 
Controls 
[Accessed 
March 
30th, 
2016 
https://www.researchgate.net/publication/38066000_Do_Stool_Form_and_Frequency_Correlate_With_Whole-
Gut_and_Colonic_Transit_Results_From_a_Multicenter_Study_in_Constipated_Individuals_and_Healthy_Controls] 
14. T2081 Bristol Stool Form in Slow Transit Constipation Correlates Inversely With Regional Colon Contractile Activity Measured 
by a Wireless Motility Capsule [Accessed March 30th, 2016 http://www.gastrojournal.org/article/S0016-5085%2810%2962894-
6/pdf] 
15. Stool 
form 
scale 
as 
a 
useful 
guide 
to 
intestinal 
transit 
time. 
[Accessed 
March 
30th, 
2016 
http://www.ncbi.nlm.nih.gov/pubmed/9299672] 

 
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16. Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction 
Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004;2:12. 
Those seeking information regarding or permission to use the TSQM are directed to Quintiles at www.quintilesims.com/TSQM 
or TSQM@quintilesims.com 
17. http://www.earthmicrobiomeproject.org/ in 
18. Caporaso, J. G., Kuczynski, J., Stombaugh, J., Bittinger, K., Bushman, F. D., Costello, E. K., Fierer, N., Pena, A. G., Goodrich, 
J. K., Gordon, J. I., Huttley, G. A., Kelley, S. T., Knights, D., Koenig, J. E., Ley, R. E., Lozupone, C. A., McDonald, D., Muegge, 
B. D., Pirrung, M., Reeder, J., Sevinsky, J. R., Turnbaugh, P. J., Walters, W. A., Widmann, J., Yatsunenko, T., Zaneveld, J. & 
Knight, R. (2010) QIIME allows analysis of high-throughput community sequencing data, Nat Methods. 7, 335-6. 
19. Caporaso JG, L. C., Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, Gormley N, 
Gilbert JA, Smith G, Knight R (2012) Ultra-high throughput microbial community analysis on the Illumina HiSeq and MiSeq 
platforms, Isme J. 6, 1621-1624. 
20. Goodrich, J. K., Di Rienzi, S. C., Poole, A. C., Koren, O., Walters, W. A., Caporaso, J. G., Knight, R. & Ley, R. E. (2014) 
Conducting a microbiome study, Cell. 158, 250-62. 
21. Werner, J. J., Koren, O., Hugenholtz, P., DeSantis, T. Z., Walters, W. A., Caporaso, J. G., Angenent, L. T., Knight, R. & Ley, 
R. E. (2012) Impact of training sets on classification of high-throughput bacterial 16s rRNA gene surveys, Isme J. 6, 94-103. 
22. Koren, O., Knights, D., Gonzalez, A., Waldron, L., Segata, N., Knight, R., Huttenhower, C. & Ley, R. E. (2013) A guide to 
enterotypes across the human body: meta-analysis of microbial community structures in human microbiome datasets, PLoS 
computational biology. 9, e1002863. 
23. Koren, O., Goodrich, J. K., Cullender, T. C., Spor, A., Laitinen, K., Backhed, H. K., Gonzalez, A., Werner, J. J., Angenent, L. 
T., Knight, R., Backhed, F., Isolauri, E., Salminen, S. & Ley, R. E. (2012) Host remodeling of the gut microbiome and metabolic 
changes during pregnancy, Cell. 150, 470-80. 
24. Koren, O., Spor, A., Felin, J., Fak, F., Stombaugh, J., Tremaroli, V., Behre, C. J., Knight, R., Fagerberg, B., Ley, R. E. & 
Backhed, F. (2011) Human oral, gut, and plaque microbiota in patients with atherosclerosis, Proc Natl Acad Sci U S A. 108 
Suppl 1, 4592-8 
25. Winge, K., Rasmussen, D. & Werdelin, L. Constipation in neurological diseases. J.      Neurol. Neurosurg. Psychiatry 74, 13–
19 (2003). 
26. Müller HH, Schäfer H., Adaptive group sequential designs for clinical trials: combining    the advantages of adaptive and of 
classical group sequential approaches. Biometrics. 2001;57:886-891.  

 
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27. Jonathan S. Denne, Sample size re calculation using conditional power. Statist. Med. 2001; 20:2645–2660 
28. Broberg, Sample size re-assessment leading to a raised sample size does not inflate type I error rate under mild conditions. 
Medical Research Methodology 2013, 13:94 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX A – Bristol Stool Scale 
 
 
The Bristol Stool Scale:  
 
How to analyze stools: 
 
Type 1: Stools appear in separate, hard lumps, similar to nuts. Type 
1 stools remained in the colon the longest amount of time; a sure sign 
you’re constipated; most common stools. 
 
Type 2: Stools are sausage-like in appearance but lumpy. Indicate 
toxic constipation and need for intestinal cleansing 
 
Type 3 (Normal): Stools come out similar to a sausage but with 
cracks in the surface. 
 
Type 4 (Normal): Stools are smooth and soft in the form of a 
sausage or snake. 
 
Type 5: Stools form soft blobs with clear-cut edges, and easily pass 
through the digestive system. Soft diarrhea, it may indicate a 
possible risk for bowel disease; also indicate you are toxic and need 
regular intestinal cleansing. 
 
Type 6: Stools have fluffy pieces with ragged edges. Considered 
mushy stools, they indicate diarrhea; and that you are toxic and 
need regular intestinal cleansing. 
 
Type 7: Stool is mostly liquid with no solid pieces. Passed quickly 
through the colon; is indicative of severe diarrhea possibly as a 
result of a viral or bacterial infection. See a doctor as soon as 
possible. 
 

 
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APPENDIX B – ROME III (Questionnaire and Instructions for Completion) 
 
Instructions for completion: 
Complete questions 41 to 67 only. 
 
Scoring Algorithm:  
 
Irritable Bowel Syndrome 
Diagnostic Criteria* 
Recurrent abdominal pain or discomfort at least 3 days/month in last 3 months associated with two or more of criteria #1– #3 below: 
Pain or discomfort at least 2–3 days/month (question 41 > 2) 
For women, does pain occur only during menstrual bleeding? (question 43=0 or 2) 
1. Improvement with defecation 
Pain or discomfort gets better after BM at least sometimes (question 46 > 0) 
2. Onset associated with a change in frequency of stool 
Onset of pain or discomfort associated with more stools at least sometimes (question 47 > 0), OR 
Onset of pain or discomfort associated with fewer stools at least sometimes (question 48 > 0) 
3. Onset associated with a change in form (appearance) of stool 
Onset of pain or discomfort associated with looser stools at least sometimes (question 49 > 0), OR 
Onset of pain or discomfort associated with harder stools at least sometimes (question 50 > 0) 
* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis 
Yes. (question 45=1) 
 
 
 
 

 
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Functional Constipation 
Diagnostic criteria* 
1. Must include two or more of the following: 
a. Straining during at least 25% of defecations. At least often. (question 54 > 1) 
b. Lumpy or hard stools at least 25% of defecations. At least often. (question 53 > 1) 
c. Sensation of incomplete evacuation at least 25% of defecations. At least sometimes. (question 55 > 0) 
d. Sensation of anorectal obstruction/blockage at least 25% of defecations. At least sometimes. (question 56 > 0) 
e. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor). At least sometimes. 
(question 57 > 0) 
f. Fewer than three defecations per week. At least often. (question 52 > 1) 
 
2. Loose stools are rarely present without the use of laxatives. 
Loose stools occur never or rarely (question 49=0), & 
3. Insufficient criteria for IBS 
Diagnostic criteria for IBS not met 
* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. Yes. (question 59=1) 
 
 
 
 
 
 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 90 of 99 
 
 
 
 
APPENDIX C – Ease of use questionnaire 
 
Please rank the following tasks and propositions on a scale from 1 to 5 
(Circle the response that best represents your opinion) 
[1] Connecting the base unit to Wi-Fi 
1 
2 
3 
4 
5 
 
Very Hard 
Hard 
Medium 
Easy 
Very Easy 
 
[2] Setting up the base unit for use 
1 
2 
3 
4 
5 
 
Very Hard 
Hard 
Medium 
Easy 
Very Easy 
 
[3] Activating capsules 
1 
2 
3 
4 
5 
 
Very Hard 
Hard 
Medium 
Easy 
Very Easy 
 
[4] Knowing if the capsules have been successfully activated or not 
1 
2 
3 
4 
5 
 
Very Hard 
Hard 
Medium 
Easy 
Very Easy 
 
[5] Following the treatment for several months once it is commercialized (there 
would be no need to connect the base unit to Wi-Fi) 
1 
2 
3 
4 
5 
 
Very Hard 
Hard 
Medium 
Easy 
Very Easy 
 
[6] How likely would you be to use the capsule if it is commercially available in the 
future? 
1 
2 
3 
4 
5 
 
Not at all likely 
Not likely 
Neutral 
Likely 
Very likely 
 
 
 
 
 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 91 of 99 
 
 
 
 
 
 
 
 
 
 
APPENDIX D – Patient Assessment of Constipation Quality of Life (PAC-QOL) Questionnaire 
 
The following questions are designed to measure the impact constipation has had on your daily life over the past 2 weeks. For each question, please check 
one box. 
The following questions ask about your symptoms related to constipation. During the 
past 2 weeks, to what extent or intensity have you . . . 
Not at all 
1 
A little bit 
2 
Moderately 
3 
Quite a bit 
4 
Extremely 
5 
1. Felt bloated to the point of bursting? 
☐ 
☐ 
☐ 
☐ 
☐ 
2. Felt heavy because of your constipation? 
☐ 
☐ 
☐ 
☐ 
☐ 
The next few questions ask about how constipation affects your daily life. During the 
past 2 weeks, how much of the time have you . . . 
None of 
the time 
1 
A little of 
the time 
2 
Some of 
the time 
3 
Most of the 
time 
4 
All of the 
time 
5 
3. Felt any physical discomfort? 
☐ 
☐ 
☐ 
☐ 
☐ 
4. Felt the need to have a bowel movement but not been able to? 
☐ 
☐ 
☐ 
☐ 
☐ 
5. Been embarrassed to be with other people? 
☐ 
☐ 
☐ 
☐ 
☐ 
6. Been eating less and less because of not being able to have bowel movements? 
☐ 
☐ 
☐ 
☐ 
☐ 
The next few questions ask about how constipation affects your daily life. During the 
past 2 weeks, to what extent or intensity have you . . . 
Not at all 
1 
A little bit 
2 
Moderately 
3 
Quite a bit 
4 
Extremely 
5 
7. Had to be careful about what you eat?  
☐ 
☐ 
☐ 
☐ 
☐ 
8. Had a decreased appetite?  
☐ 
☐ 
☐ 
☐ 
☐ 
9. Been worried about not being able to choose what you eat (for example, at a 
friend’s house)? 
☐ 
☐ 
☐ 
☐ 
☐ 
10. Been embarrassed about staying in the bathroom for so long when you were 
away from home? 
☐ 
☐ 
☐ 
☐ 
☐ 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 92 of 99 
 
 
 
11. Been embarrassed about having to go to the bathroom so often when you 
were away from home? 
☐ 
☐ 
☐ 
☐ 
☐ 
12. Been worried about having to change your daily routine (for example, 
traveling, being away from home)? 
☐ 
☐ 
☐ 
☐ 
☐ 
 
 
 
The next few questions ask about your feelings related to constipation. During the past 
2 weeks, how much of the time have you . . . 
None of 
the time 
1 
A little of 
the time 
2 
Some of 
the time 
3 
Most of the 
time 
4 
All of the 
time 
5 
13. Felt irritable because of your condition?  
☐ 
☐ 
☐ 
☐ 
☐ 
14. Been upset by your condition?  
☐ 
☐ 
☐ 
☐ 
☐ 
15. Felt obsessed by your condition?  
☐ 
☐ 
☐ 
☐ 
☐ 
16. Felt stressed by your condition?  
☐ 
☐ 
☐ 
☐ 
☐ 
17. Felt less self-confident because of your condition?  
☐ 
☐ 
☐ 
☐ 
☐ 
18. Felt in control of your situation?  
☐ 
☐ 
☐ 
☐ 
☐ 
The next questions ask about your feelings related to constipation. During the past 2 
weeks, to what extent or intensity have you . . . 
Not at all 
1 
A little bit 
2 
Moderately 
3 
Quite a bit 
4 
Extremely 
5 
19. Been worried about not knowing when you are going to be able to have a 
bowel movement? 
☐ 
☐ 
☐ 
☐ 
☐ 
20. Been worried about not being able to have a bowel movement? 
☐ 
☐ 
☐ 
☐ 
☐ 
21. Been increasingly bothered by not being able to have a bowel movement? 
☐ 
☐ 
☐ 
☐ 
☐ 
The next questions ask about your life with constipation. During the past 2 weeks, how 
much of the time have you . . . 
 
None of 
the time 
1 
A little of 
the time 
2 
Some of 
the time 
3 
Most of the 
time 
4 
All of the 
time 
5 
22. Been worried that your condition will get worse?  
☐ 
☐ 
☐ 
☐ 
☐ 
23. Felt that your body was not working properly?  
☐ 
☐ 
☐ 
☐ 
☐ 
24. Had fewer bowel movements than you would like? 
☐ 
☐ 
☐ 
☐ 
☐ 
The next questions ask about your degree of satisfaction related to constipation. 
During the past 2 weeks, to what extent or intensity have you been . . . 
Not at all 
1 
A little bit 
2 
Moderately 
3 
Quite a bit 
4 
Extremely 
5 
25. Satisfied with how often you have a bowel movement?  
☐ 
☐ 
☐ 
☐ 
☐ 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 93 of 99 
 
 
 
26. Satisfied with the regularity of your bowel movements?  
☐ 
☐ 
☐ 
☐ 
☐ 
27. Satisfied with the time it takes for food to pass through the intestines? 
☐ 
☐ 
☐ 
☐ 
☐ 
28. Satisfied with your treatment? 
☐ 
☐ 
☐ 
☐ 
☐ 
 
 
 
 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 94 of 99 
 
 
 
APPENDIX E– TSQM Questionnaire 
 
TSQM (Version 1.4) 
Treatment Satisfaction Questionnaire for Medication 
 
Instructions:  Please take some time to think about your level of satisfaction or 
dissatisfaction with the treatment you are taking in this clinical trial.  We are 
interested in your evaluation of the effectiveness, side effects, and convenience of 
the treatment over the last two to three weeks, or since you last used it.  For each 
question, please place a single check mark next to the response that most closely 
corresponds to your own experiences. 
 
1. How satisfied or dissatisfied are you with the ability of the treatment to prevent or treat your 
condition?  
 
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
2. How satisfied or dissatisfied are you with the way the treatment relieves your symptoms?  
 
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 95 of 99 
 
 
 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
3. How satisfied or dissatisfied are you with the amount of time it takes the treatment to start 
working?  
 
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 
 
4.  As a result of taking this treatment, do you experience any side effects at all? 
 
□1   Yes 
□0   No  (if No, then please skip to Question 9) 
 
 
5. How bothersome are the side effects of the treatment you take to treat your condition?  
 
□1   Extremely Bothersome 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 96 of 99 
 
 
 
□2   Very Bothersome 
□3   Somewhat Bothersome 
□4   A Little Bothersome 
□5   Not at All Bothersome 
 
6. To what extent do the side effects interfere with your physical health and ability to function 
(i.e., strength, energy levels, etc.)?  
 
□1   A Great Deal 
□2   Quite a Bit 
□3   Somewhat 
□4   Minimally 
□5   Not at All 
 
7. To what extent do the side effects interfere with your mental function (i.e., ability to think 
clearly, stay awake, etc.)?  
 
□1   A Great Deal 
□2   Quite a Bit 
□3   Somewhat 
□4   Minimally 
□5   Not at All 
 
8. To what degree have treatment side effects affected your overall satisfaction with the 
treatment?  

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 97 of 99 
 
 
 
 
□1   A Great Deal 
□2   Quite a Bit 
□3   Somewhat 
□4   Minimally 
□5   Not at All 
 
9. How easy or difficult is it to use the treatment in its current form?  
 
□1   Extremely Difficult 
□2   Very Difficult 
□3   Difficult 
□4   Somewhat Easy 
□5   Easy 
□6   Very Easy 
□7   Extremely Easy 
 
10. How easy or difficult is it to plan when you will use the treatment each time?  
 
□1   Extremely Difficult 
□2   Very Difficult 
□3   Difficult 
□4   Somewhat Easy 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 98 of 99 
 
 
 
□5   Easy 
□6   Very Easy 
□7   Extremely Easy 
 
11. How convenient or inconvenient is it to take the treatment as instructed?  
 
□1   Extremely Inconvenient 
□2   Very Inconvenient 
□3   Inconvenient 
□4   Somewhat Convenient 
□5   Convenient 
□6   Very Convenient 
□7   Extremely Convenient 
 
 
12. Overall, how confident are you that taking this treatment is a good thing for you?  
 
□1   Not at All Confident 
□2   A Little Confident 
□3   Somewhat Confident 
□4   Very Confident 
□5   Extremely Confident 
 
13. How certain are you that the good things about your treatment outweigh the bad things?  
 

 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-270 
Doc No: 270CLD  
Rev: 01 Date: 24 Jan 2019 
Page 99 of 99 
 
 
 
□1   Not at All Certain 
□2   A Little Certain 
 
□3   Somewhat Certain 
□4   Very Certain 
□5   Extremely Certain 
 
14. Taking all things into account, how satisfied or dissatisfied are you with this treatment?  
 
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 
 
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