Clinical trial NCT03261960
Conditions: Colonoscopy
Sponsor: Braintree Laboratories
Start date: 2017-08-08; Completion date: 2018-03-26
Enrollment: 389 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to compare the safety and efficacy of BLI4700 bowel preparation to an FDA-approved bowel preparation as 2-day, split-dose bowel preparations prior to colonoscopy in adult patients.

Detailed description:

Arms: arm 1: BLI4700 Bowel Preparation arm 2: FDA Approved Bowel Preparation
Interventions: intervention 1: BLI4700 intervention 2: Magnesium bowel preparation
Intervention descriptions: intervention 1: Oral bowel preparation intervention 2: Oral bowel preparation

Protocol documents:
Prot_SAP_000.pdf: 
NCT03261960 
STUDY PROTOCOL 
 
A Safety and Efficacy Comparison of BLI4700 Bowel Preparation 
versus an FDA-approved Comparator in Adult Subjects prior to 
Colonoscopy 
 
DOCUMENT DATE: 07/28/2017 


 
Version dated 7-28-17 
 
Page 1 of 40 
 
 
A Safety and Efficacy Comparison of BLI4700 Bowel Preparation 
versus an FDA-approved Comparator in Adult Subjects prior to 
Colonoscopy 
 
Braintree Protocol BLI4700-302 
 
Version Dated 7-28-17 
 
 
 
SPONSOR 
 
 
Braintree Laboratories, Inc. 
60 Columbian St. West 
    
  
 
 
Braintree, MA  02185 
 
 
 
 
PH: 781-843-2202 
 
 
 
 
 
______________________________________ 
 
_______________ 
Mark v.B. Cleveland, Ph.D.   
 
 
 
Date 
Sr. Vice President, R&D/RA 
Braintree Laboratories, Inc.  
 
 
______________________________________ 
 
_______________ 
Principal Investigator Signature 
 
 
 
Date 
 
 
______________________________________ 
 
 
Principal Investigator Name (printed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
 
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Protocol Number BLI4700-302 
Version dated 7-28-17 
 
Page 2 of 40 
 
1. 
INTRODUCTION .......................................................................................................... 5 
2. 
STUDY OBJECTIVE .................................................................................................. 12 
3. 
STUDY PLAN .............................................................................................................. 12 
3.1. 
STUDY DESIGN ........................................................................................................ 12 
3.2. 
NUMBER OF SUBJECTS............................................................................................. 13 
3.3. 
DURATION OF STUDY .............................................................................................. 13 
3.4. 
STUDY PREPARATIONS ............................................................................................ 13 
3.5. 
SUBJECT SELECTION ................................................................................................ 14 
3.5.1. 
Inclusion Criteria .......................................................................................... 14 
3.5.2. 
Exclusion Criteria ......................................................................................... 15 
4. 
STUDY PROCEDURES .............................................................................................. 16 
4.1. 
VISIT 1 .................................................................................................................... 16 
4.1.1. 
Informed Consent .......................................................................................... 17 
4.1.2. 
Treatment Assignment / Blinding ................................................................. 18 
4.1.3. 
Study Drug ..................................................................................................... 19 
4.1.4. 
Dietary Restrictions ....................................................................................... 19 
4.1.5. 
Medication Restrictions ................................................................................. 20 
4.1.6. 
Subject Questionnaires .................................................................................. 20 
4.2. 
VISIT 2 .................................................................................................................... 21 
4.2.1. 
Drug Accountability ...................................................................................... 22 
4.2.2. 
Symptom Scale ............................................................................................... 22 
4.3. 
VISIT 3: 24 – 48 HOURS POST COLONOSCOPY ......................................................... 23 
4.4. 
VISITS 4 AND 5: FOLLOW UP OF ADVERSE EVENTS AND LABORATORY RESULTS .... 23 
4.4.1. 
End of Study Telephone Call ........................................................................ 23 
4.5. 
TABULATED STUDY PROCEDURES ........................................................................... 24 
4.6. 
PHYSICIAN ASSESSMENTS ....................................................................................... 25 
4.6.1. 
Segmental Cleansing Assessment ................................................................. 25 
4.6.2. 
Overall Cleansing Assessment ...................................................................... 25 
4.6.3. 
Additional Efficacy Measures ....................................................................... 25 
4.7. 
PREGNANCY ............................................................................................................ 26 
4.8. 
CONCOMITANT MEDICATIONS ................................................................................. 27 
5. 
ADVERSE EVENTS .................................................................................................... 27 
5.1. 
ADVERSE EVENT DEFINITION AND REPORTING ....................................................... 27 
5.2 
EXPECTED ADVERSE EVENTS .................................................................................. 28 
6. 
SERIOUS ADVERSE REACTIONS AND DISCONTINUATION OF STUDY ... 29 
7. 
INSTITUTIONAL REVIEW BOARD (IRB) AND INFORMED CONSENT ....... 30 
8. 
MANAGEMENT OF INTERCURRENT EVENTS ................................................. 30 
8.1. 
MODIFICATION OF PROTOCOL ................................................................................. 30 
8.2. 
SUBJECTS DISCONTINUED FROM THE STUDY ........................................................... 31 
9. 
DATA ANALYSIS ....................................................................................................... 31 
9.1. 
STUDY ENDPOINTS - EFFICACY ............................................................................... 31 
9.2. 
STUDY ENDPOINTS - SAFETY ................................................................................... 34 
9.3. 
SAMPLE SIZE ........................................................................................................... 35 
9.4. 
STUDY POPULATIONS .............................................................................................. 36 
9.4.1. 
Intention-to-Treat (ITT) Population ............................................................. 36 
9.4.2. 
Modified Intention-to-Treat (mITT) Population .......................................... 36 
9.4.3. 
Per-Protocol Population ................................................................................ 36 


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10. DRUG INVENTORY AND DISPOSITION .............................................................. 37 
11. STUDY MONITORING .............................................................................................. 37 
12. DOCUMENTS AND NOTIFICATIONS ................................................................... 37 
12.1. INFORMED CONSENT ............................................................................................... 37 
12.2. INSTITUTIONAL REVIEW BOARD ............................................................................. 37 
12.3. AMENDMENTS TO THE PROTOCOL ........................................................................... 37 
12.4. DATA RECORDS ....................................................................................................... 37 
13. PUBLICATION AND AGREEMENT ....................................................................... 38 
14. INVESTIGATORS AGREEMENT ........................................................................... 38 
15. REFERENCES ............................................................................................................. 39 
16. APPENDICES .............................................................................................................. 40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Number BLI4700-302 
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CLINICAL PROTOCOL SUMMARY SHEET 
 
STUDY TITLE:  
A Safety and Efficacy Comparison of BLI4700 Bowel Preparation 
versus an FDA-approved Comparator in Adult Subjects prior to 
Colonoscopy 
 
PROTOCOL: 
 
BLI4700-302 
 
VERSION DATE:  7-28-17 
 
IND NUMBER:  
124,988 
 
STUDY PHASE:   
3 
 
OBJECTIVE:  
To compare the safety and efficacy of BLI4700 bowel preparation to 
PREPOPIK as 2-day, split-dose bowel preparations prior to 
colonoscopy in adult patients. 
 
STUDY DESIGN:  This will be a randomized, parallel, multi-center, single-blind study. 
 
SUBJECTS:  
Approximately 400 male and female adult subjects will be enrolled and undergo 
colonoscopy. It is anticipated that approximately 450 subjects will be randomized 
to achieve 400 completed colonoscopies. 
 
STUDY  
 
 
MEDICATIONS:  
Treatment 1: BLI4700 bowel preparation 
 
 
 
Treatment 2:  PREPOPIK 
 
 
DURATION:  
Subject participation in this study may last up to 60 days. 
 
 
EFFICACY  
 
ENDPOINTS: 
Efficacy will be based on overall preparation success as determined by 
 
the blinded colonoscopist. Additional efficacy measures include the 
proportion of excellent preparations, segmental cleansing, time to 
cecum, volume of intraprocedural water used to improve visualization, 
percent of procedures that reach the cecum. 
 
 
SAFETY 
 
ENDPOINTS: 
Safety endpoints include:  
 
• Adverse event reports 
• Changes in serum chemistry and hematology parameters 
• Subject reported prep-related symptoms 
• Orthostatic heart rate and blood pressure  
 
 
 




















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PREPOPIK 
PREPOPIK (Ferring Pharmaceuticals, Inc.) is FDA approved for cleansing of the colon 
as preparation for colonoscopy in adults. PREPOPIK consists of 2 packets, each 
holding 16.1 grams of powder for oral solution. Each packet contains 10mg sodium 
picosulfate, 3.5g magnesium oxide and 12g anhydrous citric acid. PREPOPIK will be 
provided to the subject in clinical packaging with a label containing a caution 
statement, study code, study sponsor and kit number. Subjects will be provided with 
instructions on how to complete the preparation. 
 
 
 
3.5. Subject Selection 
3.5.1. Inclusion Criteria 
Subjects will be admitted to the study if they are: 
1. Male or female outpatients who are undergoing colonoscopy for a routinely 
accepted indication, including (but not limited to):  
 
▪ 
Routine screening 
▪ 
Polyp or neoplasm history 
▪ 
Rectal bleeding 
▪ 
Other gastrointestinal bleeding 
▪ 
Abdominal pain 
▪ 
Unknown diarrhea or constipation etiology 
▪ 
Anemia of unknown etiology 
▪ 
Inflammatory bowel disease 
▪ 
Abnormal endosonography 
▪ 
Evaluation of barium enema results  
▪ 
Laser therapy 
 
2. 18 to 85 years of age (inclusive)  
 
3. If female, and of child-bearing potential, is using an acceptable form of birth 
control (hormonal birth control, IUD, double-barrier method, depot contraceptive, 
abstinent, or vasectomized spouse). Subjects practicing abstinence must agree to 
use an acceptable form of birth control should they become sexually active during 
the study.  Pharmacologic methods of contraception must be stable for at least one 
month prior to Visit 1 and remain stable until 1 month after colonoscopy. 
 
4. Negative serum pregnancy test at screening, if applicable 
 
5. In the Investigator’s judgment, subject is mentally competent to provide informed 
consent to participate in the study 
 


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3.5.2. Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from the study: 
 
1. Subjects with dysphagia or an aversion to swallowing tablets.  
 
2. Subjects with known or suspected ileus, gastrointestinal obstruction, gastroparesis, gastric 
retention, bowel perforation, toxic colitis or megacolon. 
 
3. Subjects with ongoing severe, acute inflammatory bowel disease  
 
4. Subjects who had previous significant gastrointestinal surgeries (e.g. colostomy, 
colectomy, gastric bypass, gastric banding, stomach stapling). Any questions 
regarding the significance of a previous gastrointestinal surgery should be directed 
to Braintree Laboratories. 
 
5. Subjects with uncontrolled pre-existing electrolyte abnormalities, or those with 
clinically significant electrolyte abnormalities based on Visit 1 laboratory results.  
 
Subjects with Visit 1 laboratory results outside the following ranges will be 
excluded regardless of investigator assessment of clinical significance:  
 
• Serum sodium > 150 mmol/L or < 132 mmol/L 
• Serum potassium > 5.5 mmol/L or < 3.5 mmol/L 
• Serum magnesium > 2.7 mg/dL or < 1.2 mg/dL 
 
6. Subjects taking diuretics, anti-hypertensive medications, including angiotensin 
converting enzyme (ACE) inhibitors and Angiotensin II receptor blockers (ARBs), 
or chronic NSAIDs, that have not been stable for 30 days. NSAID use for 
occasional pain is not exclusionary. 
 
7. Subjects with uncontrolled hypertension (systolic blood pressure > 170 mmHg and 
diastolic blood pressure > 100 mmHg). 
 
8. Subjects taking antibiotics within 7 days of colonoscopy.  
 
9. Subjects with severe renal insufficiency (GFR < 30 mL/min/1.73m2).  
 
10. Subjects with known severe hepatic insufficiency (Child Pugh C) 
 
11. Subjects with cardiac insufficiency (NYHA Functional Classifications 3 or 4). 
 
12. Subjects with an abnormal and clinically significant physical examination or ECG 
finding at Visit 1. 
 
 
13. Subjects undergoing insulin therapy for any indication. 
 




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• Physical examination 
• Vital signs: including assessment of orthostatic hypotension (while seated and after 
standing for a minimum of 2 minutes) including height and bodyweight, pulse, 
respiratory rate and temperature 
• A 12-lead ECG will be performed by qualified, trained site personnel.  ECG output 
must be reviewed by a physician investigator. Any clinically significant cardiac 
abnormalities identified on the ECG should disqualify a subject. Data from the ECG 
will be collected in the eCRF. 
• Blood samples will be collected for testing at a central laboratory, as shown below.  
Serum Chemistry: ALT, anion gap (calculated), AST, bicarbonate, total 
bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase, creatinine, 
eGFR (calculated), GGT, magnesium, phosphorus, potassium, sodium, sulfate 
(Visits 1, 2 and 3 only), total protein, uric acid and osmolality. Creatine kinase 
results > 2.5 times the upper normal limit will trigger a test for CK-MB.   
 
Hematology: Basophils, HCT, HGB, Lymphocytes, MCH, MCV, MPV, 
Neutrophils, Platelets, RBC, WBC 
 
Urinalysis: dipstick analysis (Visits 1, 2 and 3 only). Urine positive for bacteria 
will require follow-up if the investigator believes the result is due to urinary 
tract infection.  
 
Investigators will be instructed to comment on all out of range values for clinical 
significance. For critical values (those indicative of a potential safety concern), 
investigators will be contacted by the central laboratory. Critical value alert levels are 
listed in the laboratory manual. 
 
A serum pregnancy test will be performed on female subjects of childbearing potential 
(see Section 4.7). Subjects meeting all entry criteria will be eligible for enrollment. 
 
4.1.1. Informed Consent 
Following the informed consent process, study subjects will sign a current IRB approved 
consent form. No study procedures may be performed prior to the subject providing 
informed consent. The subject’s original signed and personally dated Informed Consent 
Form (together with any subsequent IRB approved amended versions) must be retained 




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protocol violation.  Subjects will be instructed not to discuss their study preparation 
assignment study staff members. 
4.1.3. Study Drug 
Eligible subjects will be provided with instructions on how to use the study 
preparation. Subjects will self-administer the study preparation starting the evening 
prior to their scheduled colonoscopy according to the instructions provided by the 
study site (full preparation instructions are included in Appendix A). Subjects will be 
instructed to bring the used preparation components when they return for colonoscopy.  
 
Subjects that have clinically significant electrolyte abnormalities, in the opinion of the 
principle investigator, based on Visit 1 laboratory results must be discontinued from 
the study. Subjects must be notified and instructed to return their unopened bowel 
preparation to the study center.  These subjects will be classified as screen failures.    
Returned un-used study drug kits will not be re-dispensed to another subject.    
4.1.4. Dietary Restrictions 
BLI4700 
Subjects assigned to BLI4700 will take their first 12 tablet dose the evening 
before colonoscopy.  This will be followed no less than four hours later by the 
second 12 tablet dose.  The second 12 tablet dose should be taken 5 to 8 hours 
before the colonoscopy.  BLI4700 subjects may have a low residue breakfast on 
the day before colonoscopy, followed by clear liquids until the colonoscopy is 
completed the following day. Examples of low residue foods will be provided 
in the subject preparation instructions (Appendix A). 
 
PREPOPIK 
Subjects assigned to PREPOPIK will take their PREPOPIK according to 
manufacturer’s labeling for split-dose administration.  These subjects may have 
clear liquids only on the day before their colonoscopy. This clear liquid diet 
must be followed until the subject completes their colonoscopy on the 
following day.  


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Examples of acceptable clear liquids are provided below: 
▪ Water 
▪ Strained fruit juices (without pulp) including apple, orange, white grape, or   
            white cranberry  
▪ Limeade or lemonade 
▪ Gatorade/ Powerade 
▪ Ginger ale 
▪ Coffee or tea (do not use any dairy or non-dairy creamer) 
▪ Chicken broth 
▪ Gelatin desserts without added fruit or topping 
 
Note: Purple/Red liquids (including red/purple varieties of Gatorade/Powerade), Milk 
and Alcoholic beverages are not permitted. 
 
Non-compliance with the dietary restrictions will be documented as a protocol 
violation, but will not require reporting to the IRB. 
4.1.5. Medication Restrictions 
Subjects assigned to Prepopik will be instructed to refrain from taking the following 
medications starting 2 hours prior to the start of Prepopik until 6 hours after completing 
Prepopik to avoid chelation with magnesium: 
• Tetracycline 
• Fluoroquinolone antibiotics 
• Iron 
• Digoxin (Lanoxin) 
• Chlorpromazine 
• Penicillamine (Cuprimine, Depen) 
 
Subjects in both preparation groups will be educated that oral medication administered 
within one hour of the start of administration of the bowel preparation may be flushed 
from the GI tract and the medication may not be absorbed.  
 
4.1.6. Subject Questionnaires 
Subjects will be provided with a Preparation Questionnaire and Dietary Questionnaire 
to document their preparation and dietary intake (refer to Appendix A for full 


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questionnaires). Subjects will complete the Dietary Questionnaire starting the day 
before the colonoscopy. Completion of the Preparation Questionnaire will commence 
with Dose 1 on the day before colonoscopy and continue through the completion of the 
required clear liquids after Dose 2 the following day. The time of all food/fluid 
ingestion will be recorded. Site staff must review the descriptions and times recorded 
on the questionnaire at Visit 2 to confirm that subjects were compliant with the dietary 
restrictions outlined in Section 4.1.4. 
 
Subjects that take any amount of bowel preparation (but do not have a colonoscopy 
performed) should still return for safety follow-up as outlined in Sections 4.2 – 4.4. 
4.2. Visit 2 
After completing both preparation doses, subjects will return to the study center for 
their colonoscopy. Sites should attempt to schedule subjects a minimum of 4 days from 
date of screening to allow for receipt and review of screening lab results up to a 
maximum of 30 days. Visits scheduled beyond 30 days from Visit 1 will be considered 
a protocol violation and subjects must have a repeat blood draw. Due to follow-up 
requirements for laboratory testing within 24 – 48 hours of Visit 2 (See Section 4.3), 
colonoscopies may not be performed on a Friday unless the research center is open on 
Saturday or Sunday to collect a follow-up blood sample.  
 
Subjects will bring back their questionnaires and study personnel will review the 
questionnaires for completeness so that any missed responses can be captured. Any 
violations of the dietary restrictions must be confirmed with the subject. Study 
personnel will perform drug accountability as described in Section 4.2.1.  
 
Vital signs will be taken.  A 12-lead ECG will be performed by qualified, trained site 
personnel.  ECG output must be reviewed by a physician investigator and subjects with 
a clinically significant abnormal result must be discontinued prior to colonoscopy. A 
physical examination will be performed. Subjects will be queried for expected 
preparation symptoms using the Symptom Scale (see Section 4.2.2) or changes to their 
concomitant medications. Subjects will complete a Preference Questionnaire (See 


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Appendix A). Blood samples for chemistry and hematology testing will be taken as 
outlined in Section 4.1.  
 
The colonoscopy will be performed by a physician according to the site’s standard 
procedures and evaluated on a 4-point scale, as shown in Section 4.6.  The colonoscopy 
procedure will be video recorded. A designated vendor will provide standardized video 
recording capabilities and centralized reading by an independent gastroenterologist. A 
subset of colonoscopies will be reviewed and graded by the central reader for the 
primary endpoint (overall cleansing assessment). The procedures and requirements for 
recording and transmitting colonoscopy videos will be outlined in a separate manual.  
 
Endoscopists should limit the use of water flush to that necessary to achieve the 
cleansing required to achieve adequate visualization. Water immersion and/or exchange 
technique should be avoided unless it is medically indicated. 
4.2.1. Drug Accountability 
Subjects will be instructed to bring their used and unused preparation components 
when they return for colonoscopy to determine compliance. Failure of a subject to 
return preparation components does not constitute a protocol violation. In order to 
maintain the blinding, only the unblinded staff members will process drug returns. The 
unblinded staff members will perform drug accountability by assessing the number of 
used PREPOPIK packets and counting any remaining BLI4700 tablets. The subjects 
will be instructed not to discuss their study preparation with any staff member. Failure 
of staff members to maintain blinding of the treatment will be documented as a 
protocol violation. 
 
All used and unused components of study preparation must be accounted for on drug 
inventory log and will be returned to the Sponsor at the completion or termination of the 
study, unless instructed otherwise by the Sponsor. 
4.2.2. Symptom Scale 
At Visit 2 (prior to sedation), study personnel will ask subjects to report their experience 
with the preparation for the most frequently occurring bowel preparation symptoms of 


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stomach cramping, stomach bloating, nausea and vomiting. Subjects reporting these 
symptoms will be asked to rate the intensity as mild, moderate or severe.  
 
4.3. Visit 3: 24 – 48 Hours Post Colonoscopy  
Subjects will return 24 – 48 hours following colonoscopy for follow-up. Blood samples 
will be collected for serum chemistry and hematology testing. Subjects will be queried for 
occurrence of adverse events and changes in concomitant medications. Subjects will be 
queried for information pertaining to the onset and treatment of serious adverse events 
occurring following the colonoscopy, and adverse events that were ongoing at Visit 2.   
Vital signs will be taken.  A 12-lead ECG will be performed by qualified, trained site 
personnel.  ECG output must be reviewed by a physician investigator. Subjects with 
abnormal and clinically significant ECG results at Visit 3 must return for follow up visits 
as outlined in Section 4.4.  
 
Subjects that miss Visit 3 must return for follow-up Visit 4. If these subjects have no out 
of range laboratory values (that were not pre-existing at Visit 1) and/or ongoing adverse 
events at Visit 4, Day 30 follow-up may be performed via telephone (See Section 4.4.1). 
 
4.4. Visits 4 and 5: Follow up of Adverse Events and Laboratory Results 
Subjects with out of range laboratory values (that were not pre-existing at Visit 1) 
and/or ongoing adverse events at Visit 3 will return for follow up on Day 7 (+/- 2 days) 
and Day 30 (+/- 2 days). Subjects requiring follow-up for abnormal laboratory values 
must undergo repeat testing. Subjects returning due to ongoing adverse events should 
be assessed to determine if the event has resolved or is clinically stable. 
4.4.1. End of Study Telephone Call 
Subjects that do not have new or ongoing adverse events or abnormal laboratory results 
at Visit 3 that require follow up (per Section 4.4) will have an End of Study telephone 
call 30 days (+/-_2 days) after colonoscopy. During this call, study personnel will ask 
if any new adverse events have occurred since Visit 3 and if the subject has had any 
changes to their concomitant medications.


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4.5. Tabulated Study Procedures 
The following graphically depicts the flow of study procedures at each visit. 
 Procedures 
Visit 1 
 
Screening 
 
 
Day before 
colonoscopy 
Visit 2 
 
Day of 
colonoscopy 
Visit 3 
 
24-48 hrs post 
colonoscopy 
Visit 4 
 
Day 7 
(+/- 2 days) 
 
*if needed* 
Visit 5 
 
Day 30 
(+/- 2 days) 
 
*if needed* 
 
Day 304 
(+/- 2 days) 
 
*if by 
telephone* 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
X 
 
 
 
 
Vital Signs (including ECG) 
X 
 
X 
X 
X 
X 
 
Review of Concomitant Medication 
X 
 
X 
X 
X 
X 
X 
Blood Collection for Laboratory Testing 
X 
 
X 
X 
X 
X 
 
Urine Collection for Laboratory Testing 
X 
 
X 
X 
 
 
 
Serum Pregnancy Test (if applicable) 1 
X 
 
 
 
 
 
 
Treatment Assignment2 
X 
 
 
 
 
 
 
Dispense Drug and Questionnaires 2 
X 
 
 
 
 
 
 
Subjects Begin Questionnaires 
 
X 
 
 
 
 
 
Subjects Take Bowel Preparations 
 
X 
X 
 
 
 
 
Symptom Scale & Preference Questionnaire 
Completed3 
 
 
X 
 
 
 
 
Drug Accountability2 
 
 
X 
 
 
 
 
Colonoscopy performed with Intra-procedural 
Safety and Efficacy Grading 
 
 
X 
 
 
 
 
Collect and assess adverse event data 
 
 
X 
X 
X 
X 
X 
1 refer to Section 4.7 
2to be performed by unblinded personnel only      3to be completed at Visit 2 prior to sedation 
4Day 30 follow-up may be performed by telephone for subjects with no new or ongoing AEs or lab abnormalities at Visit 3 


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4.6. Physician Assessments 
4.6.1. Segmental Cleansing Assessment 
The blinded colonoscopist will rate each colon segment (proximal, mid, distal) using 
the following scale, factoring in the amount of effort required during both insertion 
and withdrawal. 
 
Score 
Grade 
Description 
1 
Poor 
Large amounts of fecal residue, additional 
bowel preparation required 
2 
Fair 
Enough feces even after washing and suctioning 
to prevent clear visualization of the entire 
colonic mucosa. 
3 
Good 
Feces and fluid requiring washing and 
suctioning, but still achieves clear visualization 
of the entire colonic mucosa. 
4 
Excellent 
No more than small bits of feces/fluid which 
can be suctioned easily; achieves clear 
visualization of the entire colonic mucosa 
 
4.6.2. Overall Cleansing Assessment 
Following completion of the procedure and after each segment has been rated, the 
blinded colonoscopist will provide a global rating of preparation quality for the 
entire colon (inclusive of their perception of all segments) using the scale outlined in 
Section 4.6.1.   
 
4.6.3. Additional Efficacy Measures 
In addition, the following data will be collected: 
1. Adequacy of preparation according to the blinded colonoscopist. If the 
preparation was not adequate, the need for re-preparation will be 
recorded.  
2. Start time of colonoscopy 
3. Time of cecal intubation 


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4. Completion time of colonoscopy 
5. Impact of preparation quality on surveillance interval 
6. Volume of water used to improve visualization (investigator’s will need 
to specify cases where a water immersion technique was utilized) 
 
4.7. Pregnancy 
Subjects that are female and of childbearing potential must have a serum pregnancy 
test done at screening. A positive result will rule out the participation of the subject 
in the study. 
 
Female study subjects must be surgically sterilized or use oral contraceptives, depot 
contraceptives, double-barrier method, intrauterine device, or testify that she is 
monogamous with a vasectomized partner, or practices abstinence and will continue 
to do so during the duration of study. Subjects practicing abstinence must agree to 
use an acceptable form of birth control should they become sexually active during 
the study. Women who are post menopausal (as defined in this section), or have had 
a partial or total hysterectomy or tubal ligation are not considered of child bearing 
potential. 
 
Oral contraceptives, hormone implants, and injections should be stable for at least 1 
month before the study, until 1 month after colonoscopy.  
 
Menopausal status is defined when menses have been absent for 12 months in a 
woman of appropriate age (usually 45 to 55 years) who has no other suspected or 
identified cause of amenorrhea. 
 
If a subject becomes pregnant during the study, the subject must be removed from 
the study and followed until one month after the end of the pregnancy.  A pregnancy 
will not be recorded as an adverse event.  
 


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4.8. Concomitant Medications 
The use of concomitant medication will be recorded from 7 days prior to screening 
until completion of the study, including sedation medications and intravenous fluids 
administered during colonoscopy. Laxatives should not be used within 72 hours of 
beginning the study preparation.    
 
5. ADVERSE EVENTS  
5.1. Adverse Event Definition and Reporting 
An Adverse Event (AE) is any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. An AE can therefore be 
any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product.  Subjects will be queried for any problems they 
experienced during and after preparation by site personnel. Any symptom on the 
symptom scale rated as mild, moderate or severe must be reported as an adverse 
event. Colonoscopy and biopsy findings are not considered adverse events unless 
considered by the investigator to be related to the preparation or colonoscopy 
procedure.  
 
Adverse event collection will commence at the time the patient provides informed 
consent and conclude 30 days after preparation exposure.  
 
Subjects will be instructed to promptly report adverse events to the Investigator. The 
Investigator will record date/time of report, date/time of onset, description of the 
adverse event, severity of adverse event, action(s) taken regarding treatment of the 
event, action(s) taken regarding study participation, duration of adverse event, and 
the Investigator's assessment of relationship of adverse event to study preparation.  
 
The Investigator should assess the severity of each adverse event using the following 
categories: 


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Grade 
Severity 
Description  
1 
Mild 
Barely noticeable, does not influence functioning 
causing no limitations of usual activities 
2 
Moderate 
Makes participant uncomfortable, influences functioning 
causing some limitations of usual activities 
3 
Severe 
Severe discomfort, treatment needed 
Severe and undesirable, causing inability to carry out usual 
Activities 
4 
Life 
threatening 
Immediate risk of death, Life threatening or disabling 
(Must be reported as serious adverse event) 
5 
Fatal 
Causes death of the participant 
(Must be reported as serious adverse event)  
 
 
The Investigator should assess the relationship to study drug for each adverse event 
using the following categories: 
Categories of 
Attribution:  
Description 
UNRELATED 
There is no evidence of any causal relationship. 
POSSIBLE 
There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of 
the trial medication). However, the influence of other factors 
may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). 
PROBABLE 
There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. 
DEFINITE 
There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. 
 
5.2 
Expected Adverse Events 
BLI4700 
Because BLI4700 tablets contain the same active ingredient (sodium sulfate) as 
SUPREP, a similar adverse event profile is expected. In Phase 3 clinical trials, the 
most frequent adverse events reported by patients taking SUPREP (reported by >3% 
of patients) included overall discomfort, abdominal pain and distension, nausea, and 
vomiting.  
 


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PREPOPIK 
In Phase 3 clinical trials, the most frequent adverse events reported by patients taking 
PREPOPIK (reported by >1% of patients) included nausea, vomiting and headache4.  
 
6. SERIOUS ADVERSE REACTIONS AND DISCONTINUATION OF 
STUDY 
A Serious Adverse Event (SAE) is any untoward medical occurrence that results in 
at least one of the following outcomes: 
 
- 
Results in death 
- 
Is life-threatening 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
- 
Is a congenital anomaly/birth defect 
- 
Requires medical or surgical intervention to prevent permanent impairment 
or damage 
 
 SAE collection will coincide with the patient providing informed consent to 
participate in the study and will conclude 30 days after preparation exposure. Pre-
scheduled or elective surgeries (that do not represent a worsening of a pre-existing 
condition) will not be considered serious adverse events. Should a serious and/or 
unexpected adverse event occur, the Investigator will notify Braintree Laboratories 
immediately or no later than 24 hours after gaining knowledge of the event.  The 
Investigator will make a decision regarding continuing study participation, and may 
request input from Braintree Laboratories. The Investigator will be responsible for 
recommending or providing the patient with appropriate medical therapy. All patients 
experiencing serious adverse events will be followed until satisfactory resolution 
occurs.  
 




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8.2. Subjects Discontinued from the Study 
Subjects may be discontinued from the study for any of the following reasons: 
• An adverse event requiring discontinuation (including failure to tolerate study 
medication). 
• Female participants who become pregnant during the study period. 
• Major protocol deviation from the study design by the subject that is observed 
or suspected by the Investigator 
• Subject chooses to withdraw from the study, for whatever reason. 
• Subject is lost to follow-up. 
• The Sponsor initiates an early discontinuation of the study. 
• The subject is withdrawn at the discretion of the Investigator. 
 
Braintree should be contacted if possible prior to discontinuation of any subject. 
 
 
8.3  Safety Interim Monitoring – Study Stopping Rule 
 
Adverse event data will be monitored on an ongoing basis. Adverse event terms from 
the study that are listed in the Common Terminology Criteria for Adverse Events 
(CTCAE, version 4.0) under the system organ classes (SOCs) of Cardiac Disorders, 
Renal and Urinary Disorders and Metabolism and Nutrition Disorders will be reviewed 
as part of the study stopping rule.  
 
Braintree Laboratories will consider stopping the study if ≥ 2 subjects develop the same 
adverse reaction (based on the MedDRA preferred term) listed in the Cardiac, Renal 
and Urinary, and Metabolism and Nutrition SOCs of Grade 3, or if a single subject 
develops one of the listed adverse reactions of Grade 4 or higher.  
 
9. DATA ANALYSIS 
9.1. Study Endpoints - Efficacy 
Primary efficacy will be assessed on the basis of a binary outcome of overall 
preparation success or failure. For statistical analyses, the following definition of 
preparation success and failure will be used: 


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Definition of successful preparation:  
1. Overall Cleansing Assessment by the colonoscopist (Section 4.6.2) of 
“Excellent” or “Good” and does not satisfy any of the following failure criteria.    
 
Definition of failed preparation:  
1. Overall Cleansing Assessment of “Fair” or “Poor” by the colonoscopist 
2. Any subject who did not have a colonoscopy based on the Investigator’s 
assessment of the cleansing (subject report of insufficient fecal output, 
unclear fecal discharge, etc.) or due to preparation related adverse events. 
3. Any subject for whom cleaning was not adequate for evaluation 
 
Unevaluable Subjects: 
Subjects who were dispensed a kit but withdrew from the study prior to taking any 
preparation (including subjects who were disqualified subsequent to Visit 1 based on 
screening laboratory results) are excluded from the efficacy and safety analyses. Any 
subject who completely or partially took study preparation but did not have a 
colonoscopy due to non-preparation related reasons (e.g. lack of insurance, inability 
to return for colonoscopy) will not be included in the efficacy analyses. All treated 
subjects will be included in the safety analysis. 
 
Success rate will be analyzed using CMH Chi-square adjusting for the effect of 
investigator site.  The formal hypothesis test result (p-value) for treatment difference 
will be presented together with a two-sided 95% confidence interval for the 
difference.  
 
Null Hypothesis H0: P1−P2≤D0 versus Alternative Hypothesis H1: P1−P2>D0, 
 
where P1 is the success probability in the BLI4700 group, P2 is the success 
probability in the PREPOPIK group (reference or control group), and D0 is the 
acceptable margin of equivalence, which we set equal to  −10%.  
 


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If necessary, we will pool the smallest centers into a “small-centers” stratum until 
each treatment arm in the smallest stratum has at least ten subjects. 
 
If the test for non-inferiority is statistically significant, we will conduct a test of the 
superiority hypothesis: 
 
Null Hypothesis H0: P1−P2<=0 versus Alternative Hypothesis H1: P1−P2>0. 
 
The two hypothesis tests are hierarchically structured so that the second test will be 
conducted only if the first test rejects the hypothesis of inferiority. Thus there is no need 
to correct the alpha levels of the tests for multiplicity. 
 
Sensitivity analyses will be performed for the primary endpoint based on stratification 
groups outlined in Section 4.1.2. 
 
Additional efficacy endpoints will include: 
• Cleansing score by segment 
• Number (%) of excellent preparations overall and by segment 
• Adequacy of cleaning and need for re-preparation 
• Duration of colonoscopy 
• Volume of intraprocedural water needed to irrigate the colon  
• Number (%) of procedures that reached the cecum 
• Time to cecum 
 
Secondary endpoints will be analyzed in a manner similar to the primary analysis 
using the CMH test adjusting for site effects for count (percentage) outcomes and 
two-way ANOVA with terms for treatment, site, and their interaction for continuous 
responses. No adjustment will be made for multiplicity in testing the secondary 
endpoints.  P values will be presented for hypothesis tests, and two-sided 95% 
confidence intervals for estimates of treatment effects. 
 
 


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9.2. Study Endpoints - Safety 
Adverse Events: 
All subjects who took preparation in any amount will be included in the safety 
analysis. All adverse events will be analyzed based on the principle of treatment 
emergence. A sign or symptom will be regarded as treatment-emergent if it was 
present prior to the first dose and subsequently worsened in severity, or was not 
present prior to the first dose but subsequently appeared. 
 
In order to define treatment emergence for events with missing start or stop dates the 
following additional criteria will be used: 
• 
if both the onset and resolution dates for a particular event are missing, then 
the event is considered treatment-emergent; 
• 
if the onset date for an event is missing and the resolution date falls after the 
initiation of the first dose, then the event is considered treatment-emergent; 
• 
if the onset date for an event falls after the initiation of the first dose and the 
resolution date is missing or present, then the event is considered treatment-
emergent; and 
• 
if the onset date for an event falls before the initiation of the first dose and the 
stop date is missing or present, then the event is not considered treatment-
emergent. 
 
Adverse events will be collected using MedDRA category designations for body 
system and preferred term. The number and percent of subjects who experienced 
each adverse event will be presented in a tabular form.  Individual tables will be 
provided for treatment-emergent adverse events, treatment-emergent adverse events 
by relationship to study drug, and treatment-emergent adverse events by severity. 
The difference in adverse events between study populations will be tested by the 
Fisher’s exact test together with a 95% confidence interval for the treatment effect 
estimate. 
 
 


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Vitals Signs and Physical Examination: 
Vital signs and physical examination data will be summarized with descriptive 
statistics. 
 
Laboratory Data: 
Results of laboratory tests for the change from baseline (Screening) and treatment 
group differences will be tested using ANOVA.  In addition, shift tables will be 
presented to describe changes in lab parameter values between screening and post-
treatment time points using normal range categories (low, normal, high).  
 
Symptom Scale Data: 
Symptom Scale data for individual symptoms for Overall Experience (stomach 
cramping, stomach bloating, nausea and vomiting) will be presented categorically by 
severity and tested by Chi-Square test. 
 
9.3. Sample Size  
Approximately four hundred (400) subjects will be randomly assigned via the 
minimization scheme to one of two preparations in a ratio of 1:1 (200 subjects per 
group) and undergo colonoscopy. Based on prior studies using a similar grading 
system, the success rate for PREPOPIK is expected to be no greater than 90%4. 
Assuming a similar success rate for BLI4700, a two-sided asymptotic 
95% confidence interval for the difference in success rates between groups (BLI4700 
– PREPOPIK) will result in a lower CI bound greater than -10%, with probability 
90%. This result would establish the non-inferiority of BLI4700 to PREPOPIK for a 
non-inferiority margin of 10%. 
 Our sample-size calculations for equivalence tests with a binary outcome use the 
method of Chow et al5. If the PREPOPIK success rate is 90% and the BLI4700 
success rate is also 90%, the sample size needed is n=310 (total across both study 
groups) for a non-inferiority margin of 10% and a target power of 90% with 
confidence 95%.  Thus with n=400 subjects we will attain 80% power even with a 
dropout rate in excess of 20%.   


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In randomized studies, the purpose of the stratification is to eliminate the 
stratification factor from the error term, thereby potentially reducing variability6.  
Moreover, because the trial will use stratification in the design, for consistency we 
will employ a stratified test in the analysis.  The CMH analysis on risk differences, 
by eliminating center effects, essentially renders the analysis equivalent to that of a 
single-center study.  The sample-size calculation described above assumes a single 
stratum that is free of between-stratum variability and therefore effectively models 
the stratified analysis that we will conduct. 
 
9.4. Study Populations 
The following populations have been defined for data analyses. 
9.4.1.Intention-to-Treat (ITT) Population 
This population includes all subjects assigned to treatment and will be used for 
sensitivity analysis of the primary efficacy endpoint. 
9.4.2. 
Modified Intention-to-Treat (mITT) Population  
This population consists of all enrolled subjects that took any portion of the study 
preparation. This population will be utilized for primary and secondary efficacy 
analyses and all safety analyses. 
9.4.3. 
Per-Protocol Population  
The per protocol (PP) population will consist of all subjects in the mITT population 
who consumed the entire bowel preparation solution and/or tablets and who have not 
violated the study eligibility criteria and have not deviated significantly from the 
protocol during the course of the study.  This population will be utilized for the 
primary and secondary efficacy analyses. Any efficacy analyses from this population 
will be considered as supportive to the ITT and mITT analyses.  Reasons for 
exclusion from the PP population will be defined prospectively in the statistical 
analysis plan and prior to unblinding of the data. 
 


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10. DRUG INVENTORY AND DISPOSITION 
At the conclusion of the study, all drug materials will be accounted for.  Federal law 
requires that, at the conclusion of the study, all drug materials must be returned to the 
study sponsor or destroyed according to local regulations.  
11. STUDY MONITORING 
 
A Braintree Laboratories Study Monitor or qualified designee will visit each study 
center prior to the commencement of the study and periodically during the course of 
the study in accordance with federal guidelines governing the sponsorship of studies. 
12. DOCUMENTS AND NOTIFICATIONS 
12.1. 
Informed Consent 
Written informed consent will be obtained from the subjects by study personnel and 
will be kept on file at the study center. Documentation of the consent process should 
be noted in the study source documents. 
12.2. 
Institutional Review Board 
Peer review and approval of the protocol by an appropriate Institutional Review 
Board is required prior to commencement of enrollment.  Amendments to the 
approved protocol must also be submitted to the Institutional Review Board and 
approved prior to their implementation.  
 
12.3. 
Amendments to the Protocol 
If Braintree Laboratories determines that there is need for an amendment, it will be 
produced in writing by Braintree Laboratories and will be made a formal part of the 
protocol following its submission and approval from the IRB.    
12.4. 
Data Records 
Site personnel will be required to enter study data into electronic case report forms 
(eCRFs) provided by Braintree Laboratories. Subject medical records will be 
reviewed to verify study data points, including potential adverse events, and to 




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15. REFERENCES 
1 – Di Palma JA, Rodriguez R, McGowan J, Cleveland MvB. A randomized clinical 
study evaluating the safety and efficacy of a new, reduced-volume, oral sulfate 
colon-cleansing preparation for colonoscopy.Am J Gastroenterol. 2009;104:2275-
2284. 
2 – Rex DK, Di Palma JA, Rodriguez R, McGowan J, Cleveland M. A randomized 
clinical study comparing reduced-volume oral sulfate solution with standard 4-liter 
sulfate-free electrolyte lavage solution as preparation for colonoscopy.Gastrointest 
Endosc. 2010;72:328-336. 
3 – Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate 
nephropathy following oral sodium phosphate bowel purgative: an underrecognized 
cause of chronic renal failure J Am Soc Nephrol.2005; 16(11):3389-96. 
4 – Rex DK, DiPalma JA, McGowan J, Cleveland Mv. A comparison of oral sulfate 
solution with sodium picosulfate: magnesium citrate in split doses as bowel 
preparation for colonoscopy.Gastrointest Endosc. 2014 Dec;80(6):1113-23 
5 – Chow S, Shao J, Wang H. 2008. Sample Size Calculations in Clinical Research. 
2nd Ed. Chapman & Hall/CRC Biostatistics Series. P. 91. 
6 – Fleiss JL.  1986.  The Design and Analysis of Clinical Experiments.  John Wiley 
& Sons. 
7 – Pocock SJ, Simon R. Sequential treatment assignment with balancing for 
prognostic factors in the controlled clinical trial. Biometrics 1975;31:103–115. 
 
 
 
 
 
 
 
 
 


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16. APPENDICES 
 
Appendix A – Preparation Instructions and Subject Questionnaires