Conditions: Constipation Chronic Idiopathic Constipation CIC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1020
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate a daily dose of BLI400 Laxative for safety and efficacy versus placebo in constipated adults.

Detailed description:

Arms:
arm 1: BLI400 Laxative arm 2: BLI400 placebo

Interventions: intervention 1: BLI400 Laxative intervention 2: BLI400 Placebo
Intervention descriptions: intervention 1: 21 gm BLI400 powder intervention 2: Equivalent amount of placebo powder

Protocol document:
Prot_SAP_000.pdf: 
NCT02819297 
STUDY PROTOCOL 
 
A Safety and Efficacy Evaluation of BLI400 Laxative in 
Constipated Adults 
 
DOCUMENT DATE: 04/13/2016 


Braintree Laboratories, Inc. 
Protocol Number BU400-302 
:>51.o<c-Lf / (Jl{ 7 / 2 W 2 
Contidential 
A Safety and Efficacy Evaluation of BLl400 Laxative in Constipated 
Adults 
Braintree Protocol BLI400-302 
SPONSOR 
Mark Cleveland 
Sr. Vice President, R&D/RA 
Braintree Laboratories, Inc. 
Version dated 4-13-2016 
Version Dated 4-13-2016 
Braintree Laboratories, Inc. 
60 Columbian St. West 
P.O. Box 850929 
Braintree, MA 02185 
PH: 781-843-2301 
Date 
o s--zl/-zc.r, 
Date 
Page I of 34 
BLI400 (NDA 211281)
Confidential  
Page 1 of 68


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 2 of 34 
 
1. 
INTRODUCTION .................................................................................................................. 6 
2. 
STUDY OBJECTIVE .......................................................................................................... 11 
3. 
STUDY PLAN ....................................................................................................................... 11 
3.1. 
STUDY DESIGN ................................................................................................................ 11 
3.2. 
NUMBER OF SUBJECTS ..................................................................................................... 11 
3.3. 
DURATION OF STUDY ...................................................................................................... 11 
3.4. 
STUDY TREATMENTS ....................................................................................................... 11 
3.5. 
SUBJECT SELECTION ........................................................................................................ 13 
3.5.1. 
Inclusion Criteria .......................................................................................... 13 
3.5.2. 
Exclusion Criteria ......................................................................................... 14 
4. 
STUDY PROCEDURES ...................................................................................................... 15 
4.1. 
VISIT 1: SCREENING ........................................................................................................ 15 
4.1.1. 
Informed Consent .......................................................................................... 16 
4.1.2. 
Enrollment and Allocation of Subject Number ............................................ 16 
4.1.3. 
Electronic Subject Diary during Screening Period ...................................... 17 
4.2. 
VISIT 2 ............................................................................................................................. 17 
4.2.1. 
Randomization ............................................................................................... 18 
4.2.2. 
Study Drug ..................................................................................................... 18 
4.3. 
TREATMENT PERIOD ........................................................................................................ 18 
4.3.1. 
Electronic Subject Diary during Treatment Period ..................................... 18 
4.3.2. 
Treatment Day 1 ............................................................................................ 19 
4.3.3. 
Visits 3 – 7 (Days 28, 56, 84, 112 and 140) ................................................... 19 
4.3.4. 
Visit 8 – Day 180 (or Early Term) ................................................................. 20 
4.3.5. 
Day 194 Follow-up Telephone Call: +/- 3 days ............................................ 20 
4.4. 
TABULATED STUDY PROCEDURES ................................................................................... 21 
4.5. 
PREGNANCY .................................................................................................................... 22 
4.6. 
CONCOMITANT MEDICATIONS ......................................................................................... 22 
5. 
ADVERSE EVENTS ............................................................................................................ 23 
5.1. 
ADVERSE EVENT DEFINITION AND REPORTING ............................................................... 23 
6. 
SERIOUS ADVERSE REACTIONS AND DISCONTINUATION OF STUDY ........... 24 
7. 
INSTITUTIONAL REVIEW BOARD AND INFORMED CONSENT ......................... 25 
8. 
MANAGEMENT OF INTERCURRENT EVENTS ......................................................... 26 
8.1. 
MODIFICATION OF PROTOCOL ......................................................................................... 26 
8.2. 
SUBJECTS DISCONTINUED FROM THE STUDY ................................................................... 26 
9. 
DATA ANALYSIS ............................................................................................................... 27 
9.1. 
SAMPLE SIZE ................................................................................................................... 27 
9.2. 
NULL AND ALTERNATIVE HYPOTHESES .......................................................................... 27 
9.3. 
PLANNED ANALYSES ....................................................................................................... 27 
9.3.1. 
Demographic and Baseline Characteristics ................................................. 27 
9.3.2. 
Efficacy Analyses ........................................................................................... 28 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 3 of 34 
9.3.3. 
Safety Analyses .............................................................................................. 29 
9.4. 
STUDY POPULATIONS ...................................................................................................... 31 
9.4.1. 
Intention-to-Treat (ITT) Population ............................................................. 31 
9.4.2. 
Modified Intention-to-Treat (mITT) Population .......................................... 31 
9.4.3. 
Per-Protocol Population ................................................................................ 31 
10. 
DRUG INVENTORY AND DISPOSITION .................................................................. 31 
11. 
STUDY MONITORING .................................................................................................. 31 
12. 
DOCUMENTS AND NOTIFICATIONS ....................................................................... 32 
12.1. INFORMED CONSENT ....................................................................................................... 32 
12.2. INSTITUTIONAL REVIEW BOARD ...................................................................................... 32 
12.3. AMENDMENTS TO THE PROTOCOL ................................................................................... 32 
12.4. DATA RECORDS ............................................................................................................... 32 
13. 
PUBLICATION AND AGREEMENT ........................................................................... 33 
14. 
INVESTIGATORS AGREEMENT ............................................................................... 33 
15. 
REFERENCES ................................................................................................................. 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 4 of 34 
CLINICAL PROTOCOL SUMMARY SHEET 
 
STUDY TITLE:  
A Safety and Efficacy Evaluation of BLI400 Laxative in Constipated Adults 
 
 
PROTOCOL: 
 
BLI400-302 
 
 
VERSION DATE:  9-15-2016 
 
 
IND NUMBER: 
118,906 
 
 
OBJECTIVE:  
 
To evaluate a daily dose of BLI400 Laxative for safety and efficacy versus placebo in 
constipated adults. 
 
STUDY DESIGN:  
 
This will be a randomized, double-blind, parallel, multi-center study. 
 
SUBJECTS:   
Approximately 600 male or female constipated adult subjects will be randomized in this 
study after completing a 14 day screening period to confirm constipation status.  
Approximately 30% of enrolled subjects will be elderly (greater than 65 years of age at 
time of randomization) 
 
 
STUDY MEDICATIONS:  
 
Group 1: 
BLI400 Laxative (21 grams of Lactitol Monohydrate, NF) 
Group 2:  
Placebo (regular maltodextrin)  
 
 
 
DURATION OF TREATMENT 
 
Subjects will take BLI400 laxative or placebo daily for 6 months. Participation in this 
study will last for approximately 7 months, including the 14 day Screening Period. 
 
 
 
 
PRIMARY ENDPOINT 
 
 
The primary endpoint is the proportion of subjects who are weekly responders for at least 9 out 
of the first 12 weeks, with at least 3 of these weeks occurring during weeks 9–12. A weekly 
responder is a subject who has ≥ 3 complete spontaneous bowel movements (CSBMs) per week 
and an increase from baseline of > 1 CSBM in that week. 
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 5 of 34 
SECONDARY ENDPOINTS  
 
Secondary endpoints will include but are not limited to the following:  
• Weekly SBM and CSBM frequency rates during weeks 1 – 12 
• Weekly stool and symptom ratings (stool consistency, stool straining, abdominal 
bloating, abdominal discomfort) during weeks 1 – 12  
• Weekly SBM and CSBM frequency rates after week 12 
• Weekly stool and symptom ratings (stool consistency, stool straining, abdominal 
bloating, abdominal discomfort) after week 12  
 
Safety will be assessed using treatment emergent adverse event, laboratory, and ECG data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 6 of 34 
1. INTRODUCTION 
 
The present approaches to the treatment of chronic idiopathic constipation (CIC) are 
limited and for some patients there are significant drawbacks that have not been resolved. 
It would be desirable to provide a source of relief for constipation that would permit 
dosing adjustments to optimize efficacy and safety and that would be pleasant to consume 
to improve patient compliance.  The treatment should not have the safety issues associated 
with oral phosphate laxatives, have an acceptable safety profile, and be effective in 
numerous types of constipation. 
Braintree Laboratories, Inc. is investigating the use of a new chemical composition, 
BLI400 (Lactitol Monohydrate NF Powder for Reconstitution) as a treatment for adult 
constipation.  Ample published literature with lactitol provides significant preclinical and 
clinical studies which support the safe and effective use of this GRAS-listed compound.  
These reports indicate that the BLI400 lactitol composition has promise as a candidate for 
further development for the treatment of constipation, as reviewed herein. 
BLI400 is a member of the pharmaceutical class of osmotic laxatives; specifically it is a 
non-absorbed, colonically metabolized sugar alcohol (polyol). Studies reviewed here 
indicate it provides relief from the symptoms of constipation by rapidly inducing a 
patient-controlled bowel movement. While lactitol appears to be minimally, if at all, 
absorbed in the small intestine,  colonic microbes split lactitol into D-galactose and D-
sorbitol, which are fermentable to organic acids including lactic, formic, propionic, 
butyric and acetic acids (as reviewed in Patil et al, 1987).  The osmotic properties of the 
small organic molecules consistently point to their pharmacodynamic effects as dependent 
on water retention with the stool.  Thus, BLI400 is a pro-drug of an essentially non-
absorbed osmotic laxative. Lactitol is generally considered to be pharmacologically inert 
and is often referred to as a “prebiotic” with no specific receptor targets for its laxative 
action.  
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 7 of 34 
Rationale for Performing Research with the Investigational Product 
Lactitol monohydrate, at a daily dose of 21 grams per day appears to be a safe and 
effective treatment for constipation, but it has not been studied and proven in clinical 
trials in the US. Lactitol appears to be a “prebiotic”, a substrate for colonic bacteria which 
convert it into osmotically active small molecules. Extensive published and non-published 
literature supports its safety and efficacy, but a Phase III clinical trial is required for its 
registration in the US.  It is envisaged there will be one, multi-site, controlled study in 
patients with documented constipation and that the design will be similar to other studies 
that have led to the approval of laxatives, such as those for MiraLAX, NDA 22-015 and 
consistent with FDA’s recommendations for study endpoints in CIC trials.  
 
Physical, Chemical, and Pharmaceutical Properties and Formulation 
Lactitol is a simple monosaccharide sugar alcohol, a synthetic derivative of the milk sugar 
lactose that was discovered in the 1920s.  It is a dry, free flowing powder, readily soluble 
in aqueous solutions.  As shown by the structure diagrams, it is an analog of the 
disaccharide lactulose. 
 
Lactitol 
 
 
 
 
Lactulose 
 
 
 
 
 
 
 
Table 1-1 
Components of a Typical Single Dose of BLI400 
Component 
Amount (g)* 
Lactitol monohydrate, NF 
21 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 8 of 34 
The product will be provided in multi-dose bottles with a measuring cap to deliver 10.5 
grams of BLI400 powder.  
 
Nonclinical Studies:  Extensive nonclinical studies have been performed with lactitol as 
support for its registration and marketing in countries outside the US and are reviewed in 
detail in the BLI400 Investigators’ Brochure.  The studies have covered basic 
pharmacology, genotoxicity and mutagenicity, acute and chronic studies including 
carcinogenicity and reproductive toxicity.  These studies were carried out in mice, rats, 
dogs and rabbits. 
 
Pharmacology: Lactitol is not degraded by the galactosidase enzymes of the small 
intestine.  However, colonic microflora degrade lactitol extensively in rats so that lactitol 
elevated the proportions of acetic acid and lowered proportions of butyric acid in the 
hindgut of rats. The osmotic effects of these organic acids appear to provide the 
pharmacodynamic basis for lactitol’s laxative action. Increased output of moist feces was 
seen in all animals species studied in a dose-related manner. The highest doses tested 
caused frank diarrhea in some studies. 
Metabolic Effects: In some studies, total serum cholesterol and triglycerides were 
reduced equally in rats fed diets containing 7% sorbitol or lactitol.  By acidifying fecal 
contents, lactitol lowered ammonia levels in animal models of hepatic encephalopathy, 
perhaps as a result of production of the poorly absorbed ammonium ion that follows 
lowering the cecal pH. Rats fed a diet containing 5% of lactitol for two weeks displayed a 
significant increase of calcium absorption.  
Toxicology Studies: Only weak edema ensued after lactitol application to intact skin, but 
erythema and edema emerged when it was applied to abraded skin. Rodents treated with 
lactitol had loose, frequent stools and cecal enlargement. This was often accompanied by 
decreased weight gain and increased water consumption. Clinical chemistry changes 
included changes in electrolyte levels, decreased cholesterol and alkaline phosphatase. 
Perhaps as compensation for the electrolyte changes that probably followed the diarrhea, 
adrenal weight and hypertrophy of the zona fasciculata were seen in the highest dose 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 9 of 34 
groups.  Renal tubular degeneration with nephrocalcinosis was occasionally seen and may 
follow the increased calcium absorption. Lactitol was not considered positive for 
mutagenicity or chromosomal damage studied in standard in vitro and in vivo assays. 
Life-long carcinogenicity studies have indicated that Leydig cell dysplasia occurred in 
rats at high lactitol doses, but this was not seen in mice dosed for 24 months or dogs 
dosed for 12 months. This species-specific effect in some rat strains was not considered 
significant to humans, since ordinary milk sugar, lactose, produces a similar effect in 
rodents.  
Clinical Pharmacology and Safety: Since lactitol is extensively degraded to organic 
acids in the colon, it is little surprise that there are no published studies on its level in 
blood after administration.  Some have estimated that only 0.6% of an oral dose of lactitol 
is excreted in urine. Similar to what is found in animals, lactitol is extensively 
metabolized in the human colon, making available a significant proportion of the 
metabolites for colonic absorption. Unlike in animals, lactitol does not seem to stimulate 
calcium absorption in humans, although in one study when 15 g of lactitol was 
administered along with calcium in solution to fasting volunteers, calcium absorption was 
diminished.  Administering lactitol increases fecal Bifidobacteria levels, while other 
bacteria (fecal anaerobes, aerobes, Enterobacteriaceae or lactobacilli) were unaffected. 
After the ingestion of 25 g lactitol, xylitol, or glucose by eight healthy male volunteers the 
rise in plasma glucose was significantly greater 30 and 60 minutes after ingestion of 
glucose while no rise in plasma glucose followed ingestion of lactitol.  
The investigation of the use of a mixture of lactitol for the treatment of constipation has 
been extensively studied, but the information is only available in published form. From 
these observations, it appears that lactitol’s adverse events are limited largely to the 
gastrointestinal system. Symptoms such as nausea, cramps, abdominal pain, flatulence 
and vomiting may be expected and could lead to withdrawal from the study if not 
controlled.  Their incidence and severity may be ameliorated in some patients by dose-
adjustment.  Changes in hematology, clinical chemistry or urinalysis may be seen, and 
their clinical significance will be assessed during the development of lactitol.  In one 
study plasma potassium was elevated with lactitol, but the values stayed within the normal 
range. 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 10 of 34 
Clinical Efficacy: Lactitol has been marketed since at least 1985 outside the US in 
Europe and other regions (where it is known as Lactitol Ex-Lax® or Importal®, for 
example) as a syrup or powder for the treatment of constipation in adults, including the 
elderly and children.  As a result a substantial body of evidence has accumulated on its 
use in treating constipation, as evidenced by more than 19 publications since 1988, 
including two recent review articles (Maydeo, 2010; Faruqui and Joshi, 2012). 
A minimal effective dose of 0.25 g/kg has been suggested, and most studies have found 
that a starting dose of 20 g of lactitol is effective and produces minimal side effects.  
Some studies that have allowed the subjects to make dosage increases to achieve relief of 
constipation symptoms and dose reductions to minimize side effects have indicated that 
this strategy can optimize therapy.  
Maydeo (2010) presented a systematic review of six published randomized, non-
randomized and open trials comparing the safety and efficacy of lactitol to those of 
lactulose. Overall, lactitol was comparable to lactulose in efficacy measures (normal stool 
consistency and number of bowel movement per week). Patients found lactitol to be more 
acceptable and were more compliant with it largely due to its superior palatability (73.2 % 
vs. 26.8 %). Lactitol was significantly better than lactulose in the frequency of adverse 
events (31.2 ± 0.8 % vs. 62.1 ±1.1 %, p= 0.0019). The physicians’ assessment favored 
lactitol as compared to lactulose (61.91% vs. 47.83%).  The following table is adapted 
from Maydeo’s summary of the reviewed trials. 
 
Parameter Evaluated 
Lactitol 
Lactulose 
Patient’s acceptance 
73.2% 
26.8% 
Consistency of stool (normal/soft) 
80.5 ± 4.5% 
75.0± 8.0% 
Bowel movement/week 
5.9 ± 0.2 
5.6 ± 0.6 
Incidence of side-effects 
31.2 ± 0.8 
62.1 ±1.1% 
Global efficacy judged by physicians 
61.9% 
47.8% 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 11 of 34 
2. STUDY OBJECTIVE 
 
To compare the safety and efficacy of BLI400 laxative versus placebo in constipated adults. 
 
3. STUDY PLAN 
3.1. Study Design 
This is a randomized, double-blind, parallel group, multi-center study in constipated adult 
subjects. 
3.2. Number of Subjects 
Approximately 600 constipated, but otherwise healthy subjects will be randomized into 
this study. Approximately 30% of enrolled subjects will be elderly (greater than 65 years 
of age at time of randomization). A “completed” subject is defined as one who took the 
study treatment and completed 6 months of treatment.  
3.3. Duration of Study  
The day after Visit 1, subjects will begin a 14 day Screening Period to confirm their 
constipation status. Qualifying subjects will be randomized at Visit 2 and will begin a 6 
month Treatment Period. Subjects will return for follow up clinic visits every 4 weeks 
during the Treatment Period.   
3.4. Study Treatments 
 
BLI400 Laxative 
BLI400 laxative will be provided polyethylene bottles containing enough study 
medication for approximately 30 days. The bottles will be equipped with a cap that can be 
used to measure 10.5 grams of BLI400. Using the provided measuring cap on the bottle, 
subjects will be instructed to mix 2 capfuls of study medication (approximately 21 g) in 4-
8 oz of juice or other beverage and take once daily, preferably in the morning. Subjects 
that develop persistent diarrhea or loose stools will be allowed to adjust their dose down 
to 10.5g (1 capful) per day.   
 
BLI400 placebo will be provided in identical polyethylene bottles containing regular 
maltodextrin.   


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 12 of 34 
 
 
Rescue Bisacodyl 
Subjects will be dispensed bisacodyl tablets at each study visit. Subjects will be instructed 
to take 5 – 10mg (1 -2 tablets) of bisacodyl if they are experiencing severe discomfort due 
to their constipation, or have not had a BM in 4 days. No more than 6 tablets (30mg) of 
bisacodyl should be taken in a week.  
 
If a subject does not have a bowel movement within 24 hours of taking a bisacodyl dose, a 
second dose should be taken. If after the second bisacodyl dose the subject does not have a 
BM within 24 hours, the subject should contact the site. The investigator should then 
consider having the subject return for an evaluation and/or discontinuing the subject from the 
study to seek alternative treatment. 
 
All study medication is required to remain at room temperature 20°-25°C (68°-77°F); 
excursions permitted between 15°-30°C (59°-86°F). 
 
All drug components will also have a clinical label containing a caution statement, study 
code, study sponsor and subject number. 
 
Sites can view weekly summaries of subject diary data, including rescue bisacodyl use. 
Investigators should consider discontinuing subjects consistently taking more than 30mg 
of bisacodyl per week. 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 13 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 subjects at least 18 years of age 
 
2. 
Constipated, defined by the following adapted ROME II definition (Drossman et al, 
2000): 
 
A. Fewer than 3 spontaneous defecations per week and at least one of the following   
     symptoms for at least 12 weeks (which need not be consecutive) in the preceding  
     12 months:  
a. Straining during > 25% of defecations 
b. Lumpy or hard stools in > 25% of defecations 
c. Sensation of incomplete evacuation for > 25% of defecations 
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, sterilized, 
abstinent, or vasectomized spouse) 
 
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 BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 14 of 34 
3.5.2. Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from the study: 
 
1. 
Report loose (mushy) or water stools in the absence of laxative use for more than 25% 
of BMs during the 12 weeks before Visit 1 
 
2. 
Meet the Rome II criteria for Irritable Bowel Syndrome: reports abdominal discomfort 
or pain that has two or more of the following three features for at least 12 weeks, 
which need not be consecutive, in the 12 months before Visit 1: 
• Relieved with defecation 
• Onset associated with a change in frequency of stool 
• Onset associated with a change in form (appearance of stool) 
 
 
3. 
Subjects with known or suspected ileus, gastrointestinal obstruction, gastric retention, 
bowel perforation, toxic colitis, toxic megacolon 
 
4. 
Subjects who have had major surgery 30 days before Visit 1; appendectomy or 
cholecystectomy 60 days before Visit 1; abdominal, pelvic, or retroperitoneal surgery 
6 months before Visit 1; bariatric surgery or surgery to remove a segment of the GI 
tract at any time before Visit 1 
 
5. 
Subjects with hypothyroidism that is being treated and for which the dose of thyroid 
hormone has not been stable for at least 6 weeks at the time of Visit 1 
 
6. 
Subjects taking laxatives, enemas or prokinetic agents that refuse to discontinue these 
treatments from Visit 1 until after completion of the study 
 
7. 
Subjects who are pregnant or lactating, or intend to become pregnant during the study 
 
8. 
Subjects of childbearing potential who refuse a pregnancy test 
 
9. 
Subjects who are allergic to any study medication component (lactitol or 
maltodextrin) 
 
10. 
Subjects taking narcotic analgesics or other medications known to cause constipation 
 
11. 
Subjects with clinically significant cardiac abnormalities identified at the Visit 1 ECG 
 
12. 
Subjects with clinically significant laboratory abnormalities, deemed as a potential 
safety issue by the Investigator 
 
13. 
Subjects who, in the opinion of the Investigator, should not be included in the study 
for any reason, including inability to follow study procedures 
 
14. 
Subjects who have participated in an investigational clinical, surgical, drug, or device 
study within the past 30 days 
 
15. 
Subjects with an active history of drug or alcohol abuse 
 
 
16. 
Subjects have been hospitalized for a psychiatric condition or have made a suicide 
attempt during the 2 years before Visit 1 
 
17. 
Subjects who withdraw consent at any time prior to completion of Visit 1 procedures 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 15 of 34 
4. STUDY PROCEDURES 
Study procedures are described as follows and depicted graphically in Section 4.4, below. 
Acceptable deviations from the visit schedule are indicated.  These variations must not be 
cumulative; i.e. visits should always be scheduled in relationship to Visit 2 (Day 0). 
4.1. Visit 1: Screening  
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 
assign a subject number 
• Assess eligibility (refer to inclusion/exclusion criteria) 
• Review of medications 
• Medical history including history of constipation (ROME criteria – see inclusion #2) 
• 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 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 and urine samples will be collected for testing at a central laboratory, as shown 
below.  
Chemistry: alkaline phosphatase, ALT, anion gap, AST, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatine kinase (CK), creatinine, eGFR, GGT, 
HCG,  inorganic phosphate, magnesium, osmolality, potassium, sodium,  uric 
acid. CK-MB will be tested in samples where the CK value is greater than 2.5 
times the upper normal limit.  
Hematology: hematocrit, hemoglobin, platelets count, red blood cell count, white 
blood cell count (and differentials) 
Pharmacokinetic (PK) Sampling: lactitol   
 
Urinalysis: including electrolytes (sodium, potassium, magnesium, calcium), 
microscopic analysis, urine osmolality 
 
Subjects with clinically significant laboratory abnormalities, deemed as a potential 
safety issue by the Investigator, may be discontinued at the Investigator’s 
discretion.  


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 16 of 34 
• Provide the subject an electronic diary and review instructions with the subject in detail to 
ensure full understanding (refer to Section 4.1.3). 
• Dispense rescue bisacodyl. Subjects will be allowed to take 5 – 10mg of bisacodyl if they 
are experiencing severe discomfort due to their constipation, or have not had a BM in 4 
days. 
• Instruct subject to maintain their normal dietary habits during study participation. 
• Schedule the next study visit to occur after 14 full screening days.  
 
Subjects that are ineligible due to prohibited medication use (Exclusion Criteria 6 and 10) 
may be washed out for a period of 14 days (72 hour washout only for laxatives). No 
additional procedures should be performed on these subjects until after they have 
completed washout.  Subjects will receive a reminder card detailing the washout period.   
Rescue bisacodyl will not be dispensed at this visit.  When subjects return following 
washout, concomitant medications should be reviewed, physical exam, vital signs, ECG, 
blood draws and serum pregnancy test should be performed (if not done previously).   
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. Enrollment and Allocation of Subject Number 
Subjects will be enrolled into the study only when they have given their written, informed 
consent to participate. 
Subjects enrolled at the screening visit will be assigned a subject number by site personnel.  
This number will consist of:  
• The 3-digit Site Number;  
• A 3-digit subject identifier number (this number is a sequentially allocated number). Each 
site will begin with 001 for the first subject screened, 002 for the second and so on.  For 
example, the third subject screened at Site 15 will become Subject Number 15003.  After a 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 17 of 34 
subject completes the informed consent process, site personnel will assign a subject 
number.  
4.1.3. Electronic Subject Diary during Screening Period 
Subjects will be asked to use an electronic subject diary to self-report their bowel 
movement and rescue medication experiences each day. Subjects will be required to enter 
data on each bowel movement as soon as possible following completion. This data will 
include assessments of BM completeness, consistency, straining and urgency.  
Each dosing episode of rescue medication will be entered. Instructions on how to 
complete the diary questions will be supplied in a separate manual.  
4.2. Visit 2 
Subjects will return to the study center as soon as possible after the 14 day Screening 
Period for Visit 2.  
 
BM Entry Criteria – to be eligible for randomization, subjects must meet the following 
criteria related to their Screening Period BMs: 
• average of fewer than 3 complete spontaneous bowel movements (CSBMs) per 
week during the 14 day Screening Period. A CSBM is defined as a bowel 
movement which has occurred with no rescue laxative use in the prior 24 hours 
and is accompanied by a sense of complete evacuation 
• average of fewer than 6 spontaneous bowel movements (SBMs) per week during 
the 14 day Screening Period. An SBM is defined as a bowel movement which has 
occurred with no rescue laxative use in the prior 24 hours  
• No more than 1 SBM with a Bristol Stool rating of 6 
• No SBMs with a Bristol Stool rating of 7 
 
Diary Compliance Criterion  to be eligible for randomization, a subject must have completed 
an average of at least one Bowel Movement Diary entry per day for 5 or more days per week 
during the 14 day Screening Period 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 18 of 34 
4.2.1. Randomization 
Subjects that meet the BM and Diary Compliance Criteria will be randomized using an 
automated interactive web response system (IWRS). The randomization schedule will be 
implemented in the automated interactive web response (IWR) system prior to kit 
distribution to the site. At the time of randomization the IWRS will assign a drug kit 
number for site personnel to dispense to the subject. Subjects will be stratified into one of 
the following two groups:  
 
Group 1: Subjects < 65 years of age at time of randomization 
Group 2: Subjects > 65 years of age at time of randomization 
 
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.  
 
Vital signs will be taken.   Subjects will be queried for any adverse events or changes to 
their concomitant medications.  
 
4.2.2. Study Drug 
During Visit 2, subjects will be provided with instructions on how to take the study 
medication and rescue medication. One bottle of study drug (a 30 day supply) will be 
dispensed per subject along with one box of rescue bisacodyl. The study drug bottle will 
be weighed for drug accountability purposes.  Subjects will take a daily dose of 2 capfuls 
of study powder until they return for Visit 3.  Subjects will be instructed to return all 
medication (including bisacodyl) and components at Visit 3.  
 
4.3. Treatment Period 
4.3.1. Electronic Subject Diary during Treatment Period 
 
Each day during the Treatment Period, subjects will complete their e-diary reporting. 
Subjects will report each bowel movement as it occurs along with related symptoms and 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 19 of 34 
characteristics (consistency, straining, urgency, completeness). Subjects will also report 
their daily study medication and rescue medication doses (if applicable) as they occur. 
4.3.2. Treatment Day 1 
Starting the morning of Treatment Day 1 (the day after randomization), subjects will 
measure two (2) capfuls of study medication and ingest it mixed in a beverage of their 
choice. When possible, subjects should take each dose at appromiately the same time 
every day (preferably in the morning). Subjects that develop persistent diarrhea or loose 
stools should contact their study center. Subjects with persistent diarrhea or loose stools 
will be allowed to adjust their dose down to 10.5g (1 capful) per day.   
  
4.3.3. Visits 3 – 7 (Days 28, 56, 84, 112 and 140)  
Subjects will return to the clinic every 4 weeks (+/- 2 days) for Visits 3 – 7.  Vital signs 
(see section 4.1 for details) will be taken.  Study personnel will weigh returned study 
medication bottles and count rescue bisacodyl tablets for accountability purposes and for 
consistency with the electronic diary reporting. Study personnel must discuss any 
electronic diary reporting irregularities (e.g. missed study medication or excessive rescue 
bisacodyl use, reporting compliance). Subjects will be queried for any adverse events or 
changes to their concomitant medications. Samples for chemistry, hematology, PK  and 
urinalysis will be repeated as outlined in Section 4.1 (Note: serum pregnancy testing will 
be conducted at Visits 1, 5 and 8 only). 
 
Subjects suspected by the Investigator of having developed lactic acidosis, characterized 
by abnormally low bicarbonate with abnormally high anion gap (deemed clinically 
significant by the investigator), should return for a redraw to test for lactate.  Subjects 
with high lactate levels believed to be caused by the study medication should be 
discontinued. 
 
A 30 day supply of study medication (1 bottle) along with 1 box of rescue bisacodyl will 
be dispensed at each visit. Unused product will not be redispensed.  No rescue medication 
will be redispensed.  Subjects will be instructed to bring all medication (including 
bisacodyl) and components at each follow up visit. 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 20 of 34 
 
Subjects that develop persistent diarrhea or loose stools should contact their study center. 
Subjects with persistent diarrhea or loose stools will be allowed to adjust their dose down 
to 10.5g (1 capful) per day.   
 
At Visit 7 (Day 140), 2 bottles of study medication will be dispensed so that subjects have 
a sufficient supply to reach Visit 8 (Day 180).  
4.3.4. Visit 8 – Day 180 (or Early Term) 
 
Subjects will return at after a approximately 180 days of dosing (+4 days) for their final 
clinic visit. 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. A 
physical examination will be performed. Study personnel will weigh study medication 
bottles and count rescue bisacodyl tablets for accountability purposes and for consistency 
with the electronic diary reporting. Study personnel must discuss any electronic diary 
reporting irregularities (e.g. missed study medication or excessive rescue bisacodyl use, 
reporting compliance). Subjects will be queried for any adverse events or changes to their 
concomitant medications. Samples for chemistry, hematology ,urinalysis  and PK will be 
repeated as outlined in Section 4.1. Subjects suspected by the Investigator of having 
developed lactic acidosis (as described in Section 4.3.3) should return for a redraw to test 
for lactate.   
 
4.3.5. Day 194 Follow-up Telephone Call: +/- 3 days 
At Day 194, approximately 2 weeks after the last study visit or early term visit, site 
personnel will contact subjects by telephone to query if any new adverse events have 
occurred and if any adverse events ongoing at Visit 8 have resolved. Subjects will also be 
asked about the status of their concomitant medications. 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment#1 
Version dated 9/15/2016 
 
Page 21 of 34 
 
 
4.4. Tabulated Study Procedures 
The following graphically depicts the flow of study procedures at each visit. 
 
Procedures 
Visit 1 
Screening 
Visit 2 
Day 0 
Visits  
3 - 7 
 
Days: 28, 56, 
84, 112, 140  
 
Visit 8/ 
ET 
Day 180 
Day 194 
 
 
 
+/-2 days 
+4 days 
+/- 3 days 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
Medical History  
X 
 
 
 
 
Physical Examination 
X 
 
 
X 
 
Vital Signs  
X 
X 
X 
X 
 
Electrocardiogram 
X 
 
 
X 
 
Review of Concomitant Medication 
X 
X 
X 
X 
X 
Dispense Electronic Diary 
X 
X 
X 
 
 
Review Diary Compliance 
 
X 
X 
 
 
Blood Samples for Chemistry & Hematology Testing2 
 X 
 
X 
X 
 
Pharmacokinetics (PK) Sample  
X 
 
X 
X 
 
Urine Sample for Urinalysis 
 X 
 
X 
X 
 
Dispense Rescue Bisacodyl 
X 
X 
X 
 
 
Randomize Eligible Subjects 
 
X 
 
 
 
Dispense Study Drug1 
 
X 
X 
 
 
Study Drug and Rescue Bisacodyl Accountability 
 
X 
X 
X 
 
Assess Safety 
 
X 
X 
X 
X 
1Two bottles of study medication will be dispensed at Visit 7 (Day 140) 
2Serum pregnancy testing will be performed at Visit 1 (Screening), Visit 5 (Day 84) and Visit 8 (Day 180) only


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment#1 
Version dated 9/15/2016 
 
Page 22 of 34 
 
 
4.5. Pregnancy 
Subjects who are female and of childbearing potential must have a serum pregnancy test 
done at Visit 1. A positive result will rule out the participation of the subject in the study. 
Additional serum pregnancy tests will be performed at Visits 5 and 8. 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. 
 
Female study subjects must be surgically sterilized or using oral contraceptives, depot 
contraceptives, double-barrier method, intrauterine device, or testifies that she is monogamous 
with a vasectomized partner. Subjects practicing abstinence must agree to use an acceptable 
form of birth control should they become sexually active during the study. 
 
Women with a history of bilateral tubal ligation are not considered of childbearing 
potential and are not required to have a pregnancy test at screening. 
 
Oral contraceptives, hormone implants, and injections are only considered effective if 
started at least 1 month before the study.  
 
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. 
 
4.6. Concomitant Medications 
The use of concomitant medication will be recorded from 7 days prior to Visit 1 until the 
end of the study at the telephone contact on Day 194. Subjects enrolled in this study will 
not be permitted to take any laxatives (other than the sponsor supplied rescue bisacodyl), 
whether prescription or over-the-counter, from Visit 1 until after completion of Treatment 
Day 180. Any restricted laxative use during the study may result in termination of 
subject’s participation. Subjects may not initiate treatment with any constipating 
medication.  


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 23 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 (inluding a clinically significant abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product.  
 
Adverse event collection will coincide with the subjects providing informed consent to 
participate in the study and will conclude with the end of study participation at Day 194 (2 
week follow-up phone call).  Diarrhea should be reported as an adverse event if a subject 
has more than 3 watery stools per day (Bristol Stool Rating = 7). Subjects with clinically 
significant laboratory results at Visit 8 which are classified by the Investigator as adverse 
events should return for a repeat blood draw. Subjects will be instructed to report promptly 
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 treatment. 
 
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 
5 
Fatal 
Causes death of the participant 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 24 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 patient’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. 
 
In published Phase 3 studies, adverse events associated with BLI400 administered at 
doses required for effective treatment of constipation included flatulence, nausea, 
vomiting, abdominal cramping or pain and bloating. These adverse reactions were 
transient and subsided rapidly upon dose adjustment or cessation. 
 
 
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 
 




Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 26 of 34 
 
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 dropped from the study for any of the following reasons: 
1) Subject did not meet BM Entry Criteria. 
2) Subject did not meet Diary Compliance Criterion. 
3) Subject took prohibited laxatives during the Screening or Treatment Period 
4) An adverse event requiring discontinuation (including failure to tolerate study 
medication). 
5) The Investigator decides that the subject should be dropped from the  
       study (e.g. serious adverse event, protocol violation, non-compliance). 
6) The subject decides to withdraw from the study. Subjects are free to  
       withdraw their consent and discontinue participation in the study at any  
       time. 
 
Braintree Laboratories should be contacted if possible prior to discontinuation of any subject. 
If a subject is discontinued from the study, Braintree Laboratories must be notified with an 
explanation for all discontinuances.  
 
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 27 of 34 
9. DATA ANALYSIS 
9.1. Sample Size 
Six hundred subjects will be randomly assigned to BLI400 (21 g/day dose) or placebo in a 
ratio of 1:1 (300 BLI400, 300 placebo).  The definition of a weekly responder is based on 
weekly assessments of complete spontaneous bowel movements (CSBMs).  
Based on data from a previous laxative study (Lembo et al, 2011) utilizing this primary 
efficacy variable (percent of subjects who are responders), it is anticipated that 
approximately 20% of subjects would be classified as responders in the  BLI400 arm, 
with a placebo response up to 10%. The proposed study size will have approximately 90% 
power to detect a difference of 10% between the active and placebo groups at a two-sided 
significance level of 0.05. 
9.2. Null and Alternative Hypotheses 
The primary objective of this study is to compare the safety and efficacy BLI400 Laxative 
to placebo in subjects with constipation. To establish this, the primary comparison of 
interest will be on the overall responder percentage based on 12 weeks of treatment. A 
weekly responder is a subject who has ≥ 3 CSBMs and an increase from baseline of > 1 
CSBM in that week. 
The null hypothesis will be that there is no difference in the response rates between 
BLI400 Laxative and placebo; the alternative hypothesis is that the response rate is higher 
for BLI400 laxative than for placebo. 
9.3. Planned Analyses 
Data analysis will be performed after all subjects have completed the study. No interim 
analyses are planned. 
9.3.1.   Demographic and Baseline Characteristics 
An analysis of baseline comparability of the following demographic and baseline 
characteristics for the treatment groups will be performed.  
• 
Age (ANOVA) 
• 
Gender (CMH Chi square) 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 28 of 34 
• 
Race/ethnicity (CMH Chi square) 
• 
Weight (ANOVA) 
• 
Screening Period Constipation Status (ANOVA) 
 
9.3.2. Efficacy Analyses 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be assessed on the basis of a binary outcome of overall 
treatment success or failure. The primary efficacy endpoint will be the proportion of 
subjects who are weekly responders for 9 out of the first 12 weeks of treatment, with at 
least 3 of these weeks occurring during weeks 9–12 of treatment. A weekly responder is a 
subject who has ≥ 3 CSBMs and an increase from baseline of > 1 CSBM in that week. A 
CSBM is a bowel movement that occurs with no rescue laxative use in the previous 24 
hours and that is accompanied by a sense of complete evacuation. 
 
The following equation will be used to calculate the weekly CSBM frequency: 
CSBM frequency = 7 x (Number of CSBMs/number of days with non-missing CSBM 
assessments)  
 
If a subject has fewer than four days of data observed for a week, then that subject’s data 
should be considered missing for that entire week and the subject considered a non-
responder. 
The primary efficacy endpoint will be analyzed using the CMH test controlling for the effect 
of study center. The presence of a treatment-by-center interaction will be investigated by the 
Breslow-Day test of homogeneity of the odds ratio.  The strategy for pooling centers will be 
based on geographical considerations, with low enrolling centers pooled by geographic 
region.  Details of any pooling performed will be documented prior to database lock and 
unblinding of the study. 
No bowel movements that occur within 24 hours of a rescue bisacodyl (or other prohibited 
laxative) dose will be included in primary or secondary efficacy analyses.  
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 29 of 34 
Secondary Endpoints 
Secondary endpoints will include the following: 
• Overall response by gender and age group (< 65, > 65 years, > 75 years) 
• Number of study medication doses taken per week  
• Number of rescue doses taken per week (includes bisacodyl and other non-study 
laxative) 
• % of subjects not meeting ROME criteria at the end of each treatment week 
• BM Frequency per week (SBM and CSBM) 
• BM Frequency per month (SBM and CSBM) 
• BM Symptom Ratings per week (straining, consistency, urgency, Bristol score) 
• BM Symptom Ratings per month (straining, consistency, urgency, Bristol score) 
• Number of diarrhea episodes per week (diarrhea is defined as > 3 watery stools per day)  
 
9.3.3.Safety Analyses 
Analysis of safety will be performed using the modified Intent-to-Treat population (see 
Section 9.4). Safety analyses may also be presented by age, gender and racial subgroup.  
 
Adverse Events 
Adverse Events will be coded using the MedDRA classification to provide a preferred 
term and primary system organ class for each event.  Proportions of subjects with adverse 
events will be presented by treatment group.  Tables of AEs will be presented by system 
organ class and preferred term, and include overall totals for AEs within each system 
organ class.  Counting will be done by subject and not by event.  A table of counts and 
percentages will also be made of those subjects with SAEs or AEs which led to 
withdrawal from the study.  
Treatment-emergent AEs are defined as adverse events that had an onset day and time on 
or after the day and time of the first dose of study drug up to 14 days after the last dose of 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 30 of 34 
study medication.  Adverse Events having missing onset dates will be considered as 
treatment-emergent. 
The difference in adverse event rates between study groups will be tested by Chi-Square 
or Fisher’s exact test with 95% confidence intervals. Adverse events will be presented for 
the overall Treatment Period. 
Laboratory Parameters  
Summary statistics (i.e., mean, minimum, maximum, standard deviation, and number of 
subjects) will be presented for each treatment group for each laboratory parameter at each 
visit.  When calculating the summary statistics only, the last observation within a visit 
window will be used if there are multiple observations.  Changes from Visit 1 (Screening) 
will be presented in a similar format.  An additional listing will be provided of those 
subjects who have clinically significant laboratory values.  The data will also be presented 
as shift tables, and clinically significant abnormalities will be examined. 
Results of laboratory tests for the change from Visit 1 (Screening) and group differences 
will be tested using ANOVA. 
Vital Signs 
Summary statistics (i.e., mean, minimum, maximum, standard deviation, and number of 
subjects) will be presented for each treatment group for each vital sign at each visit.  
When calculating the summary statistics only, the last observation within a visit window 
will be used if there are multiple observations.  The data will also be presented as shift 
tables and clinically significant abnormalities will be examined. 
ECG variables will be tabulated and presented for data collected at each visit. Data will be 
tabulated and summarized with descriptive statistics (N, mean, SD, CV%, SEM, 
minimum, and maximum) for each of the ECG variables. The differences in ECG 
variables between Visit 1 (Screening) and Visit 8 will be tested using ANOVA.  
 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 31 of 34 
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 randomized 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 randomized subjects that took at least one dose of study 
medication. 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 
have not violated the study eligibility criteria and have not deviated significantly from the 
protocol during the course of the study.  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. 
 
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 the 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. 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 32 of 34 
12. DOCUMENTS AND NOTIFICATIONS 
12.1. Informed Consent 
Written informed consent will be obtained from the subjects by the Investigator 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 
The Investigator and Braintree Laboratories will discuss any amendments to the study 
protocol.  If an agreement is reached regarding the need for the amendment, it will be 
produced in writing by Braintree Laboratories and will be made a formal part of the 
protocol only after approval by an Institutional Review Board. 
 
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. 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 
BLI400 laxative, 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. 
 


Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 33 of 34 
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 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 BLI400-302 Amendment #1 
Version dated 9-19-2016-2016 
 
Page 34 of 34 
15. REFERENCES 
 
 
Drossman, D. (2000)  Rome II: The Functional Gastrointestinal Disorders. Lawrence, KS: 
Allen Press. 
 
Faruqui AA, Joshi, C. Lactitol: A Review of its Use in the Treatment of Constipation. 
International Journal of Recent Advances in Pharmaceutical Research 2012; 2(1): 1-5. 
 
Lembo AJ, Schneier HA, Shiff SJ, Kurtz CB, MacDougall JE, Jia XD, Shao JZ, Lavins 
BJ Currie, MG Fitch, Jeglinski BI, Eng P, Fox SM, Johnston JM. Two Randomized Trials 
of Linactotide for Chronic Constipation. NEJM. 2011; 365(6): 527-536. 
 
Maydeo, A. Lactitol or lactulose in the treatment of chronic constipation: result of a 
systematic. J Indian Med Assoc. 2010;108(11):789-92. 
 
Patil DH, Grimble GK, Silk DB. Lactitol, a new hydrogenated lactose derivative: 
intestinal absorption and laxative threshold in normal human subjects. Br J Nutr. 
1987;57(2):195-9.