Clinical trial NCT04458675
Conditions: Chronic Idiopathic Constipation
Sponsor: Vibrant Ltd.
Start date: 2018-07-26; Completion date: 2019-03-30
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The was performed to assess the safety and efficacy of the vibrant capsule vs. placebo for the treatment of subjects with functional Constipation.

Detailed description:
Visit 1 -Screening: Subjects will be screened to the study at the screening visit, PAC-QOL questionnaire will be completed and subject will have a run-in time for a period of 2-3 weeks, assuring 14 consecutive days of eDiary with an average of \< 3 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 or Vibrant placebo for a treatment period of 8 weeks. Subjects, in both arms, will have their first administration of Vibrant capsule / Vibrant placebo on site at the day of baseline visit and will be instructed on their treatment administration at home and will be requested to ingest the capsules at a specific time of the day. At baseline, subjects will also be trained on how to use the base unit at home.

Subjects will be instructed to complete a simple subject eDiary each day throughout the duration of the study (including the run-in period).

The eDiary will include questions on:

* Daily BM, SBM, CSBM
* Change of their 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 consistancy, straining, bloating, and the other questions in the eDiary
* Medication
* AE (including diarhrea)

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 safety and treatment efficacy and additional capsule dispencing.

Visit 4 Final visit -after another 4 weeks of treatment - an on site visit will take place to evaluate subject's safety and treatment efficacy and collect the base unites and remaning capsules. 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.

Subjects will be asked to refrain from taking any medication or supplement to relieve their constipation, during the entire study period.

Subjects will receive phone calls at least once a week and subject 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.

Data about time of activation of the capsules will be automatically registered and transmitted by the base unit for Vibrant capsules

Arms: arm 1: Active capsule arm 2: Placebo capsule
Interventions: intervention 1: Vibrant capsule intervention 2: Placebo
Intervention descriptions: intervention 1: The capsule vibration mechanically stimulates the inner wall of the GI and stimulates motility intervention 2: A biodegradable capsule, which visually similar to the Vibrant active capsule

Protocol documents:
Prot_SAP_000.pdf: 
 
VIBRATING CAPSULE 
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NCT number - NCT04458675 
 
Vibrant Ltd. 
Study Protocol 
 
Study number: V-250 
Protocol number: 250CLD  
Protocol Date: Oct 7th  , 2018  
Rev. 02 
 
A prospective, Multicenter, Randomized, 
Single Blind, Placebo-Controlled Study to 
Assess the Efficacy and Safety of Vibrant 
Capsule vs. Vibrant Placebo for the 
Treatment of Chronic Idiopathic 
Constipation (CIC) 
 
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: 
 
 
 
Lior Ben-Tsur                         -----------------------------  
         ------------------------ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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 ............................................................................................................. 14 
6. 
BACKGROUND ............................................................................................................... 14 
7. 
DEVICE NAME AND INTENDED USE ............................................................................... 17 
7.1 
Device Name ................................................................................................................. 17 
7.2 
Intended Use ................................................................................................................ 17 
8. 
DEVICE DESCRIPTION .................................................................................................... 17 
8.1 
Capsule ......................................................................................................................... 18 
8.1.1 Vibrant Active: .............................................................................................................. 18 
8.1.2 Vibrant Placebo: ........................................................................................................... 19 
8.2 
Accessory: activation base unit ..................................................................................... 19 
8.3 
Mode of operation ........................................................................................................ 20 
9. 
RISKS & BENEFITS .......................................................................................................... 20 
9.1 
Risks .............................................................................................................................. 22 
9.2 
Benefits ......................................................................................................................... 24 
10. 
ANIMAL INVESTIGATIONS ......................................................................................... 24 
11. 
HUMAN CLINICAL INVESTIGATIONS .................................................................. 25 
12. 
STUDY OBJECTIVE ......................................................................................................... 33 
13. 
STUDY ENDPOINTS ........................................................................................................ 33 
13.1 Primary endpoint .......................................................................................................... 33 
13.2 Secondary endpoints .................................................................................................... 34 
14. 
STUDY CONDUCT & POPULATION ................................................................................. 35 
14.1 Inclusion Criteria ........................................................................................................... 35 
14.2 Exclusion Criteria .......................................................................................................... 35 
14.3 Duration of Study .......................................................................................................... 36 
15. 
STUDY TREATMENT ...................................................................................................... 37 
15.1 Study Design ................................................................................................................. 37 
15.2 Medical History ............................................................................................................. 39 
15.3 Constipation History ..................................................................................................... 39 
15.4 Physical Examination .................................................................................................... 39 


 
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15.5 Assessment of pelvic floor dysfunction (defecatory disorder) ...................................... 39 
15.6 Blood and urine tests .................................................................................................... 40 
15.7 Screening visit (day -21 to -14) ..................................................................................... 40 
15.8 Run-in period (day -21 to -14, to -1) ............................................................................. 40 
15.9 Treatment ..................................................................................................................... 41 
15.10 Rescue Treatment ......................................................................................................... 42 
15.11 Termination visit ........................................................................................................... 43 
15.12 Concomitant medication .............................................................................................. 43 
15.13 Prohibited medication .................................................................................................. 44 
15.14 Recording ...................................................................................................................... 44 
15.15 Study Schedule ............................................................................................................. 44 
15.16 Deviations from study protocol .................................................................................... 45 
15.17 Investigative Center Selection Criteria .......................................................................... 46 
16. 
ADVERSE EVENTS RECORDING………….. ....................................................................... ..46 
16.1 Reporting Requirements ............................................................................................... 46 
16.2 Definitions .................................................................................................................... 46 
16.3 Anticipated Adverse Events .......................................................................................... 48 
16.4 Adverse Event Reporting .............................................................................................. 49 
16.4.1 Intensity or Severity ...................................................................................................... 49 
16.4.2 Relatedness................................................................................................................... 49 
16.4.3 Outcome ....................................................................................................................... 50 
16.4.4 Treatment or Action taken ............................................................................................ 50 
16.5 Expedited Reporting of Serious Adverse Events ........................................................... 50 
16.6 Follow- Up of Unresolved Events .................................................................................. 51 
17. 
STATISTICAL CONSIDERATIONS ..................................................................................... 51 
17.1 Study Design and Objectives ......................................................................................... 51 
17.2 Study Endpoints ............................................................................................................ 52 
17.3 Statistical Hypothesis .................................................................................................... 52 
17.4 Sample size ................................................................................................................... 52 
17.5 Interim Analyses ........................................................................................................... 52 
17.5.1      Procedure ................................................................................................................ 52 
17.5.2 Blinding ......................................................................................................................... 52 
17.5.3 Decision Rules ............................................................................................................... 53 
17.5.4 Controlling the Alpha level for the primary endpoint ....... Error! Bookmark not defined. 
17.6 Randomization .............................................................................................................. 53 
17.7 Blinding ......................................................................................................................... 53 
17.8 Data Analysis Sets ......................................................................................................... 53 
17.8.1 Intent to Treat (ITT) ...................................................................................................... 53 
17.8.2 Modified Intent to Treat (mITT) .................................................................................... 53 
17.8.3 Per-Protocol (PP) .......................................................................................................... 54 
17.8.4 Statistical Analysis of Analysis Sets ............................................................................... 54 
17.9 Statistical Analysis ......................................................................................................... 54 


 
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17.9.1 General Considerations................................................................................................. 54 
17.9.2 Significance levels and handling of type I error ............................................................ 54 
17.9.2.1 
Type I Error ............................................................................................................ 54 
17.9.3 Demographic and Other Baseline Variables .................................................................. 54 
17.9.4 Disposition of Subjects .................................................................................................. 55 
17.9.5 Efficacy Analysis ............................................................................................................ 55 
17.9.6 Treatment by Center Interaction .................................................................................. 55 
17.9.7 Safety Analysis .............................................................................................................. 56 
17.9.8 Handling of Missing Data .............................................................................................. 56 
18. 
DATA MONITORING PLAN ............................................................................................. 56 
19. 
DATA CONFIDENTIALITY................................................................................................ 58 
20. 
FUNDING....................................................................................................................... 58 
21. 
ETHICS ........................................................................................................................... 58 
22. 
INFORMED CONSENT .................................................................................................... 59 
23. 
REGULATORY AND HEALTH AUTHORITY AUDITS .......................................................... 60 
24. 
ELECTRONIC REPORTING OF DATA ............................................................................... 60 
25. 
RECORD RETENTION ..................................................................................................... 60 
26. 
PROTOCOL MODIFICATIONS ......................................................................................... 61 
27. 
PUBLICATION POLICY .................................................................................................... 61 
28. 
SUBJECT / STUDY DISCONTINUATION ........................................................................... 61 
29. 
DEVICE ACCOUNTABILITY ............................................................................................. 62 
30. 
APPENDICES .................................................................................................................. 63 
31. 
REFERENCES .................................................................................................................. 63 
 
 


 
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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 
TSQM 
US 
USADE 
Serious Adverse Event 
Serious Adverse Device Effect 
Spontaneous Bowel Movement 
Treatment Satisfaction Questionnaire for Medication 
United States 
Unanticipated Serious Adverse Device Effect 


 
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4. Protocol Synopsis 
 
Title 
A prospective, multicenter, randomized, single blind, Placebo-controlled 
study to assess the efficacy and safety of Vibrant capsule vs. Vibrant 
placebo for the Treatment of Chronic Idiopathic Constipation (CIC). 
Indication 
The Vibrant Capsule is intended for the treatment of subjects with functional 
Constipation. 
Objectives 
The objectives are to assess the efficacy and safety of the Vibrant capsule 
administered 5 times per week  
Number of 
Subjects 
up 60 pts 
 
Number of 
centers 
The study will be performed in up to 20 centers in the USA. 
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, multicenter, randomized, single blind, placebo-
controlled study, to evaluate the efficacy and safety of the Vibrant Capsule 
vs. Vibrant placebo in relieving constipation in subjects with functional 
constipation. 
 
Two arms will be assessed:  
- 
Vibrant Capsule administered 5 times per week 
- 
Vibrant Placebo Capsule administered 5 times per week 
 
An interim analysis will be performed after all the subjects have completed 
4 weeks of treatment. The following parameters will be assessed: main 
safety parameters, and a pecific efficacy parameter.  
 Depending on the results of the interim analyis: 
 The study will be stopped, 
 The study will continue as planned. 
 
Method  
 
Subjects will come for 4 visits: Screening (visit 1), baseline (visit 2), after 4 
treatment weeks (visit 3), after 4 treatment weeks 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 and subject will have a 


 
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run-in time for a period of 2-3 weeks, assuring 14 consecutive days of 
eDiary with an average of < 3 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 
or Vibrant placebo for a treatment period of 8 weeks. Subjects, in both arms, 
will have their first administration of Vibrant capsule / Vibrant placebo on 
site at the day of baseline visit and will be instructed on their treatment 
administration at home and will be requested to ingest the capsules at a 
specific time of the day. At baseline, subjects will also be trained on how to 
use the base unit at home.  
  
Subjects will be instructed to complete a simple subject eDiary each day 
throughout the duration of the study (including the run-in period).  
The eDiary will include questions on: 
 Daily BM, SBM, CSBM  
 Change of their 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 consistancy, straining, bloating, 
and the other questions in the eDiary    
 Medication 
 AE (including diarhrea) 
 
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 safety and treatment efficacy and additional capsule 
dispencing.  
Visit 4 Final visit –after another 4  weeks of treatment - an on site visit will 
take place to evaluate subject's safety and treatment efficacy and collect the 
base unites and remaning capsules. 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. 
Subjects will be asked to refrain from taking any medication or supplement 
to relieve their constipation, during the entire study period.  
Subjects will receive phone calls at least once a week and subject 
compliance will be monitored  throughout the 8 weeks of the study. 


 
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Subjects will be authorized to use rescue medication after 3 consecutive 
days without a bowel movement.  
Data about time of activation of the capsules will be automatically registered 
and transmitted by the base unit for Vibrant capsules.  
 
Endpoints 
Primary endpoints  
Efficacy: 
The primary efficacy endpoint is CSBM 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. 
CSBM & SBM is defined as a bowel movement that occurs at least 48h after 
laxative/rescue intake without digital maneuver) 
• 
Subjects with less than 2 weeks (with at least 5 days per week) of 
valid diary entries during the treatment period will be considered as 
non-evaluable. 
  
Safety Endpoints: 
• 
Safety endpoints include all adverse events related and unrelated to 
the study treatment 
 
 
Secondary efficacy endpoints include:  
• 
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. 
• 
Change from baseline in average stool consistency, using the Bristol 
Stool Scale 
• 
Change from baseline in average straining. 
• 
PAC-QoL 
 
 
Additional efficacy endpoints  
• 
Change from baseline in average bloating. 
• 
Number / percentage of subjects who reported using rescue 
medication during treatment period 
• 
Change from baseline in weekly number of Spontaneous Bowel 
Movement (SBM). 


 
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• 
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. 
• 
Ease of use 
• 
TSQM (validated treatment satisfaction questionnaire)  
Subject 
Population 
Subjects with Functional 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 <3 Spontaneous Bowel Movements 
(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 
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. 


 
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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. 
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. 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 
 
Sample size: 
No formal sample size calculations were performed. A sample size of 40 
subjects (20 in each arm) is deemed sufficient to fulfill the main goals of 
the study. 
The sample size may be increased to up to 44 subjects to account for a 
potential ~10% drop-out rate. 
 
Main Efficacy Analysis: 
Statistical analyses will be mainly descriptive in nature. The subject’s 
CSBM success status (i.e. if the subjects achieve an increase from baseline 
of at least 1 weekly CSBM during at least 6 of the 8 treatment weeks) will 
be presented in tabular form by study arm, along with 95% Wilson score 
Confidence Intervals (CI).  
 
 
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 


 
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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. 
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 


 
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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 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. 


 
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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.  
 
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). 
 
8. 
DEVICE DESCRIPTION 
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). 
 Delay Mechanism - A delay mechanism was incorporated in this device to allow 
sufficient time for the capsule to arrive at the large intestine before it starts vibrating. The 
delay mechanism is the time between swallowing the capsule and activation and inducing 
vibrations within the large intestine. This is obtained by a software programing 
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 Sequence Mechanism – sequence of vibration, specifically adapted for subjects with 
constipation. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 that will define number of hours 
from the activation to the vibrating phase (delay time). 
This delay will allow the capsule to reach the large intestine before starting the vibrations. 
  
 
 
The capsules are packaged in a blister of 10 units (cf. Fig. 2 below).  
Figure 1. The capsule and components 


 
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8.1.2 
Vibrant Placebo:  
A biodegradable capsule, which visually similar to the Vibrant active capsule. 
 
8.2 
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.  
 
 
1. Base Unit 
2. USB cable  
3. AC/DC USB adapter  
 
 
 
 
 
 
 
 
 
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 
 
 
 


 
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Figure 2. 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 and a short “buzz” is heard, indicating 
that the base unit is ready for use.  
 
Activation of the Vibrant Capsule using the base unit 
 
 
 
8.3 
Mode of operation 
The Activation base is shipped in a protective package containing the following: 
- 
Base Unit 
- 
USB cable  
- 
AC/DC USB adapter  
- 
Instructions for use 
The Vibrant Capsules are shipped in a blister containing 10 capsules. 
 
Capsule activation: 
1. The capsule will be placed in the designated groove in the center 
2. The green "Ready" indicator light turns on 
3. The capsule is ready to be administered by the subject. 
4. Capsule will reach the large intestine (within approximately 6-8 hours) and start 
predefined vibrating program, inducing peristaltic activity.  
5. Capsule will be extracted from the body during normal bowel movement. 
 
Additional details can be found within the Investigator's Brochure (Document # 114CLD,) and 
the Instruction For Use (IFU) for the vibrating capsule (Document # 117LAB). 
 
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.  


 
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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 
 
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. System delay mechanism verification test 
d. pH Resistance test 
e. Mechanical integrity test  
f. Evaluation of capsules Vibrations sequence 
g. Electrical safety and EMC  
h. Environmental and transportation test. 
 


 
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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.  
 
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 patient who has 
this device may result in patient injury  


 
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 A thorough understanding of the technical principles, clinical applications and risks 
associated with the Vibrant capsules is necessary before using this product 
 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 
 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  
 
The Vibrant capsule is administered by prescription only and should not be given to 
anyone without a prescription  
 
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 patients 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. 
 
 
 


 
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9.2 
Benefits 
 
 
Human Clinical Investigations 
 
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 
vibrating movement. The time of defecation and stool consistency were recorded. The capsules 


 
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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, 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 


 
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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.  
 
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. 


 
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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 
 
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% 


 
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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: 
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.  


 
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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  
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% 
. 
. 
. 
 


 
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The primary efficacy endpoints results are: –  
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). 
 
 
 
 
 
 
 
 
 
 


 
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Graph 1: Vibration during 48 hours 
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: 
 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" 
 


 
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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  
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 


 
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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: 
 
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 the Vibrant capsule administered 5 times 
per week. 
 
13. 
STUDY ENDPOINTS 
13.1 
Primary endpoint 
 
 
Efficacy: 


 
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The primary efficacy endpoint is the CSBM 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 
• 
CSBM & SBM is defined as a bowel movement that occurs at least 48h after 
laxative/rescue intake without digital maneuver) 
• 
Subjects with less than 2 weeks (with at least 5 days per week) of valid diary entries 
during the treatment period will be considered as non-evaluable.  
 
Safety: 
Safety endpoints include all adverse events related and unrelated to the study treatment 
13.2 
Secondary endpoints 
 
Secondary efficacy endpoints include:  
- 
SBM success rate, defined as 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 
Subjects with less than 2 weeks (with at least 5 days per week) of valid diary entries 
during the treatment period will be considered as non-evaluable. 
- 
Change from baseline in average stool consistency, using the Bristol Stool Scale 
- 
Change from baseline in average straining. 
- 
PAC-QoL 
 
Additional effciacy endpoints 
- 
Change from baseline in average bloating. 
- 
Number / percentage of subjects who reported using rescue medication during 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 capsule activation. 
- 
Ease of use  
- 
TSQM (validated treatment satisfaction questionnaire) 
 


 
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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 <3 Spontaneous Bowel Movements (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 
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 


 
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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. 
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 symptoms and medication usage 
17. 
Subject participated in a previous Vibrant study 
18. 
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 up to 60 pts. 


 
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15. 
STUDY TREATMENT 
15.1 
Study Design 
 
The study is a prospective, multicenter, randomized, single blind, placebo-controlled study to 
evaluate the efficacy and  safetyof  Vibrant capsule vs. Vibrant placebo. 
 
The objective is to assess the efficacy and safety of the Vibrant Capsule with a frequency of 
administration of 5 capsules per week. 
 
The study will be performed in up to 20 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 inclusion 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.  
 
Subjects 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 throroughly assessed. Subject demographic and 
medical information acquired from the subject or the subject's medical chart, including age, gender, 
previous medical history, risk factors etc. will be also recorded on the eCRF.  
In addition, subjects will undergo a physical examination including digital rectal examination, vital 
sign measurements and blood tests.  
 
Rome III questionnaire to confirm the diagnosis of Chronic Idiopathic Constipation and fill out the 
Bristol Stool Scale questionnaire will be assessed.  Findings will be recorded on the eCRF. 
 


 
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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, and will perform a daily self-assessment of their normal 
spontaneous bowel movements for 14 consecutive days  (run-in period), utilizing the eDiary. 
Subjects will also be asked to record clinical symptoms and usage of any medication or supplement 
on the eDiary during the run-in period.  
 
After the run-in period the subjects will visit the medical center for the baseline visit. Eligibility 
will be re-assessed and confirmed based on the subject's completed eDiary and Rome III 
questionnaire. The subject will be trained in the medical center to use the base unit. He will activate 
himself the first capsule and will ingest it in front of the medical staff. All the other capsules will 
be ingested from the home of the subject. Only the first ingestion will take place in the medical 
center.  
During the treatment period, subjects will ingest Vibrant Capsule 5 days per week: one capsule on 
Mondays, Tuesdays, Thursdays, Friday  and saterdays  . Subject will not ingest any capsule 
onWednesdays, and Sundays. The subject will ingest a total of 40 capsules in 8 weeks considering 
the sequence. 
If the baseline visit falls on a Sunday or Wednesday, the subject should ingest the first capsule on 
site and skip the next day.  
 
Following this the subject should follow the normal schedule. 
 
Capsule intake will ideally be performed during the evening, between 9 PM and 10 PM (except on 
days where a capsule is ingested on site). 
 
The subjects will be asked to refrain from taking any medication or supplement they are using to 
relieve their constipation until they complete the study (rescue treatment is allowed as per section 
15.10).  
After 8 weeks, treatment will be ceased and subjects will visit the medical center one last time for 
evaluation and completion of Rome III questionnaire and other assessments.   
 
Subjects will be instructed to complete a simple subject eDiary throughout the duration of the study 
starting from the run-in period. This will include daily recordings of capsule intake, number and 
time of bowel movements, clinical symptoms, adverse events, satisfaction score and 
medication/supplements usage, including rescue medication. 
 
Please refer to section 15.15 for a detailed study schedule. 
 


 
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Data collection will include physician identification, investigational device identification data and 
usage of the capsule. This data will be documented on the eCRF, together with the occurrence of 
any adverse events during the capsule usage. 
 
All subject adverse events (whether device related or not) will be recorded during the course of the 
clinical study. All serious adverse events/complications will be reported immediately (within 24 
hours) to the study sponsor/monitor , to the Institutional Review Board and according to the local 
regulatory requirements. 
 
15.2 
Medical History 
Subject 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. 
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.   
 


 
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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) 
At the screening visit, subjects will be evaluated for eligibility and undergo physical examination, 
digital rectal examination, vital sign measurements and blood tests. They will undergo a thorough 
interview about their constipation and the Rome III questionnaire (see appendix B) will be 
completed. The Bristol Stool Scale (see Appendix A) and PAC-QOL (see Appendix E) will also 
be completed by the subject.  
 
The investigator will confirm their eligibility and their physical and mental suitability to participate 
in this study.  
Subjects exiting the trial at this stage will be considered screening failure subjects and be replaced 
with new subjects. 
 
The subject will be trained by the study coordinator to access and use the eDiary.  
The eDiary contains questions about bowel movements and their associated clinical symptoms 
(straining, abdominal pain, abdominal discomfort, abdominal gas, bloating, need for digital 
maneuver, sensation of complete evacuation), usage of rescue medication, adverse events and 
usage of other medication or supplements (name of drug, dosage, number of takes per day, reason 
for medication).  
The information will be transferred to the eCRF every day.  
 
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. The daily diary can be found in Appendix D. 
  
15.8 
Run-in period (day -21 to -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. 
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. 
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. The run-


 
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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. 
 
 
The subjects will receive at least 1 short phone call/week from the study coordinator, if needed.  
The phone calls will be about 5-10 minutes long and will ask check subject compliance with the 
eDiary, occurrence of adverse events, and use of rescue medication, subject understanding of what 
he 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. 
Subjects who fail to fill in their diary 3 times or more (not due to technical issues) during the run-
in period may be considered as screening failures due to lack of compliance. 
15.9 
Treatment 
On day 0 (baseline visit), the subject will arrive to the clinic. Eligibility will be re-assessed and 
confirmed based on the Rome III questionnaire and on the subject's completed diary. Subjects need 
to have an average of less than 3 SBM per week during the two weeks of run-in..  
 
Eligible subjects will be randomized to: 
- 
Vibrant arm –with a frequency of administration of 5 capsules per week, OR 
- 
Vibrant Placebo arm –with a frequency of administration of 5 capsules per week 
 
Treatment duration is 8 weeks. 
The subject will be trained by the study coordinator to use the base unit and activate the capsules. 
After an oral explanation, the subject will read the base unit user manual, and the study coordinator 
will make sure the subject fully understands how to use the base unit. The subject will then activate 
the first capsule, in front of the study coordinator, and swallow it.  
The subject will then be released home with the base unit and capsules for the first four weeks of 
treatment. The subject will be asked to continue with the daily completion of the eDiary. The first 
2 weeks of treatment will be considered as a subjects’ training period. 
Actual point of enrollment for the subject is considered the day of first capsule intake. 
 
Subjects will be asked to refrain from any medication or supplement they are using to relieve their 
constipation, throughout the treatment period. A rescue treatment will be authorized upon need 
(refer to section 15.10 for details).  


 
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Capsule intake should take place ideally during the evening between 9 PM and 10 PM, on 
Mondays, Tuesdays, Thursdays, Fridays and Saturdays.  
The first intake, which will take place in the medical center during the day, will not follow these 
rules.  
 
Capsule distribution for the subject will be in 2 time points: 
- 
Day 0 (baseline visit): capsules for 4 weeks of treatment will be provided 
- 
Day 28 ± 2 days (treatment visit 1): capsules for 4 weeks of treatment will be provided 
 
The subjects will receive at least one phone call per week from the study coordinator.  
The phone calls will be about 5-10 minutes long and will check subject compliance with capsule 
ingestion and 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. 
Compliance of the subject will be closely monitored.  
 
Overall the subject will visit the site once during the treatment period: 4 weeks after the baseline 
visit. The last visit will be 4 weeks after baseline and will be the termination visit. The subject will 
receive the capsules in 2 separate visits: 
- 
Baseline visit: 20 capsules for 4 weeks of treatment (5 capsules for each week) and a spare 
blister with 10 capsules 
- 
Visit 1 during treatment period: 20 capsules for 4 weeks of treatment (5 capsules for each 
week). 
The subject will receive 1 blister of spare capsules at the baseline visit and must bring back to the 
site all remaining capsules in his/her possession for each visit. The capsules must be counted and 
accounted for. 
During each 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 topic relevant.  
 
 
15.10 
Rescue Treatment 
 
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.  


 
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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® suppository/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. 
In a situation where the investigator prescribes a rescue medication/supplement that is not in the 
above list, the investigator will need to mention it and give the reason in a note to file or 
appropriate form. 
 
Subjects who take rescue medication three times or more during the run-in period will be 
considered as screening failures. 
 
A spontaneous bowel movement is defined as a bowel movement that occurs at least 48h after 
laxative/rescue intake and without digital maneuver. 
A complete spontaneous bowel movement is defined as a spontaneous bowel movement 
associated with a feeling of complete evacuation by the subject. 
 
15.11 
Termination visit 
After 8 weeks, treatment will be ceased. Subjects will visit again the medical center for 
evaluation and completion of the, ease of use questionnaire, PAC-QOL, TSQM (Treatment 
Satisfaction Questionnaire for Medication)16 , termination form and end of study form. The 
subject will be evaluated for occurrence of adverse events, concomitant medication/rescue and 
compliance to the eDiary and treatment. 
The subjects will bring back all remaining capsules in their possession as well as the base unit. 
The capsules must be counted and accounted for. 
 
The ease of use , PAC-QOL questionnaires and TSQM can be found in Appendix C E and F 
respectively. 
15.12 
Concomitant medication 
All medication taken by the subject in addition to the investigational device is termed 
concomitant medication.  All concomitant medication taken during the study must be 


 
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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 daily on the eDiary.  
15.13 
Prohibited medication 
The medications listed below will be prohibited during the entire study:  
- 
Medications that may affect intestinal motility  
- 
Prokinetics 
- 
Anti-Parkinsonian medications 
- 
Opiates 
- 
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. 
15.14 
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 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. 
15.15 
Study Schedule   
Table 1 summarizes the required data collection from assessments and tests performed during the 
study. 
 
Procedures 
Screening 
Baseline 
Treatment 
visit 1 
Termination 
visit 
  
  


 
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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 
+ 
 
 
 
  
Blood test 
+ 
 
 
 
  
Urine Pregnancy test (if 
applicable) 
 
+ 
 
 
  
Administration of 
capsule 
 
+ 
 
 
  
Rome III 
+ 
+ 
 
 
  
Bristol Stool 
+ 
 
 
 
  
PAC-QOL 
+ 
 
 
+ 
 
TSQM & Ease of use 
 
 
 
+ 
 
Subject eDiary 
+ 
+ 
+ 
+ 
  
Adverse Events 
+ 
+ 
+ 
+ 
  
Concomitant Medication 
+ 
+ 
+ 
+ 
  
Table 1 – Study Schedule of Assessments 
 
15.16 
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 
Wednesday or Sunday, 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. 
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 


 
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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. 
 
15.17 
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. 
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 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 


 
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(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. 
 
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.  
 
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.  
 


 
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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 
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 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. 
Anticipated Adverse Events include those that are reasonably expected to occur in association 
with a clinical investigation assessing a treatment for functional 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  


 
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 
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 
by the investigator 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:  
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. 


 
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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 16.5 Expedited Reporting of 
Serious Adverse Events). 
Recovered without sequelae - The subject returned to baseline status 
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: 
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 
 


 
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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. 
 
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, multicenter,  randomized, single blind, placebo-
controlled study, designed to assess the efficacy and safety of the Vibrant capsules vs. placebo.  
After a run-in period of 14-21 days, subjects will be randomized with a ratio of 1:1 to either 
active capsule, 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 is planned after all the subjects will complete the first 4 
weeks of treatment. 
 
Data from this study may be combined with data from the company’s upcoming V-310 study since 
they both will follow the same protocol. 


 
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17.2 
Study Endpoints 
 
 The study endpoints are detailed in section 13 
17.3 
Statistical Hypothesis 
 
 In this study, statistical analyses of safety and efficacy measures will be mainly descriptive in 
nature, no hypothesis will be tested. 
17.4 
Sample size 
No formal sample size calculations were performed. A sample size of up to 60 subjects including 
a potential ~10% drop-out rate.  (30 in each arm) is deemed sufficient to fulfill the main goals of 
the study. 
 
 
 
17.5 
Interim Analyses 
 One interim analysis is planned, after all the subjects will complete the first 4 weeks of 
treatment.  
 
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.  
The primary efficacy endpoint will be adjusted for the interim analysis. The efficacy endpoint for 
the interim analysis is the adjusted CSBM success rate, defined as an increase from the run-in 
period of at least one weekly Complete Spontaneous Bowel Movement (CSBM) during at least 3 
of the 4 first weeks of treatment. 
For each analysis set, the adjusted CSBM success rate will be presented in a tabular form by 
study arm, along with 95% Wilson score Confidence Intervals (CI). 
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 adjusted CSBM success rates 
(and CI’s) for each analysis set and study arm. 
 


 
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17.5.3 
Decision Rules 
The sponsor reserves its right to stop the study due to futility, safety issue, or for any other 
reason. 
  
 
 
 
17.6 
Randomization 
 
After a subject meets the eligibility criteria, he/she will be equally allocated (with a 1:1ratio) to one 
of the following treatment groups based on a randomization scheme with fixed blocks stratified by 
center:  
• 
Active capsule 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 single 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 assessment will not be 
part of the relevant analysis. 


 
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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 efficacy assessment will be presented on the ITT, mITT 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 . 
The efficacy and safety endpoints are mainly descriptive in nature. 
Nevertheless, if statistical tests will be performed, they will be two-sided and 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 . 
17.9.2 
Significance levels and handling of type I error 
17.9.2.1 Type I Error 
The significance level for this study is 5% using two-tailed tests. The endpoints are mainly 
descriptive in nature, no adjustment for multiple testing will be performed.  
  
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 
   Main Efficacy Analysis: 
Statistical analyses will be mainly descriptive in nature.  
The subject’s CSBM 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). 
 
 
The SBM success rate will be analyzed in the same manner. 
 
The change from baseline in number of weekly CSBM will be modeled with an Analysis of 
Covariance (ANCOVA) model, with baseline weekly number of CSBMs 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 count of weekly SBM, and in symptoms will be analyzed with 
similar ANCOVA models, with their respective baseline values as covariate. 
 
 
Time to occurrence of SBM after intake of the first Vibrant capsule (either active or sham) 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 ease of use will be presented in tabular form. 
17.9.6 
The PAC-QoL, the rescue medication use, and the 
rate od SBM during the first 24 hours after the 
first dose will be presented in tabular 
form.Treatment by Center Interaction 
It is expected that only a few subjects will receive each study treatment per site, therefore it will 
not be possible to assess the treatment by center interaction. 
 


 
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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. 
 
  
 
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): 


 
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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. 
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. 


 
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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. 
 
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 enrolled 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. 
 


 
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Other investigator responsibilities relative to the EC include the following: 
1. During the conduct of the study, the investigator will submit progress reports to the EC 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 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; 
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 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 correspon-
dence with the EC; 
7. The investigator must notify EC 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 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 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.  


 
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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, 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. 
 
 
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 


 
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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. The amendment will be 
prepared and approved by the sponsor according to the sponsor’s relevant SOP. The amendment 
must be submitted to the IRB. When applicable, the amendment’s implementation will take place 
only once approved by the IRB. 
If for any unexpected reasons, there is any requirement to deviate from the treatments stated 
above, the protocol deviation should be discussed 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. 
 
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. 
 


 
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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 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%  
 
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 


 
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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. 
 
30. 
APPENDICES 
A. Appendix A – Bristol Stool Scale 
B. Appendix B - Rome III questionnaire and instructions for completion 
C. Appendix C – Ease of use questionnaire 
D. Appendix D - Subject daily diary 
E. Appendix E – Patient Assessment of Constipation Quality of Life (PAC-QOL) 
Questionnaire 
F. Appendix F – 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-


 
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detail/?name=only_27_of_european_subjects_with_chronic_constipation_are_satisfied_w
ith_current_treatment_options&file=89240 
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_Co
rrelate_With_Whole-
Gut_and_Colonic_Transit_Results_From_a_Multicenter_Study_in_Constipated_Individu
als_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 
 
 
 
 


 
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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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX D – Subject Diaries 
 
Subject Initials: |__|-|__| 
Subject Identification Number: |__|__|-|__|__|__| 
Name of the center/site: ___________________ 
Location of the center/site: _________________ 
 
Day |__|__|of Study 
  
             Date:                          |__|__| / |__|__|__| / 20|__|__| 
 
 
                         Day              Month                 Year 
 
FORM 1: Capsules 
 
 I haven’t started treatment  
 
 I have started treatment  
If you started treatment, please specify for the day: 
 
How many capsules did you take out of the blister package?   |__| 
 
How many capsules did you swallow?  |__| 
 
Comments: 
______________________________________________________________________ 
 
______________________________________________________________________ 
What is your level of satisfaction with the treatment? 
0          1         2      3        4          5         6        7        8        9       10                                                                                       
                                                                                                                       
                                  
No satisfaction                                                               Great satisfaction 


 
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FORM 2: Bowel movements 
 
Please note: the diary paper form allows you to enter information about up to 3 bowel 
movement for ONE day. 
 
Number of bowel movements for the day: 
 
 |__| 
If you had at least one bowel movement today, please answer, for each bowel 
movement: 
 
BOWEL MOVEMENT 1 
 
1. Time of defecation: 
|__|__|:|__|__|  am/pm 
 
2. What was consistency of the bowel movement? 
1 = Separate hard lumps, like nuts (hard to pass) 
2 = sausage-shaped, but lumpy 
3 = like a sausage but with cracks on its surface 
4 = Like a sausage or snake, smooth and soft 
5 = Soft blobs with clear-cut edges (passed easily) 
6 = fluffy pieces with ragged edges, a mushy stool 
7 = watery, no solid pieces, entirely liquid 
3. Were you left with a feeling of complete evacuation?        Yes    No 
4. How much straining was needed to have the bowel movement? 
        0  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
           
No straining                              
                                                
Unbearable straining 
 
 
 
5. Did you use digital maneuver in order to have the bowel movement?  Yes   No 
 
 


 
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BOWEL MOVEMENT 2 
 
1. Time of defecation: 
|__|__|:|__|__|  am/pm 
 
2. What was consistency of the bowel movement? 
1 = Separate hard lumps, like nuts (hard to pass) 
2 = sausage-shaped, but lumpy 
3 = like a sausage but with cracks on its surface 
4 = Like a sausage or snake, smooth and soft 
5 = Soft blobs with clear-cut edges (passed easily) 
6 = fluffy pieces with ragged edges, a mushy stool 
7 = watery, no solid pieces, entirely liquid 
3. Were you left with a feeling of complete evacuation?        Yes    No 
4. How much straining was needed to have the bowel movement? 
        0  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
           
No straining                              
                                                
Unbearable straining 
 
 
 
5. Did you use digital maneuver in order to have the bowel movement?  Yes   No 
 
 
 
 
 
 
 
 
 
 


 
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BOWEL MOVEMENT 3 
 
1. Time of defecation: 
|__|__|:|__|__|  am/pm 
 
2. What was consistency of the bowel movement? 
1 = Separate hard lumps, like nuts (hard to pass) 
2 = sausage-shaped, but lumpy 
3 = like a sausage but with cracks on its surface 
4 = Like a sausage or snake, smooth and soft 
5 = Soft blobs with clear-cut edges (passed easily) 
6 = fluffy pieces with ragged edges, a mushy stool 
7 = watery, no solid pieces, entirely liquid 
3. Were you left with a feeling of complete evacuation?        Yes    No 
4. How much straining was needed to have the bowel movement? 
        0  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
           
No straining                              
                                         
Unbearable straining 
 
 
 
5. Did you use digital maneuver in order to have the bowel movement?  Yes   No 
 
 


 
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FORM 3: daily experience 
 
Please score your experience today, whether you had a bowel movement or not 
1. What is your level of abdominal pain for the day? 
        0  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
           
No pain                              
                                       
Unbearable pain 
 
 
2. What is your level of abdominal discomfort for the day? 
        0  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
           
No discomfort                              
                                         
Unbearable discomfort 
 
 
3. What is your level of bloating for the day? 
        0  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
           
No abdominal gas                              
                                      
Unbearable abdominal gas  
 
 
4. What is your level of abdominal gas for the day? 
        0  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
           
No bloating 
                                           
Unbearable bloating 
 
 
 
 


 
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Has there been any change to your general health condition?        Yes    No 
If yes, please detail: 
_____________________________________________________________________________ 
_____________________________________________________________________________ 
_____________________________________________________________________________ 
_____________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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FORM 4: rescue medication 
 
Have you taken any rescue medication?                                Yes    No 
If yes, please detail below the name and dosage 
 
 
 
FORM 5: other medication 
Have you taken any other medication/supplements?          Yes    No 
Name of drug Dosage Unit 
Time of the intake 
Number of 
takes/day 
Comments 
 
 
 
|__|__|:|__|__| am/pm    
 
 
 
 
|__|__|:|__|__| am/pm    
 
If yes, please detail below the name and reason for intake 
Name of drug 
Dosage Unit Number of 
takes/day 
Reason 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX E – 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? 
☐ 
☐ 
☐ 
☐ 
☐ 
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)? 
☐ 
☐ 
☐ 
☐ 
☐ 
 
 
 


 
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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?  
☐ 
☐ 
☐ 
☐ 
☐ 
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? 
☐ 
☐ 
☐ 
☐ 
☐ 
 
 
 
 


 
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PROTOCOL FOR STUDY V-250 
Doc No: 250CLD  
Rev: 02Date: 07 Oct 2018 
Page 79 of 84 
 
 
 
 
APPENDIX F– 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 


 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-250 
Doc No: 250CLD  
Rev: 02Date: 07 Oct 2018 
Page 80 of 84 
 
 
 
□3   Dissatisfied 
□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?  


 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-250 
Doc No: 250CLD  
Rev: 02Date: 07 Oct 2018 
Page 81 of 84 
 
 
 
 
□1   Extremely Bothersome 
□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 
 


 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-250 
Doc No: 250CLD  
Rev: 02Date: 07 Oct 2018 
Page 82 of 84 
 
 
 
8. To what degree have treatment side effects affected your overall satisfaction with the 
treatment?  
 
□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 


 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-250 
Doc No: 250CLD  
Rev: 02Date: 07 Oct 2018 
Page 83 of 84 
 
 
 
□4   Somewhat Easy 
□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 
 


 
VIBRATING CAPSULE 
PROTOCOL FOR STUDY V-250 
Doc No: 250CLD  
Rev: 02Date: 07 Oct 2018 
Page 84 of 84 
 
 
 
13. How certain are you that the good things about your treatment outweigh the bad things?  
 
□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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