Clinical trial NCT04446312
Conditions: Colonoscopy
Sponsor: Braintree Laboratories
Start date: 2020-07-13; Completion date: 2021-02-05
Enrollment: 500 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the safety and efficacy of BLI4900 bowel preparation to an FDA-approved control as 2-day, split-dose bowel preparations prior to colonoscopy in adult patients.

Detailed description:

Arms: arm 1: Experimental bowel preparation solution for oral ingestion arm 2: FDA approved bowel preparation solution for oral ingestion
Interventions: intervention 1: Bowel Prep
Intervention descriptions: intervention 1: Orally ingested liquid bowel preparation

Protocol documents:
Prot_SAP_000.pdf: 
NCT04446312 
STUDY PROTOCOL 
 
A Safety and Efficacy Comparison of BLI4900 Bowel Preparation 
versus an FDA-approved Comparator in Adult Subjects prior to 
Colonoscopy 
 
DOCUMENT DATE: 01/10/2020 






 
Version dated 01-10-2020 
 
Page 1 of 34 
 
 
A Safety and Efficacy Comparison of BLI4900 Bowel Preparation 
versus an FDA-approved Comparator in Adult Subjects prior to 
Colonoscopy 
 
Braintree Protocol BLI4900-302 
 
Version Dated 01-10-2020 
 
 
 
SPONSOR 
 
 
Braintree Laboratories, Inc. 
60 Columbian St. West 
    
  
 
 
Braintree, MA  02185 
 
 
 
 
PH: 781-843-2202 
 
 
 
 
 
______________________________________ 
 
_______________ 
Sue Hall, Ph.D.  
 
 
 
 
 
Date 
Head of R&D  
 
 
______________________________________ 
 
_______________ 
Principal Investigator Signature 
 
 
 
Date 
 
 
______________________________________ 
 
 
Principal Investigator Name (printed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 2 of 34 
1.
INTRODUCTION .......................................................................................................... 5
1.1. 
CLINICAL EXPERIENCE WITH THE BLI4900 ACTIVE INGREDIENTS ............................ 6 
1.1.1.PEG-3350 ................................................................................................................ 6 
1.1.2.Sulfate Salts ............................................................................................................ 7 
2.
STUDY OBJECTIVE .................................................................................................... 8 
3.
STUDY PLAN ................................................................................................................ 8 
3.1. 
STUDY DESIGN .......................................................................................................... 8 
3.2. 
NUMBER OF SUBJECTS............................................................................................... 8 
3.3. 
DURATION OF STUDY ................................................................................................ 8 
3.4. 
STUDY PREPARATIONS .............................................................................................. 8 
3.5. 
SUBJECT SELECTION ................................................................................................ 10 
3.5.1.Inclusion Criteria ................................................................................................. 10 
3.5.2.Exclusion Criteria ................................................................................................ 11 
4.
STUDY PROCEDURES .............................................................................................. 13 
4.1. 
VISIT 1 .................................................................................................................... 13 
4.1.1. 
Informed Consent .......................................................................................... 14 
4.1.2. 
Treatment Assignment / Blinding ................................................................. 14 
4.1.3. 
Study Drug ..................................................................................................... 15 
4.1.4. 
Dietary Restrictions ....................................................................................... 15 
4.1.5. 
Medication Restrictions ................................................................................. 16 
4.1.6. 
Subject Questionnaires .................................................................................. 16 
4.2. 
VISIT 2 .................................................................................................................... 16 
4.2.1. 
Drug Accountability ...................................................................................... 17 
4.3. 
VISIT 3: 48 - 72 HOURS POST COLONOSCOPY .......................................................... 17 
4.4. 
VISIT 4 (DAY 7): FOLLOW UP OF ADVERSE EVENTS AND LABORATORY RESULTS .. 17 
4.5. 
VISIT 5 (DAY 30): FOLLOW UP OF ADVERSE EVENTS AND LABORATORY RESULTS 18 
4.5.1. 
End of Study Telephone Call ........................................................................ 18 
4.6. 
TABULATED STUDY PROCEDURES ........................................................................... 19 
4.7. 
PHYSICIAN ASSESSMENTS ....................................................................................... 20 
4.7.1. 
Segmental Cleansing Assessment ................................................................. 20 
4.7.2. 
Overall Cleansing Assessment ...................................................................... 20 
4.7.3. 
Additional Efficacy Measures ....................................................................... 20 
4.8. 
PREGNANCY ............................................................................................................ 21 
4.9. 
CONCOMITANT MEDICATIONS ................................................................................. 21 
5.
ADVERSE EVENTS .................................................................................................... 22 
5.1. 
ADVERSE EVENT DEFINITION AND REPORTING ....................................................... 22 
5.2 
EXPECTED ADVERSE EVENTS .................................................................................. 23 
6.
SERIOUS ADVERSE REACTIONS AND DISCONTINUATION OF STUDY ... 24
6.1. 
BLOOD SAMPLING FOR SAE SUBJECTS ................................................................... 24 
7.
INSTITUTIONAL REVIEW BOARD (IRB) AND INFORMED CONSENT ....... 25 
8.
MANAGEMENT OF INTERCURRENT EVENTS ................................................. 25 
8.1. 
MODIFICATION OF PROTOCOL ................................................................................. 25 
8.2. 
SUBJECTS DISCONTINUED FROM THE STUDY ........................................................... 25 
8.3. 
SAFETY INTERIM MONITORING – STUDY STOPPING RULE ....................................... 25 
9.
DATA ANALYSIS ....................................................................................................... 26 
9.1. 
STUDY ENDPOINTS - EFFICACY ............................................................................... 26 
9.2. 
STUDY ENDPOINTS - SAFETY ................................................................................... 27 
9.3. 
SAMPLE SIZE ........................................................................................................... 28 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 3 of 34 
9.4. 
STUDY POPULATIONS .............................................................................................. 29 
9.4.1. 
Intention-to-Treat (ITT) Population ............................................................. 29 
9.4.2. 
Safety Population .......................................................................................... 29 
9.4.3. 
Modified Intention-to-Treat (mITT) Population .......................................... 29 
10. DRUG INVENTORY AND DISPOSITION .............................................................. 29 
11. STUDY MONITORING .............................................................................................. 30 
12. DOCUMENTS AND NOTIFICATIONS ................................................................... 30 
12.1. INFORMED CONSENT ............................................................................................... 30 
12.2. INSTITUTIONAL REVIEW BOARD ............................................................................. 30 
12.3. AMENDMENTS TO THE PROTOCOL ........................................................................... 30 
12.4. DATA RECORDS ....................................................................................................... 30 
13. PUBLICATION AND AGREEMENT ....................................................................... 30 
14. INVESTIGATORS AGREEMENT ........................................................................... 31 
15. REFERENCES ............................................................................................................. 32 
16. APPENDICES .............................................................................................................. 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 4 of 34 
CLINICAL PROTOCOL SUMMARY SHEET 
STUDY TITLE: 
A Safety and Efficacy Comparison of BLI4900 Bowel Preparation 
versus an FDA-approved Comparator in Adult Subjects prior to 
Colonoscopy 
PROTOCOL: 
BLI4900-302 
VERSION DATE: 
01-10-2020
IND NUMBER:  
134507 
STUDY PHASE: 
3 
OBJECTIVE:  
To compare the safety and efficacy of BLI4900 bowel preparation to 
SUPREP Bowel Prep Kit 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 450 male and female adult subjects will be enrolled at up to 25 
US centers and undergo colonoscopy. It is anticipated that approximately 520 
subjects will be randomized to achieve 450 completed colonoscopies. 
STUDY 
MEDICATIONS: 
Treatment 1: BLI4900  
Treatment 2:  SUPREP Bowel Prep Kit 
DURATION: 
Subject participation in this study may last up to 60 days. 
EFFICACY  
The primary efficacy endpoint is based on overall preparation success 
ENDPOINTS: 
(overall cleansing grades of Excellent or Good) as determined by the 
local blinded colonoscopist following completion of the colonoscopy. 
Additional efficacy endpoints include: proportion of Excellent overall 
cleaning grades and adenoma detection rate. Preparation quality on 
insertion will be evaluated by blinded central readers. 
SAFETY 
ENDPOINTS: 
Safety endpoints include: 
• Treatment-emergent adverse events
• Changes in serum chemistry and hematology parameters
• Orthostatic heart rate and blood pressure


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 5 of 34 
1. INTRODUCTION 
 
In sigmoidoscopy, colonoscopy, radiographic examination and other medical or 
diagnostic procedures on the colon, it is important that the colon be thoroughly purged 
and cleansed. In particular, it is essential that as much fecal matter as possible be 
removed from the colon to permit adequate visualization of the intestinal mucosa.  
 
Large-volume (e.g. 4L) orally administered compositions have been developed for use 
as gastrointestinal “washes” for diagnostic purposes. Such orally administered 
preparations are usually formulated as dilute or isotonic solutions of polyethylene 
glycol 3350 (PEG-3350) and electrolyte-containing salts such as sodium sulfate, 
sodium bicarbonate, sodium chloride and potassium chloride (1). These orally 
administered compositions are useful in the rapid cleansing of the colon for diagnostic 
purposes.  However, due to the large volume of poorly tasting fluid that must be 
ingested, patient compliance is often poor. 
 
One attempt to answer this problem has been to reduce the volume of preparation and 
improve its palatability. To this end, a sulfate-based bowel preparation kit, SUPREP ® 
Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral 
Solution, was cleared by FDA in 2010. SUPREP requires the patient to consume two 
separate administrations of this oral sulfate solution (OSS).  Each administration 
purges the colon of fecal material.  The colon is cleansed after the second 
administration. Each administration is followed by 946 ml supplemental water to 
prevent dehydration.  The total volume of fluid intake (including SUPREP) is about 
3L.  SUPREP was specifically formulated to prevent fluid and electrolyte disturbances, 
unlike the phosphate preparations (2).   
 
Nevertheless, some physicians have adopted a bowel preparation that consists of PEG-
3350 combined with a “sports drink” such as Gatorade® (PEG-SD).  It combines PEG-
3350 (available over-the-counter and one of the active ingredients of several FDA-
approved bowel cleansing preparations), with the electrolytes and sugar found in the 
sports drink. It is an osmotically unbalanced formulation and its effects on fluid and 
electrolyte balance have not been studied. It appears that the patients’ perception of this 
product is so acceptable that physicians recommend its use, despite evidence that it is 
less effective and perhaps less safe than those cleared by FDA (3,4,5).  
 
Table 1 shows that the quantities of the electrolytes in PEG-SD are much less than in 
marketed bowel preparation products, which is not surprising as the sports drink was 
developed to replace electrolytes lost in sweat, not from diarrhea.  
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 6 of 34 
Table 1: Comparison of Composition (Grams) in Two Marketed Bowel Cleansing 
Products and PEG-SD* 
NuLYTELY 
GoLYTELY 
PEG-SD** 
Prep Volume 
4L 
4L 
~ 2 L 
PEG 
420.00 
236.00 
238 
Na 
5.95 
10.37 
0.865 
Cl 
7.52 
15.04 
0.804 
K 
0.76 
1.55 
0.22 
HCO3 
4.16 
8.32 
0 
*Matro et al, 2014. **PEG-SD contains 112g of sugars
Although it is unapproved by the FDA, doctors make this decision because of a variety 
of factors, such as cost, taste and patient requests.  
For example, Matro et al (3) randomized patients to receive PEG-SD (N = 180) or 
PEG-EA (N=184), which is an approved bowel preparation (MOVIPREP®), and 
collected clinical chemistry data at baseline and on the day of colonoscopy. Although 
the incidence of hyponatremia (serum sodium < 135 mmol/L) was higher in the 
osmotically unbalanced PEG-SD group, (3.9%) vs the PEG-EA treated group (2.2%), it 
did not differ statistically.  For other electrolytes, small but statistically significant 
changes from baseline to colonoscopy occurred with PEG-SD for sodium, potassium 
and chloride (P = 0.001, 0.012, 0.001, respectively).  
Regarding the efficacy of PEG-SD, properly powered studies such as that of Matro et 
al conclude that PEG-SD is inferior in the rate of preparations considered “excellent” 
by the endoscopist. Patients consuming the PEG-SD also drink additional fluids and 
are usually instructed to receive a de-bulking laxative such as OTC bisacodyl prior to 
the PEG-SD consumption. Bisacodyl is a poorly absorbed stimulant laxative that acts 
to stimulate peristalsis in the colon resulting in stool evacuation.  
1.1. Clinical Experience with the BLI4900 Active Ingredients 
1.1.1. PEG-3350 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 7 of 34 
1.1.2. Sulfate Salts 
The goal of the current Phase 3 study is to evaluate the safety and efficacy of BLI4900 
versus SUPREP Bowel Prep Kit (SUPREP) in a large, multi-center study in adult 
patients.  


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 8 of 34 
2. STUDY OBJECTIVE
The objective of this study is to compare the safety and efficacy of BLI4900 to 
SUPREP as 2-day, split-dose bowel preparations prior to colonoscopy in adult patients. 
3. STUDY PLAN
3.1. Study Design
This is a randomized, parallel, multi-center, single-blind study in adult subjects. 
3.2. Number of Subjects 
Approximately 520 male and female subjects who are undergoing colonoscopy for 
routinely accepted indications will be enrolled in this study. Enrollment will continue 
until approximately 450 subjects have undergone a colonoscopy. 
3.3. Duration of Study 
Subject participation in this study will last up to 60 days. A screening visit (Visit 1) 
should be performed within 30 days of the colonoscopy. Subjects meeting all eligibility 
criteria during the screening visit will be assigned to receive either BLI4900 or SUPREP 
using a dynamic minimization scheme. Subjects will return to the clinic for Visit 2 on the 
day of their colonoscopy.  A follow up visit (Visit 3) will occur 48-72 hours after 
colonoscopy. Subjects with abnormal laboratory values and/or ongoing adverse events 
will have a follow-up visit 7 days after colonoscopy (Visit 4). If resolution of the 
abnormal laboratory value or adverse event has not occurred by Day 7, an additional 
clinic visit is required 30 days after colonoscopy (Visit 5). 
3.4. Study Preparations 
BLI4900 
The BLI4900 preparation consists of two 1-liter doses, each dose containing the 
following ingredients in solid form.  
Component 
BLI4900-6 
Grams / 1 L 
Contained in 1-liter bottle 
Polyethylene glycol (PEG) 3350 
Sodium Sulfate 
Magnesium Sulfate, Anhydrous 
Potassium Chloride 
Sodium Chloride 
Lemon-Lime Flavor Powder 
Neotame 
Advantame 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 9 of 34 
Contained in sachet 
Malic Acid 
Citric Acid, Anhydrous 
Sucralose 
Aerosil 200 Pharma 
Subjects will consume a total of 2 liters of solution (two 1-liter doses). Each 1-liter 
dose will be contained in a separate bottle. Each bottle is accompanied by a sachet that 
will be poured into each bottle prior to reconstitution. The bottles and sachets will have 
a clinical label containing a caution statement, study code, study sponsor and kit 
number. Subjects will be provided with instructions on how to complete the 
preparation. 
SUPREP Bowel Prep Kit 
SUPREP Bowel Prep Kit (Braintree Laboratories, Inc.) is FDA approved for cleansing 
of the colon as preparation for colonoscopy in adults. SUPREP consists of two 6 ounce 
doses, each containing the following ingredients in liquid form:  
Component 
Grams 
Na2SO4 
17.51 
MgSO4 
1.6 
K2SO4 
3.13 
Sodium Benzoate 
0.098 
Flavoring agents 
1.35 
Artificial Sweetener 
1.2 
Each dose will be supplied in a 6 ounce amber plastic bottle with a Clic-Loc closure. 
Each bottle will have a clinical label containing a caution statement, study code, study 
sponsor and kit number. Subjects will be provided with instructions on how to 
complete the preparation. 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 10 of 34 
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


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 11 of 34 
3.5.2. Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from the study: 
1. Subjects with known or suspected ileus, gastrointestinal obstruction, gastroparesis, gastric
retention, bowel perforation, toxic colitis or megacolon.
2. Subjects with inflammatory bowel disease who have a history of any bowel
resection (small intestine or colon), suspected active inflammation, or symptoms
suggestive of obstruction or known bowel stricture.
3.
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.
4. Subjects who have regularly used laxatives or colon motility altering drugs in the
last month (i.e. more than 2-3 times per week) and/or laxative use within 72 hours
prior to administration of the preparation
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.


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 12 of 34 
13. Subjects undergoing insulin therapy for any indication.
14. Subjects with impaired consciousness that predisposes them to pulmonary aspiration.
15. Subjects undergoing colonoscopy for foreign body removal and/or decompression.
16. Subjects who are pregnant or lactating, or intending to become pregnant during the study.
17. Subjects of childbearing potential who refuse a pregnancy test.
18. Subjects allergic to any BLI4900 components or SUPREP components.
19. Subjects taking tricyclic antidepressants.
20. Subjects using drugs of abuse, including abused prescription medications.
21. Subjects who are withdrawing from alcohol or benzodiazepines.
22. Subjects who, in the opinion of the Investigator, should not be included in the study
for any reason, including inability to follow study procedures.
23. Subjects who have participated in an investigational surgical, drug, or device study 
within the past 30 days.
24. Subjects who withdraw consent before completion of Visit 1 procedures.


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 13 of 34 
4. STUDY PROCEDURES
Study procedures are described as follows and depicted graphically in Section 4.5, 
below. 
4.1. Visit 1 
At the screening visit, the following procedures will be undertaken: 
•
Subject is fully informed about the study and gives written agreement to study
participation in the form of a signed informed consent form (refer to Section 4.1.1) and
is assigned a subject number
•
Assess eligibility (refer to inclusion/exclusion criteria)
•
Review of medications
•
Medical history - medical history will be recorded to include all ongoing conditions at
Visit 1 as well as any significant conditions, defined as:
Abdominal surgeries, Renal failure/dysfunction, Liver failure/dysfunction, 
Cardiac disorders (e.g. myocardial infarction, coronary artery disease 
tachycardia), Hypertension, Diabetes, Cancer (must indicate type of cancer), 
Electrolyte abnormalities 
•
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), glucose, 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. 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 14 of 34 
 
A serum pregnancy test will be performed on female subjects of childbearing potential 
(see Section 4.8). 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 
by the Investigator in the subject’s file.  A copy of the original signed and dated Informed 
Consent Form must be given to the subject. 
4.1.2. 
Treatment Assignment / Blinding 
Subjects that meet all eligibility criteria will be assigned to a treatment group by a 
dynamic minimization scheme (12) implemented using an automated interactive web 
response system (IWRS). At the time of enrollment, the IWRS will assign a drug kit 
number for site personnel to dispense to the subject. In addition to being stratified by 
site, subjects will be stratified into one of the following three groups. Subjects meeting 
Group 1 criteria will be assigned to Group 1 regardless of whether or not they meet the 
Group 2 criterion.  
 
Group 1: Subjects who meet any of the following criteria: 
• History of prior failed bowel preparation (inadequate examination) 
• Currently taking opioid medications 
• Body Mass Index > 35 
 
Group 2: Subjects scheduled for a colonoscopy 12:00 PM or later 
 
Group 3: Subjects not meeting Group 1 or 2 criteria 
 
The dynamic minimization system will, at the time of each new enrollment, compute a 
measure of treatment balance for each of the two possible treatment assignments.  It 
will then select a treatment arm by pseudo-randomization:  With probability 0.8, it will 
assign the subject to the arm that gives greater balance; with probability 0.2, it will 
assign the subject to the arm that gives lesser balance.  The site personnel must only 
dispense a drug kit that has been assigned by the IWRS.  Dispensing kits out of order is 
considered a protocol violation.  
  
In this single-blinded study, to ensure an unbiased evaluation of the study preparations, 
the colonoscopist will not be allowed to perform any study drug-related activities 
(treatment assignment, drug dispensing, return and accountability). Any failure to 
maintain blinding of the treatment to the colonoscopist will be documented as a 
protocol violation.  Subjects will be instructed not to discuss their study preparation 
assignment with study staff members. 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 15 of 34 
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 
BLI4900 
Subjects assigned to BLI4900 will take their first 1-liter dose the evening 
before colonoscopy.  This will be followed no less than four hours later by the 
second 1-liter dose.  The second dose should be taken 5 to 8 hours before the 
colonoscopy.  BLI4900 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). 
SUPREP Bowel Prep Kit 
Subjects assigned to SUPREP will take their SUPREP according to 
manufacturer’s labeling for split-dose administration.  Subjects may have a 
light breakfast on the day before colonoscopy, followed by clear liquids until 
the colonoscopy is completed the following day.  
Examples of acceptable clear liquids are provided in the Dietary Questionnaire 
(Appendix A). 
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. 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 16 of 34 
4.1.5. Medication Restrictions 
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 
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 – 4.5. 
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 repeat screening laboratory assessments.  
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 changes to their 
concomitant medications and adverse events. Subjects will complete a Preference 
Questionnaire (See Appendix A). Blood samples for chemistry and hematology testing 
will be taken as outlined in Section 4.1.  
If a colonoscopy is not done, clearly document if the subject had taken any portion of 
preparation and the reason why the colonoscopy was not attempted. 
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 4.7.  The colonoscopy 
procedure will be video recorded. A designated vendor will provide standardized video 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 17 of 34 
recording capabilities and centralized reading by an independent gastroenterologist. 
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 unused 
preparation materials. 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. 
4.3. Visit 3: 48 - 72 Hours Post Colonoscopy 
Subjects will return 48 - 72 hours following colonoscopy for follow-up. If a subject is 
unable to be seen during this 48 – 72 hour window, subjects should be seen as soon as 
possible after 72 hours (not prior to 48 hours). 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 4.5.1). 
4.4. Visit 4 (Day 7): 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) 
to undergo repeat laboratory testing and vital signs measurements. Subjects returning 
due to ongoing adverse events should be assessed to determine if the event has 
resolved or is clinically stable.  If the adverse event has resolved or laboratory value(s) 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 18 of 34 
have returned to normal range, Day 30 follow-up may be performed via telephone (See 
Section 4.5.1). 
4.5. Visit 5 (Day 30): Follow up of Adverse Events and Laboratory Results 
Subjects with an adverse event that had not resolved or laboratory value that had not 
normalized by Visit 4 will return for follow up on Day 30 (+/- 2 days). All subjects 
requiring follow-up must undergo repeat laboratory testing and vital signs 
measurements. Subjects returning due to ongoing adverse events should be assessed to 
determine if the event has resolved or is clinically stable. 
 
4.5.1. End of Study Telephone Call 
Subjects that do not have new or ongoing adverse events or abnormal laboratory results 
at Visit 3, or that have resolved by Visit 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.


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
 
Version dated 01-10-2020 
 
 
 
Page 19 of 34 
 
 
4.6. 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 
 
48 - 72 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 
 
 
 
 
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 4.8 
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 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 20 of 34 
4.7. Physician Assessments 
4.7.1. Segmental Cleansing Assessment 
The blinded colonoscopist will rate each colon segment (proximal, mid, distal) 
during withdrawal 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 
4.7.2. Overall Cleansing Assessment 
Following completion of the procedure, 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 4.7.1.   
4.7.3. 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
4. Completion time of colonoscopy
5. Volume of water used to improve visualization (investigators will need to
specify cases where a water immersion technique was utilized)


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 21 of 34 
4.8. 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.  
4.9. 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.    


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 22 of 34 
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. Colonoscopy and biopsy 
findings are not considered adverse events unless considered by the investigator to 
be related to the preparation or colonoscopy procedure.  
Any blood pressure result that is deemed clinically significant and not present at 
Visit 1 must be reported as an adverse event. In addition, any 30 mmHg change in 
systolic or diastolic blood pressure from Visit 1 must be reported as an adverse 
event.   
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: 
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) 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 23 of 34 
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 
BLI4900 
Because BLI4900 contains the same active ingredients as approved bowel 
preparations (PEG3350 and sulfates), a similar adverse event profile is expected. In 
Phase 3 clinical trials of SUPREP (which includes sodium and magnesium sulfate), 
the most frequent adverse events reported by > 3% of patients included overall 
discomfort, abdominal pain and distension, nausea, and vomiting. The most 
frequently reported adverse events occurring in > 3% of patients taking NuLYTELY 
(which contains PEG3350) are nausea, abdominal fullness and bloating.  
SUPREP Bowel Prep Kit 
In a Phase 3 clinical study of SUPREP given in a 2-day, split-dose regimen, the most 
frequent adverse events reported by patients taking SUPREP (reported by >2% of 
patients) included overall discomfort, abdominal distension, abdominal pain, nausea 
and vomiting (11).  


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 24 of 34 
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.  
Braintree Laboratories must be kept apprised of all follow-up information related to 
serious adverse events. In addition, Investigators must comply with the SAE reporting 
requirements of the Institutional Review Board with oversight of the study.  
Any serious and/or unexpected adverse events that occur during the study will be 
reported to Braintree Laboratories as follows: 
Contact Telephone Numbers: 
During Business hours 
(M-F, 8:30 am – 5:00 pm EDT) 
After hours or weekends 
 
Braintree Laboratories and its medical monitor will review the report and determine 
whether an FDA Form 3500A will also be completed and sent to FDA. 
6.1. Blood Sampling for SAE Subjects 
Subjects that experience an SAE must to return to the clinic as soon as possible to 
provide blood samples for pharmacokinetic testing of sulfate and polyethylene glycol 
3350 (and metabolites). The time of blood sampling must be recorded. If a subject 
refuses to return for this procedure, the site must document this in their progress 
notes.  


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 25 of 34 
7. INSTITUTIONAL REVIEW BOARD (IRB) AND INFORMED
CONSENT
IRB review and approval of the study protocol and Informed Consent Form will be 
obtained prior to initiation of the study.  Amendments to the study protocol and consent 
form generated during the course of the study will also require IRB approval. 
8. MANAGEMENT OF INTERCURRENT EVENTS
8.1. Modification of Protocol
Neither an Investigator nor Braintree Laboratories will modify the protocol without 
first obtaining the concurrence of the other and the IRB. Investigators that 
continually violate the protocol or commit a serious violation may be subject to 
termination from the study. The study may be halted if at any time an Investigator or 
Braintree Laboratories deems the incidence or severity of adverse events to be 
unacceptable. 
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 (no less frequent than 
biweekly). Adverse event terms from the study that are listed in the Common 
Terminology Criteria for Adverse Events (CTCAE, version 5.0) 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 notify FDA and 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 Disorders 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.  


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 26 of 34 
9. DATA ANALYSIS 
9.1. Study Endpoints - Efficacy 
 
Primary Efficacy Endpoint 
 
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: 
 
Definition of successful preparation:  
1. Overall Cleansing Assessment by the local 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 local 
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 cleansing 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 BLI4900 group, P2 is the success 
probability in the SUPREP group (reference or control group), and D0 is the 
acceptable margin of non-inferiority, which we set equal to  −10%.  
 
If the test for non-inferiority is statistically significant, we will conduct a test of 
superiority comparing the proportion of overall Excellent preparations: 
 
Null Hypothesis H0: P1−P2≤0 versus Alternative Hypothesis H1: P1−P2>0. 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 27 of 34 
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. The primary endpoint of cleansing 
success will also be analyzed based on demographic subgroups (elderly, gender, 
race, ethnicity).  
 
Additional Efficacy Endpoints: 
 
Additional efficacy endpoints will include: 
• Adenoma Detection Rate (proportion of subjects with a confirmed 
adenoma based on histopathological examination) 
• Cleansing score by segment 
• Number (%) of excellent preparations by segment 
• Adequacy of cleansing 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 
 
Cleansing will also be evaluated using an exploratory definition of preparation success 
based on segmental scoring by the central reader. Using the grading scale outlined in 
Section 4.7.1, each colon segment (proximal, mid, distal) will be graded by the central 
reader on insertion. To be considered successful, all segment grades must be rated as 
Excellent or Good. If any segment is rated as Fair or Poor, the preparation will be 
considered a failure. This analysis will be conducted using the same statistical 
methodology as the primary efficacy endpoint (-10% non-inferiority margin).  
 
Additional efficacy 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 
additional efficacy endpoints.  P values will be presented for hypothesis tests, and 
two-sided 95% confidence intervals for estimates of treatment effects. 
 
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. 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 28 of 34 
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. Treatment-emergent adverse events will also be analyzed based on 
demographic subgroups (elderly, gender, race, ethnicity). 
 
Vitals Signs: 
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 ANCOVA.  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).  
 
9.3. Sample Size  
Approximately five hundred and twenty (520) subjects will be randomly assigned via 
the minimization scheme to one of two preparations in a ratio of 1:1 (260 subjects 
per group) and undergo colonoscopy. Based on prior studies using a similar grading 
system, the success rate for SUPREP is expected to be approximately 95% (11). 
Assuming a success rate for BLI4900 of approximately 91%, a two-sided asymptotic 
confidence interval for the difference in success rates between groups (BLI4900 – 
SUPREP) will result in a lower CI bound greater than – 10%, with probability 80%. 
This result would establish the non-inferiority of BLI4900 to SUPREP at a non-
inferiority margin of 10%. 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 29 of 34 
Our sample-size calculations for non-inferiority tests with a binary outcome use the 
method of Chow et al (13). If the SUPREP success rate is 95% and the BLI4900 
success rate is 91%, the sample size needed is n=446 (total across both study groups) 
for a non-inferiority margin of 10% and a target power of 80%.  Thus with the study 
requirement of 520 subjects undergoing colonoscopy (assuming a dropout rate of 
approximately 10%), we will attain 80% power.  
In randomized studies, the purpose of the stratification is to eliminate the 
stratification factor from the error term, thereby potentially reducing variability (14).  
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 may be used for 
sensitivity analysis of the primary efficacy endpoint. 
9.4.2. 
Safety Population 
This population consisted of all randomized subjects that took any portion of study 
medication. The safety population will be used for all safety analyses. 
 
9.4.3. 
Modified Intention-to-Treat (mITT) Population  
This population consists of all randomized subjects that took at least one dose of 
study medication. The only exception is subjects who took the study preparation and 
did not undergo colonoscopy for a reason other than safety or efficacy (e.g. lack of 
insurance coverage, unable to return to the clinic for colonoscopy). This population 
will be used for all efficacy analyses.  
 
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.  
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 30 of 34 
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 
ensure correctness and consistency with the CRF entries. Copies of subjects’ 
laboratory reports, colonoscopy and pathology reports (if applicable) will be 
collected for Braintree Laboratories after subject identifiers have been redacted by 
site staff. The Investigator should retain copies of paper and electronic data, patient 
consent/assent forms, and other study documents for a period of two years following 
the date of approval of a New Drug Application or supplement for BLI4900, or, if 
the application is not approved, for two years after the drug investigation program is 
discontinued. These records will be made available at reasonable times for inspection 
and copying if requested by a properly authorized employee of Braintree 
Laboratories or the Department of Health and Human Services in accordance with 
federal regulations. 
13. PUBLICATION AND AGREEMENT 
 
The results of this study will be published if mutually agreed by Braintree 
Laboratories and the Investigator and at a mutually agreed upon date. Investigator 
agrees to submit to Braintree Laboratories, within sixty (60) days of the proposed 
submission date, any proposed publication or presentation for prior review.  


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 31 of 34 
Braintree Laboratories will, within thirty (30) days after receipt, advise if there is any 
proprietary or patentable information, which should not be disclosed at the present 
time. Investigator shall not release any such proposed publication or presentation, if 
so notified by Braintree Laboratories. 
 
14. INVESTIGATORS AGREEMENT   
 
I agree to perform the protocol according to Federal Regulations and as detailed in 
this document to the best of my ability.  I recognize that if I fail to do so my 
participation in this study may be terminated.  I also agree to the publication 
provisions stated in Section 13, above. My signature on the cover page of this 
protocol serves as documentation of my acceptance of the terms noted above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 32 of 34 
15. REFERENCES 
1 - Davis GR, et al. Development of a Lavage Solution Associated with Minimal 
Water and Electrolyte Absorption or Secretion. Gastroenterology. 1980;78(5 Pt 
1):991-5.  
 
2 - Patel V, et al. Intestinal and Renal Effects of Low-Volume Phosphate and Sulfate 
Cathartic Solutions Designed for Cleansing the Colon: Pathophysiological Studies in 
Fve Normal Subjects. Am J Gastroenterol. 2009;104(4):953-65.  
 
3 - Matro R, et al.  Randomised clinical trial: polyethylene glycol 3350 with sports 
drink vs. polyethylene glycol with electrolyte solution as purgatives for colonoscopy 
- the incidence of hyponatraemia. Aliment Pharmacol Ther. 2014;40(6):610-9. 
 
4 - Schoenfeld P. Safety of MiraLAX/Gatorade Bowel Preparation Has Not Been 
Established in Appropriately-Designed Studies. Clin Gastroenterol Hepatol. 
2013;11(5):582.  
 
5 - Lewis, J and Schoenfeld, P. Severe Hyponatremia and Miralax-Gatorade Bowel 
Preparation. Am J Gastro. 106(2):5582-3, 2011. 
 
6 - Hammer HF, Santa Ana CA, Schiller LR, Fordtran JS. Studies of osmotic 
diarrhea induced in normal subjects by ingestion of polyethylene glycol and 
lactulose. J Clin Invest. 1989;84(4):1056-62. 
 
7 - Smyth HF Jr, Carpenter CP, Weil CS. The toxicology of the polyethylene 
glycols. J Am Pharm Assoc. 1955;44(1):27-30. 
 
8 - Pockros  PJ, Foroozan P: Golytely lavage versus a standard colonoscopy 
preparation - effect on normal colonic mucosal histology. Gastroenterology. 
1985;88(2):545-8.  
 
9 - Rothfuss KS, Bode JC, Stange EF, Parlesak A. Urinary excretion of polyethylene 
glycol 3350 during colonoscopy preparation. Z Gastroenterol. 2006;44(2):167-72. 
 
10 - Pelham RW et al. Clinical trial: single- and multiple-dose pharmacokinetics of 
polyethylene glycol (PEG-3350) in healthy young and elderly subjects. Aliment 
Pharmacol Ther. 2008;28(2):256-65. 
 
11 - Di Palma JA, Rodriguez R, McGowan J, Cleveland Mv. 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(9):2275-84. 
12 – Pocock SJ, Simon R. Sequential treatment assignment with balancing for 
prognostic factors in the controlled clinical trial. Biometrics 1975;31:103–115. 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
 
Page 33 of 34 
 
13 – Chow S, Shao J, Wang H. 2008. Sample Size Calculations in Clinical Research. 
2nd Ed. Chapman & Hall/CRC Biostatistics Series. P. 91. 
14 – Fleiss JL.  1986.  The Design and Analysis of Clinical Experiments.  John 
Wiley & Sons. 
 


Braintree Laboratories, Inc. 
Confidential 
Protocol Number BLI4900-302 
Version dated 01-10-2020 
Page 34 of 34 
16. APPENDICES
Appendix A – Preparation Instructions and Subject Questionnaires