Clinical trial NCT02819310
Conditions: Constipation Chronic Idiopathic Constipation CIC
Sponsor: Braintree Laboratories
Start date: 2016-06-01; Completion date: 2017-08-01
Enrollment: 330 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is to evaluate the safety of chronic use of BLI400 laxative in constipated adults.

Detailed description:

Arms: arm 1: BLI400 Laxative
Interventions: intervention 1: BLI400 Laxative
Intervention descriptions: intervention 1: oral laxative

Protocol documents:
Prot_SAP_000.pdf: 
NCT02819310 
 
STUDY PROTOCOL 
 
An Open Label Study of Chronic Use of BLI400 Laxative in 
Constipated Adults 
 
DOCUMENT DATE: 04/13/2016 


Braintree Laboratories, Inc. 
Protocol Number BLI400-303 
Confidential 
An Open Label Study of Chronic Use of BLI400 Laxative in Constipated 
Adults 
SPONSOR 
Mark Cleveland 
Braintree Protocol BLl400-303 
Version Dated 4-13-2016 
Braintree Laboratories, Inc. 
60 Columbian St. West 
P.O. Box 850929 
Braintree, MA 02185 
PH: 781-843-2301 
Date 
Sr. Vice President, R&D 
~Gr:ories nc.,_ __ _ 
Principal Investigator 
Michael P. DeMicco, MD, FACG, ABAM 
Anahiem Clinical Trials, LLC 
Version dated 4-13-2016 
Date 
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1.
INTRODUCTION .................................................................................................................. 5
2.
STUDY OBJECTIVE .......................................................................................................... 10
3.
STUDY PLAN ....................................................................................................................... 10
3.1. 
STUDY DESIGN ................................................................................................................ 10 
3.2. 
NUMBER OF SUBJECTS ..................................................................................................... 10 
3.3. 
DURATION OF STUDY ...................................................................................................... 10 
3.4. 
STUDY TREATMENTS ....................................................................................................... 10 
3.5. 
SUBJECT SELECTION ........................................................................................................ 12 
3.5.1. 
Inclusion Criteria .......................................................................................... 12 
3.5.2. 
Exclusion Criteria ......................................................................................... 13 
4.
STUDY PROCEDURES ...................................................................................................... 14
4.1. 
VISIT 1 (DAY 0) ............................................................................................................... 14 
4.1.1. 
Informed Consent .......................................................................................... 15 
4.1.2. 
Enrollment and Allocation of Subject Number ............................................ 15 
4.1.3. 
Study Drug ..................................................................................................... 16 
4.2. 
TREATMENT PERIOD ........................................................................................................ 16 
4.2.1. 
Treatment Day 1 ............................................................................................ 16 
4.2.2. 
Visit 2 (Month 2) +/- 4 days ........................................................................... 16 
4.2.3. 
Visit 3 (Month 4) +/- 4 days ........................................................................... 17 
4.2.4. 
Visit 4 (Month 6) +/- 4 days ........................................................................... 17 
4.2.5. 
Visit 5 (Month 9) +/- 4 days ........................................................................... 17 
4.2.6. 
Visit 6 (Month 12 or Early Term) +/- 4 days ................................................ 17 
4.2.7. 
Follow-up Telephone Call (Day 374) +/- 4 days .......................................... 18 
4.3. 
TABULATED STUDY PROCEDURES ................................................................................... 19 
4.4. 
PREGNANCY .................................................................................................................... 20 
4.5. 
CONCOMITANT MEDICATIONS ......................................................................................... 20 
5.
ADVERSE EVENTS ............................................................................................................ 21
5.1. 
ADVERSE EVENT DEFINITION AND REPORTING ............................................................... 21 
6.
SERIOUS ADVERSE EVENTS REPORTING ................................................................ 23
7.
INSTITUTIONAL REVIEW BOARD AND INFORMED CONSENT ......................... 24
8.
MANAGEMENT OF INTERCURRENT EVENTS ......................................................... 24
8.1. 
MODIFICATION OF PROTOCOL ......................................................................................... 24 
8.2. 
SUBJECTS DISCONTINUED FROM THE STUDY ................................................................... 24 
9.
DATA ANALYSIS ............................................................................................................... 25
9.1. 
SAMPLE SIZE ................................................................................................................... 25 
9.2. 
PARAMETERS TO BE ANALYZED ...................................................................................... 25 
9.3. 
PLANNED ANALYSES ....................................................................................................... 25 
9.3.1. 
Demographic and Baseline Characteristics ................................................. 25 
9.3.2. 
Safety Analyses .............................................................................................. 25 
9.3.3. 
Efficacy Analyses (Patient Reported Outcomes) .......................................... 27 
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9.4. 
STUDY POPULATIONS ...................................................................................................... 27 
9.4.1. 
Intention-to-Treat (ITT) Population ............................................................. 27 
9.4.1. 
Modified Intention-to-Treat (mITT) Population .......................................... 27 
9.4.2. 
Per-Protocol Population ................................................................................ 28 
10.
DRUG INVENTORY AND DISPOSITION .................................................................. 28
11.
STUDY MONITORING .................................................................................................. 28
12.
DOCUMENTS AND NOTIFICATIONS ....................................................................... 28
12.1. INFORMED CONSENT ....................................................................................................... 28 
12.2. INSTITUTIONAL REVIEW BOARD...................................................................................... 28 
12.3. AMENDMENTS TO THE PROTOCOL ................................................................................... 29 
12.4. DATA RECORDS ............................................................................................................... 29 
13.
PUBLICATION AND AGREEMENT ........................................................................... 29
14.
INVESTIGATORS AGREEMENT ............................................................................... 30
15.
REFERENCES ................................................................................................................. 31
16.       APPENDIX A  ………………………………………………………………………..... 32 
      APPENDIX B  ………………………………………………………………………..... 35 
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CLINICAL PROTOCOL SUMMARY SHEET 
 
STUDY TITLE:  
 
An Open Label Study of Chronic Use of BLI400 Laxative in Constipated Adults 
 
PROTOCOL: 
 
BLI400-303 
 
VERSION DATE:  4-13-2016 
 
IND NUMBER: 
118,906 
 
OBJECTIVE:  
 
To evaluate the safety of chronic use of BLI400 Laxative in constipated adults. 
 
STUDY DESIGN:  
 
This is an open-label, multi-center study in constipated outpatients.   
 
SUBJECTS:   
Approximately 300 male or female adult subjects with a history of constipation will be 
enrolled in this study (including approximately 100 elderly subjects). 
 
STUDY MEDICATIONS:  
 
BLI400 Laxative (21 grams of Lactitol Monohydrate, NF) 
 
 
DURATION OF TREATMENT 
 
Subjects will take BLI400 laxative daily for 12 months (52 weeks). Participation in this 
study will last for approximately 54 weeks, including the 14 day follow up telephone call. 
 
 
 
PRIMARY ENDPOINT 
 
 
Safety will be analyzed through the use of adverse event and ECG data, and the 
comparison of chemistry, hematology, and urinalysis values as measured at baseline and 
at specific time points throughout the study.  
 
 
 
 
 
 
 
 
 
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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.  
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 
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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 
 
The product will be provided in multi-dose bottles with a measuring cap to deliver 10.5 
grams of BLI400.  
 
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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 
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 
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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. 
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 
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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% 
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2. STUDY OBJECTIVE 
 
To evaluate the safety of chronic use of BLI400 laxative in constipated adults. 
 
3. STUDY PLAN 
3.1. Study Design 
This is an open-label, multi-center study in which constipated subjects will receive 
BLI400 for 12 months. 
3.2. Number of Subjects 
Approximately 300 constipated subjects will be enrolled into this study, including 
approximately 100 elderly subjects (> 65 years of age at Visit 1).  
3.3. Duration of Study  
Qualifying subjects will receive BLI400 at Visit 1 and will begin a 12-month Treatment 
Period. Subjects will return for clinic visits at the end of Months 2, 4, 6, 9 and 12. A 
follow up call will take place 2 weeks after the end of treatment. A completed subject is 
defined as a subject that completes the Visit 6 (Month 12) visit.  
 
3.4. Study Treatments 
 
BLI400 Laxative 
BLI400 laxative will be provided polyethylene bottles containing sufficient study 
medication for 30 days of dosing.  The bottles will be equipped with a cap that can be 
used to measure 10.5 grams of BLI400.  Each bottle will also have a clinical label 
containing a caution statement, study code, study sponsor and subject number. Subjects 
will be instructed to mix the contents of 2 capfuls (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. 
 
 
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Rescue Bisacodyl 
Subjects will be dispensed bisacodyl at each study visit (previously dispensed bisacodyl 
may be redispensed if needed, although this is not encouraged). 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. 
 
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). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 urine pregnancy test at screening, if applicable
5.
In the Investigator’s judgment, subject is mentally competent to provide informed
consent to participate in the study
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3.5.2. Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from the study: 
 
 
1. 
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 Visit 6 
 
 
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 BLI400 component (lactitol) 
 
 
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, may be discontinued at the Investigator’s discretion.  
 
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 
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4. STUDY PROCEDURES
Study procedures are described as follows and depicted graphically in Section 4.3, 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 1 (Day 0). 
4.1. Visit 1 (Day 0) 
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)

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.

Urine pregnancy test (if applicable)

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, 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) 
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.  
If the subject is eligible for the study, assign a subject number. 
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
Subjects will complete the Patient Assessment of Constipation Quality of Life 
questionnaire (PAC-QOL, refer to Appendix A) and the Patient Assessment of 
Constipation Symptom questionnaire (PAC-SYM, refer to Appendix B)

Dispense 2 bottles of BLI400

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 60 days
Subjects that are ineligible due to prohibited medication use (Exclusion Criterion 10) may 
be washed out for a period of 14 days. No additional procedures should be performed on 
these subjects. After the washout period, subjects may be enrolled and all Visit 1 
procedures should be repeated (with the exception of obtaining informed consent).   
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;

The 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 15-003.
After a subject completes all screening procedures and eligibility has been confirmed, site
personnel will assign a subject number.
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4.1.3. Study Drug 
After it has been confirmed that all eligibility criteria have been met, site personnel will 
utilize the IWRS to assign a drug kit number to the subject.  
Site personnel must only dispense the drug kit that has been assigned by the IWRS. 
Dispensing of incorrect kits is considered a protocol violation.  
Subjects will be provided instructions on how to take the study medication and rescue 
medication. Two bottles will be dispensed per subject. The study drug bottles will be 
weighed for drug accountability purposes.  Subjects will be instructed to return all bottles 
at each follow up visit.  
4.2. Treatment Period 
4.2.1. Treatment Day 1 
Starting on the morning of Treatment Day 1 (the day after Visit 1), subjects will measure 
2 capfuls of study medication and ingest it mixed in a beverage of their choice.  Subject 
will take a daily dose of 2 capfuls until they return for Visit 2. Subjects that develop 
persistent diarrhea or loose stools should contact their study center. These subjects will be 
allowed to adjust their dose down to 10.5g (1 capful) per day.    
4.2.2. Visit 2 (Month 2) +/- 4 days  
Subjects will continue to take BLI400 daily and will return to the clinic for Visit 2 (Day 
60). Vital signs (see section 4.1 for details) and ECGs will be recorded. Study personnel 
will weigh returned bottles and count rescue bisacodyl for accountability purposes. 
Subjects will be queried for any adverse events or changes to their concomitant 
medications. Subjects will complete the PAC-QOL and PAC-SYM questionnaires. 
Samples for chemistry, hematology and urinalysis will be repeated as outlined in 
Section 4.1. Subjects will be dispensed 2 new bottles of study medication. Subjects will 
be instructed to return all bottles and bisacodyl at the next follow up visit. 
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4.2.3. Visit 3 (Month 4) +/- 4 days  
Subjects will continue to take BLI400 daily and will return to the clinic for Visit 3 (Day 
120).  Vital signs (See section 4.1 for details) will be recorded. Study personnel will 
weigh returned bottles and count rescue bisacodyl for accountability purposes. Subjects 
will be queried for any adverse events or changes to their concomitant medications. 
Subjects will complete the PAC-QOL and PAC-SYM questionnaires. Samples for 
chemistry, hematology and urinalysis will be repeated as outlined in Section 4.1. 
Subjects will be dispensed 2 new bottles of study medication. Subjects will be instructed 
to return all bottles and bisacodyl at the next follow up visit. 
4.2.4. Visit 4 (Month 6) +/- 4 days  
Subjects will continue to take BLI400 daily and will return to the clinic for Visit 4 (Day 
180). Vital signs (See section 4.1 for details) will be recorded. Study personnel will 
review returned bottles and rescue bisacodyl for accountability purposes. Subjects will be 
queried for any adverse events or changes to their concomitant medications. Subjects will 
complete the PAC-QOL and PAC-SYM questionnaires. Samples for chemistry, 
hematology and urinalysis will be repeated as outlined in Section 4.1. Subjects will be 
dispensed 3 new bottles of study medication. Subjects will be instructed to return all 
bottles and bisacodyl at the next follow up visit. 
4.2.5. Visit 5 (Month 9) +/- 4 days  
Subjects will continue to take BLI400 daily and will return to the clinic for Visit 5 (Day 
270). Vital signs (See section 4.1 for details) will be recorded. Study personnel will 
review returned bottles and rescue bisacodyl for accountability purposes. Subjects will be 
queried for any adverse events or changes to their concomitant medications. Subjects will 
complete the PAC-QOL and PAC-SYM questionnaires. Samples for chemistry, 
hematology and urinalysis will be repeated as outlined in Section 4.1. Three new bottles 
of study medication will be dispensed at this visit. Subjects will be instructed to return all 
bottles and bisacodyl at Visit 6. 
4.2.6. Visit 6 (Month 12 or Early Term) +/- 4 days 
Subjects will return at Day 360 for their final clinic visit. Vital signs (see section 4.1 
for details) and ECGs will be recorded. A physical examination will be performed. 
Study 
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personnel will weigh returned bottles and count bisacodyl for accountability purposes. 
Subjects will be queried for any adverse events or changes to their concomitant 
medications. Subjects will complete the PAC-QOL and PAC-SYM questionnaires. 
Samples for chemistry, hematology and urinalysis will be repeated as outlined in 
Section 4.1.  Clinically significant laboratory abnormalities present at Visit 6 should be 
followed until resolved or are considered stable.  
4.2.7. Follow-up Telephone Call (Day 374) +/- 4 days 
At Day 374, 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 6 have resolved.  Subjects will also be 
asked about the status of their concomitant medications. 
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4.3. Tabulated Study Procedures 
The following graphically depicts the flow of study procedures at each visit. 
Procedures 
Visit 1 
Day 0 
Visit 2 
Month 2 
+/- 4 days 
Visit 3 
Month 4 
+/- 4 days 
Visit 4 
Month 6 
+/- 4 days 
Visit 5 
Month 9 
+/- 4 days 
Visit 6 
Month 12/ 
ET 
+/- 4 days 
Day 374 
+/- 4 days 
Informed Consent 
X 
Inclusion/Exclusion Criteria Review 
X 
Medical History 
X 
Physical Examination 
X 
X 
Vital Signs1 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
X 
X 
Review of Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test (if applicable)2 
X 
Enroll Eligible Subjects 
X 
Subject to Complete PAC-QOL, PAC-SYM 
X 
X 
X 
X 
X 
X 
Blood Sample for Chemistry Testing 
X 
X 
X 
X 
X 
X 
Blood Sample for Hematology Testing 
X 
X 
X 
X 
X 
X 
Urine Sample for Urinalysis 
X 
X 
X 
X 
X 
X 
Blood Sample for Serum Pregnancy Testing 
X 
X 
Dispense Study Drug and Rescue Bisacodyl 
X 
X 
X 
X 
X 
Study Drug and Rescue Bisacodyl Accountability 
X 
X 
X 
X 
X 
Assess Safety 
X 
X 
X 
X 
X 
X 
1
2
blood pressure and pulse while seated and after standing for 2 minutes, temperature, weight and height (@Visit 1 
only) refer to Section 4.4 
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4.4. Pregnancy 
 
Subjects who are female and of childbearing potential must have a urine pregnancy test 
done at screening. A positive result will rule out the participation of the subject in the 
study. Serum pregnancy tests will be performed at Visits 4 (Month 6) and 6 (Month 12). 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 urine 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. 
 
4.5. 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 374. 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 Visit 6. 
Any restricted laxative use during the study may result in termination of subject’s 
participation. Subjects may not initiate treatment with any constipating medication.  
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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. 
 
Adverse event collection will coincide with the subject providing informed consent to 
participate in the study and will conclude with the end of study participation at Day 374 
Follow-up Call.  Diarrhea should be reported as an adverse event if a subject has more 
than 3 watery stools per day. Subjects with clinically significant laboratory results at Visit 
6 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 
 
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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. SERIOUS ADVERSE EVENTS REPORTING 
 
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 subject providing informed consent to participate in 
the study and will conclude 30 days after a subject’s last dose of study medication. Should 
a serious and/or unexpected adverse event occur, the Investigator must notify Braintree 
Laboratories immediately.  The Investigator will make a decision regarding continuing the 
subject’s study participation, and may request input from Braintree Laboratories. The 
Investigator will be responsible for recommending or providing the subject with appropriate 
medical therapy. All subjects experiencing serious adverse events will be followed until 
satisfactory resolution occurs. Braintree Laboratories must be kept apprised of all follow-ups 
relative 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 
 
 
 
 
781-843-2301 
(M-F, 8:30 am – 5:00 pm EDT)  
 
 
After hours or weekends 
 
 
 
 
781-964-9051 
 
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. 
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7. INSTITUTIONAL REVIEW BOARD AND INFORMED CONSENT 
Institutional Review Board (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 dropped from the study for any of the following reasons: 
1) Subject took prohibited medications during the Treatment Period 
2) An adverse event requiring discontinuation (including failure to tolerate study 
medication). 
3) The Investigator decides that the subject should be dropped from the  
       study (e.g. serious adverse event, protocol violation, non-compliance). 
4) 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.  
 
 
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9. DATA ANALYSIS
9.1. Sample Size 
Consistent with ICH E1A Guideline for Industry, the Extent of Population Exposure to 
Assess Clinical Safety: for Drugs Intended for Long-term Treatment of Non-Life-
Threatening Conditions (March 1995), 300 subjects will be treated with BLI400 for 12 
months. This will allow for detection of adverse events that may increase in frequency or 
severity over time. 
9.2. Parameters to be Analyzed 
The primary objective of this study is to investigate the safety of BLI400 used chronically for 
12 months in subjects with constipation. Safety will be analyzed using ECG, vital signs, 
chemistry, hematology and urinalysis and adverse event data. Treatment emergent adverse 
event rates will be descriptively presented by preferred term, severity, and relationship to 
treatment.  
9.3. Planned Analyses 
9.3.1.Demographic and Baseline Characteristics 
Baseline demographic characteristics will be tabulated with N, mean, standard deviation, 
and range of values where appropriate 

Age

Gender

Race/ethnicity

Constipation History
9.3.2.Safety Analyses 
Analysis of safety will be performed using the modified Intent to Treat population (see 
Section 9.4). 
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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 for the overall study population, and each demographic subgroup 
(age, gender and race). 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 until the Day 374 Follow-up Call.  
Adverse Events having missing onset dates will be considered as treatment emergent. 
The difference in adverse event rates between study periods will be tested by Chi-Square 
or Fisher’s exact test with 95% confidence intervals. 
Laboratory Parameters  
Summary statistics (i.e., mean, minimum, maximum, standard deviation, and number of 
subjects) will be presented for each laboratory parameter at each visit. Laboratory data 
will be summarized for the overall population and the elderly and non-elderly subgroups. 
When calculating the summary statistics only, the last observation within a visit window 
will be used if there are multiple observations.  Changes from baseline (Visit 1) 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 baseline (Visit 1) and group differences 
will be tested using ANOVA. 
 
 
 
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Vital Signs 
Summary statistics (i.e., mean, minimum, maximum, standard deviation, and number of 
subjects) will be presented for each vital sign at each visit and compared to the values 
obtained at Visit 1.  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 (Baseline), Visit 2 and Visit 6 will be tested using ANOVA.  
 
9.3.3. Efficacy Analyses (Patient Reported Outcomes) 
Subject constipation symptoms and quality of life indicators will be analyzed using data 
from the subject-completed PAC-SYM and PAC-QOL instruments. Change from baseline 
to each visit time point will be presented for each collected measure and will be tested 
using ANOVA. Data for each measure and time point will also be presented categorically 
by severity and tested using Chi-Square or Fisher’s exact test. 
 
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 enrolled subjects that were dispensed study medication. 
9.4.1. Modified Intention-to-Treat (mITT) Population  
This population consists of all enrolled subjects that took at least one dose of study 
medication. This population will be utilized for all safety analyses. 
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9.4.2. 
Per-Protocol Population  
The per-protocol (PP) population will consist of all subjects in the mITT population who 
have not violated study entry criteria and have not deviated significantly from the protocol 
during the course of the study.  Any 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 in the clinical study report. 
 
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. 
 
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.  
 
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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. 
 
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. 
 
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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. 
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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 
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. 
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APPENDIX A 
Patient Assessment of Constipation – Quality of Life (PAC-QOL) Questionnaire 
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Patient Assessment of Constipation – Quality of Life (PAC-QOL) Questionnaire 
 
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Patient Assessment of Constipation – Quality of Life (PAC-QOL) Questionnaire 
 
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APPENDIX B 
 
Patient Assessment of Constipation – Symptom (PAC-SYM) Questionnaire 
 
 
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An Open Label Study of Chronic Use of BLI400 Laxative in Constipated 
Adults 
 
Braintree Protocol BLI400-303 
 
 
Version Dated 4-13-2016 
 
 
SPONSOR 
 
 
Braintree Laboratories, Inc. 
60 Columbian St. West 
     
 
 
 
P.O. Box 850929 
    
  
 
 
Braintree, MA  02185 
 
 
 
 
PH: 781-843-2301 
 
 
 
 
 
 
 
 
______________________________________ 
 
_______________ 
 
Mark Cleveland  
 
 
 
 
 
Date 
Sr. Vice President, R&D/RA 
Braintree Laboratories, Inc.  
 
 
 
______________________________________ 
 
_______________ 
Principal Investigator  
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
INTRODUCTION .................................................................................................................. 5 
2. 
STUDY OBJECTIVE .......................................................................................................... 10 
3. 
STUDY PLAN ....................................................................................................................... 10 
3.1. 
STUDY DESIGN ................................................................................................................ 10 
3.2. 
NUMBER OF SUBJECTS ..................................................................................................... 10 
3.3. 
DURATION OF STUDY ...................................................................................................... 10 
3.4. 
STUDY TREATMENTS ....................................................................................................... 10 
3.5. 
SUBJECT SELECTION ........................................................................................................ 12 
3.5.1. 
Inclusion Criteria .......................................................................................... 12 
3.5.2. 
Exclusion Criteria ......................................................................................... 13 
4. 
STUDY PROCEDURES ...................................................................................................... 14 
4.1. 
VISIT 1 (DAY 0) ............................................................................................................... 14 
4.1.1. 
Informed Consent .......................................................................................... 15 
4.1.2. 
Enrollment and Allocation of Subject Number ............................................ 15 
4.1.3. 
Study Drug ..................................................................................................... 15 
4.2. 
TREATMENT PERIOD ........................................................................................................ 16 
4.2.1. 
Treatment Day 1 ............................................................................................ 16 
4.2.2. 
Visit 2 (Month 2) +/- 4 days ........................................................................... 16 
4.2.3. 
Visit 3 (Month 4) +/- 4 days ........................................................................... 16 
4.2.4. 
Visit 4 (Month 6) +/- 4 days ........................................................................... 17 
4.2.5. 
Visit 5 (Month 9) +/- 4 days ........................................................................... 17 
4.2.6. 
Visit 6 (Month 12 or Early Term) +/- 4 days ................................................ 17 
4.2.7. 
Follow-up Telephone Call (Day 374) +/- 4 days .......................................... 18 
4.3. 
TABULATED STUDY PROCEDURES ................................................................................... 19 
4.4. 
PREGNANCY .................................................................................................................... 20 
4.5. 
CONCOMITANT MEDICATIONS ......................................................................................... 20 
5. 
ADVERSE EVENTS ............................................................................................................ 21 
5.1. 
ADVERSE EVENT DEFINITION AND REPORTING ............................................................... 21 
6. 
SERIOUS ADVERSE EVENTS REPORTING ................................................................ 23 
7. 
INSTITUTIONAL REVIEW BOARD AND INFORMED CONSENT ......................... 24 
8. 
MANAGEMENT OF INTERCURRENT EVENTS ......................................................... 24 
8.1. 
MODIFICATION OF PROTOCOL ......................................................................................... 24 
8.2. 
SUBJECTS DISCONTINUED FROM THE STUDY ................................................................... 24 
9. 
DATA ANALYSIS ............................................................................................................... 25 
9.1. 
SAMPLE SIZE ................................................................................................................... 25 
9.2. 
PARAMETERS TO BE ANALYZED ...................................................................................... 25 
9.3. 
PLANNED ANALYSES ....................................................................................................... 25 
9.3.1. 
Demographic and Baseline Characteristics ................................................. 25 
9.3.2. 
Safety Analyses .............................................................................................. 25 
9.3.3. 
Efficacy Analyses (Patient Reported Outcomes) .......................................... 27 


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9.4. 
STUDY POPULATIONS ...................................................................................................... 27 
9.4.1. 
Intention-to-Treat (ITT) Population ............................................................. 27 
9.4.1. 
Modified Intention-to-Treat (mITT) Population .......................................... 27 
9.4.2. 
Per-Protocol Population ................................................................................ 28 
10. 
DRUG INVENTORY AND DISPOSITION .................................................................. 28 
11. 
STUDY MONITORING .................................................................................................. 28 
12. 
DOCUMENTS AND NOTIFICATIONS ....................................................................... 28 
12.1. INFORMED CONSENT ....................................................................................................... 28 
12.2. INSTITUTIONAL REVIEW BOARD ...................................................................................... 28 
12.3. AMENDMENTS TO THE PROTOCOL ................................................................................... 29 
12.4. DATA RECORDS ............................................................................................................... 29 
13. 
PUBLICATION AND AGREEMENT ........................................................................... 29 
14. 
INVESTIGATORS AGREEMENT ............................................................................... 30 
15. 
REFERENCES ................................................................................................................. 31 
16 
     APPENDIX A  ………………………………………………………………………..... 32 
 
     APPENDIX B  ………………………………………………………………………..... 35 
 
 


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CLINICAL PROTOCOL SUMMARY SHEET 
 
STUDY TITLE:  
 
An Open Label Study of Chronic Use of BLI400 Laxative in Constipated Adults 
 
PROTOCOL: 
 
BLI400-303 
 
VERSION DATE:  4-13-2016 
 
IND NUMBER: 
118,906 
 
OBJECTIVE:  
 
To evaluate the safety of chronic use of BLI400 Laxative in constipated adults. 
 
STUDY DESIGN:  
 
This is an open-label, multi-center study in constipated outpatients.   
 
SUBJECTS:   
Approximately 300 male or female adult subjects with a history of constipation will be 
enrolled in this study (including approximately 100 elderly subjects). 
 
STUDY MEDICATIONS:  
 
BLI400 Laxative (21 grams of Lactitol Monohydrate, NF) 
 
 
DURATION OF TREATMENT 
 
Subjects will take BLI400 laxative daily for 12 months (52 weeks). Participation in this 
study will last for approximately 54 weeks, including the 14 day follow up telephone call. 
 
 
 
PRIMARY ENDPOINT 
 
 
Safety will be analyzed through the use of adverse event and ECG data, and the 
comparison of chemistry, hematology, and urinalysis values as measured at baseline and 
at specific time points throughout the study.  
 
 
 
 
 
 
 
 
 


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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.  
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 


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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 
 
The product will be provided in multi-dose bottles with a measuring cap to deliver 10.5 
grams of BLI400.  
 


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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 
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 


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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. 
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 


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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% 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. STUDY OBJECTIVE 
 
To evaluate the safety of chronic use of BLI400 laxative in constipated adults. 
 
3. STUDY PLAN 
3.1. Study Design 
This is an open-label, multi-center study in which constipated subjects will receive 
BLI400 for 12 months. 
3.2. Number of Subjects 
Approximately 300 constipated subjects will be enrolled into this study, including 
approximately 100 elderly subjects (> 65 years of age at Visit 1).  
3.3. Duration of Study  
Qualifying subjects will receive BLI400 at Visit 1 and will begin a 12-month Treatment 
Period. Subjects will return for clinic visits at the end of Months 2, 4, 6, 9 and 12. A 
follow up call will take place 2 weeks after the end of treatment. A completed subject is 
defined as a subject that completes the Visit 6 (Month 12) visit.  
 
3.4. Study Treatments 
 
BLI400 Laxative 
BLI400 laxative will be provided polyethylene bottles containing sufficient study 
medication for 30 days of dosing.  The bottles will be equipped with a cap that can be 
used to measure 10.5 grams of BLI400.  Each bottle will also have a clinical label 
containing a caution statement, study code, study sponsor and subject number. Subjects 
will be instructed to mix the contents of 2 capfuls (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. 
 
 


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Rescue Bisacodyl 
Subjects will be dispensed bisacodyl at each study visit (previously dispensed bisacodyl 
may be redispensed if needed, although this is not encouraged). 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. 
 
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). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 urine pregnancy test at screening, if applicable 
 
5. 
In the Investigator’s judgment, subject is mentally competent to provide informed 
consent to participate in the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5.2. Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from the study: 
 
 
1. 
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 Visit 6 
 
 
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 BLI400 component (lactitol) 
 
 
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, may be discontinued at the Investigator’s discretion.  
 
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 


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4. STUDY PROCEDURES 
Study procedures are described as follows and depicted graphically in Section 4.3, 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 1 (Day 0). 
4.1. Visit 1 (Day 0) 
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) 
• 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. 
• Urine pregnancy test (if applicable)  
• 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, 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) 
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.  
If the subject is eligible for the study, assign a subject number. 
• Subjects will complete the Patient Assessment of Constipation Quality of Life questionnaire 
(PAC-QOL, refer to Appendix A) and the Patient Assessment of Constipation Symptom 
questionnaire (PAC-SYM, refer to Appendix B)  


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• Dispense 2 bottles of BLI400  
• 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 60 days  
 
Subjects that are ineligible due to prohibited medication use (Exclusion Criterion 10) may 
be washed out for a period of 14 days. No additional procedures should be performed on 
these subjects. After the washout period, subjects may be enrolled and all Visit 1 procedures 
should be repeated (with the exception of obtaining informed consent).   
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;  
• The 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 15-003.  After a 
subject completes all screening procedures and eligibility has been confirmed, site personnel 
will assign a subject number.  
 
4.1.3. Study Drug 
After it has been confirmed that all eligibility criteria have been met, site personnel will 
utilize the IWRS to assign a drug kit number to the subject.  


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Site personnel must only dispense the drug kit that has been assigned by the IWRS.  
Dispensing of incorrect kits is considered a protocol violation.  
 
Subjects will be provided instructions on how to take the study medication and rescue 
medication. Two bottles will be dispensed per subject. The study drug bottles will be 
weighed for drug accountability purposes.  Subjects will be instructed to return all bottles 
at each follow up visit.  
 
4.2. Treatment Period 
4.2.1. Treatment Day 1 
Starting on the morning of Treatment Day 1 (the day after Visit 1), subjects will measure 
2 capfuls of study medication and ingest it mixed in a beverage of their choice.  Subject 
will take a daily dose of 2 capfuls until they return for Visit 2. Subjects that develop 
persistent diarrhea or loose stools should contact their study center. These subjects will be 
allowed to adjust their dose down to 10.5g (1 capful) per day.    
4.2.2. Visit 2 (Month 2) +/- 4 days  
Subjects will continue to take BLI400 daily and will return to the clinic for Visit 2 (Day 
60). Vital signs (see section 4.1 for details) and ECGs will be recorded. Study personnel 
will weigh returned bottles and count rescue bisacodyl for accountability purposes. 
Subjects will be queried for any adverse events or changes to their concomitant 
medications. Subjects will complete the PAC-QOL and PAC-SYM questionnaires. 
Samples for chemistry, hematology and urinalysis will be repeated as outlined in Section 
4.1. Subjects will be dispensed 2 new bottles of study medication. Subjects will be 
instructed to return all bottles and bisacodyl at the next follow up visit. 
4.2.3. Visit 3 (Month 4) +/- 4 days  
Subjects will continue to take BLI400 daily and will return to the clinic for Visit 3 (Day 
120).  Vital signs (See section 4.1 for details) will be recorded. Study personnel will 
weigh returned bottles and count rescue bisacodyl for accountability purposes. Subjects 
will be queried for any adverse events or changes to their concomitant medications. 


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Subjects will complete the PAC-QOL and PAC-SYM questionnaires. Samples for 
chemistry, hematology and urinalysis will be repeated as outlined in Section 4.1. Subjects 
will be dispensed 2 new bottles of study medication. Subjects will be instructed to return 
all bottles and bisacodyl at the next follow up visit. 
4.2.4. Visit 4 (Month 6) +/- 4 days  
Subjects will continue to take BLI400 daily and will return to the clinic for Visit 4 (Day 
180). Vital signs (See section 4.1 for details) will be recorded. Study personnel will 
review returned bottles and rescue bisacodyl for accountability purposes. Subjects will be 
queried for any adverse events or changes to their concomitant medications. Subjects will 
complete the PAC-QOL and PAC-SYM questionnaires. Samples for chemistry, 
hematology and urinalysis will be repeated as outlined in Section 4.1. Subjects will be 
dispensed 3 new bottles of study medication. Subjects will be instructed to return all 
bottles and bisacodyl at the next follow up visit. 
4.2.5. Visit 5 (Month 9) +/- 4 days  
Subjects will continue to take BLI400 daily and will return to the clinic for Visit 5 (Day 
270). Vital signs (See section 4.1 for details) will be recorded. Study personnel will 
review returned bottles and rescue bisacodyl for accountability purposes. Subjects will be 
queried for any adverse events or changes to their concomitant medications. Subjects will 
complete the PAC-QOL and PAC-SYM questionnaires. Samples for chemistry, 
hematology and urinalysis will be repeated as outlined in Section 4.1. Three new bottles 
of study medication will be dispensed at this visit. Subjects will be instructed to return all 
bottles and bisacodyl at Visit 6. 
4.2.6. Visit 6 (Month 12 or Early Term) +/- 4 days 
Subjects will return at Day 360 for their final clinic visit. Vital signs (see section 4.1 for 
details) and ECGs will be recorded. A physical examination will be performed. Study 
personnel will weigh returned bottles and count bisacodyl for accountability purposes. 
Subjects will be queried for any adverse events or changes to their concomitant 
medications. Subjects will complete the PAC-QOL and PAC-SYM questionnaires. 
Samples for chemistry, hematology and urinalysis will be repeated as outlined in Section 


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4.1.  Clinically significant laboratory abnormalities present at Visit 6 should be followed 
until resolved or are considered stable.  
4.2.7. Follow-up Telephone Call (Day 374) +/- 4 days 
At Day 374, 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 6 have resolved.  Subjects will also be 
asked about the status of their concomitant medications. 


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4.3. Tabulated Study Procedures 
The following graphically depicts the flow of study procedures at each visit. 
Procedures 
Visit 1 
Day 0 
Visit 2 
Month 2 
 
+/- 4 days 
Visit 3 
Month 4 
 
+/- 4 days 
Visit 4 
Month 6 
 
+/- 4 days 
Visit 5 
Month 9 
 
+/- 4 days 
Visit 6 
Month 12/ 
ET 
 
+/- 4 days 
Day 374 
 
+/- 4 days 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
X 
 
Vital Signs1  
X 
X 
X 
X 
X 
X 
 
Electrocardiogram 
X 
X 
 
 
 
X 
 
Review of Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test (if applicable)2 
X 
 
 
 
 
 
 
Enroll Eligible Subjects 
X 
 
 
 
 
 
 
Subject to Complete PAC-QOL, PAC-SYM 
X 
X 
X 
X 
X 
X 
 
Blood Sample for Chemistry Testing 
X 
X 
X 
X 
X 
X 
 
Blood Sample for Hematology Testing 
X 
X 
X 
X 
X 
X 
 
Urine Sample for Urinalysis 
X 
X 
X 
X 
X 
X 
 
Blood Sample for Serum Pregnancy Testing 
 
 
 
X 
 
X 
 
Dispense Study Drug and Rescue Bisacodyl  
X 
X 
X 
X 
X 
 
 
Study Drug and Rescue Bisacodyl Accountability 
 
X 
X 
X 
X 
X 
 
Assess Safety 
 
X 
X 
X 
X 
X 
X 
1blood pressure and pulse while seated and after standing for 2 minutes, temperature, weight and height (@Visit 1 only) 
 
2refer to Section 4.4 


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4.4. Pregnancy 
 
Subjects who are female and of childbearing potential must have a urine pregnancy test 
done at screening. A positive result will rule out the participation of the subject in the 
study. Serum pregnancy tests will be performed at Visits 4 (Month 6) and 6 (Month 12). 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 urine 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. 
 
4.5. 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 374. 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 Visit 6. 
Any restricted laxative use during the study may result in termination of subject’s 
participation. Subjects may not initiate treatment with any constipating medication.  


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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. 
 
Adverse event collection will coincide with the subject providing informed consent to 
participate in the study and will conclude with the end of study participation at Day 374 
Follow-up Call.  Diarrhea should be reported as an adverse event if a subject has more 
than 3 watery stools per day. Subjects with clinically significant laboratory results at Visit 
6 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 
 


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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 




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7. INSTITUTIONAL REVIEW BOARD AND INFORMED CONSENT 
Institutional Review Board (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 dropped from the study for any of the following reasons: 
1) Subject took prohibited medications during the Treatment Period 
2) An adverse event requiring discontinuation (including failure to tolerate study 
medication). 
3) The Investigator decides that the subject should be dropped from the  
       study (e.g. serious adverse event, protocol violation, non-compliance). 
4) 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.  
 
 


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9. DATA ANALYSIS 
9.1. Sample Size 
Consistent with ICH E1A Guideline for Industry, the Extent of Population Exposure to 
Assess Clinical Safety: for Drugs Intended for Long-term Treatment of Non-Life-
Threatening Conditions (March 1995), 300 subjects will be treated with BLI400 for 12 
months. This will allow for detection of adverse events that may increase in frequency or 
severity over time. 
9.2. Parameters to be Analyzed 
The primary objective of this study is to investigate the safety of BLI400 used chronically for 
12 months in subjects with constipation. Safety will be analyzed using ECG, vital signs, 
chemistry, hematology and urinalysis and adverse event data. Treatment emergent adverse 
event rates will be descriptively presented by preferred term, severity, and relationship to 
treatment.  
 
9.3. Planned Analyses 
9.3.1.Demographic and Baseline Characteristics 
Baseline demographic characteristics will be tabulated with N, mean, standard deviation, 
and range of values where appropriate 
• Age  
• Gender  
• Race/ethnicity  
• Constipation History  
 
9.3.2.Safety Analyses 
Analysis of safety will be performed using the modified Intent to Treat population (see 
Section 9.4). 
 
 
 


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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 for the overall study population, and each demographic subgroup (age, 
gender and race). 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 until the Day 374 Follow-up Call.  
Adverse Events having missing onset dates will be considered as treatment emergent. 
The difference in adverse event rates between study periods will be tested by Chi-Square 
or Fisher’s exact test with 95% confidence intervals. 
Laboratory Parameters  
Summary statistics (i.e., mean, minimum, maximum, standard deviation, and number of 
subjects) will be presented for each laboratory parameter at each visit. Laboratory data will 
be summarized for the overall population and the elderly and non-elderly subgroups. When 
calculating the summary statistics only, the last observation within a visit window will be 
used if there are multiple observations.  Changes from baseline (Visit 1) 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 baseline (Visit 1) and group differences will 
be tested using ANOVA. 
 
 
 


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Vital Signs 
Summary statistics (i.e., mean, minimum, maximum, standard deviation, and number of 
subjects) will be presented for each vital sign at each visit and compared to the values 
obtained at Visit 1.  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 (Baseline), Visit 2 and Visit 6 will be tested using ANOVA.  
 
9.3.3. Efficacy Analyses (Patient Reported Outcomes) 
Subject constipation symptoms and quality of life indicators will be analyzed using data 
from the subject-completed PAC-SYM and PAC-QOL instruments. Change from baseline 
to each visit time point will be presented for each collected measure and will be tested 
using ANOVA. Data for each measure and time point will also be presented categorically 
by severity and tested using Chi-Square or Fisher’s exact test. 
 
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 enrolled subjects that were dispensed study medication. 
9.4.1. Modified Intention-to-Treat (mITT) Population  
This population consists of all enrolled subjects that took at least one dose of study 
medication. This population will be utilized for all safety analyses. 


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9.4.2. 
Per-Protocol Population  
The per-protocol (PP) population will consist of all subjects in the mITT population who 
have not violated study entry criteria and have not deviated significantly from the protocol 
during the course of the study.  Any 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 in the clinical study report. 
 
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. 
 
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.  
 


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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. 
 
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. 
 


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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A 
 
Patient Assessment of Constipation – Quality of Life (PAC-QOL) Questionnaire 
 
 
 
 
 


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Patient Assessment of Constipation – Quality of Life (PAC-QOL) Questionnaire 
 
Patient Assessment of Constipation – Quality of Life (PAC-QOL) Questionnaire 


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APPENDIX B 
 


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Patient Assessment of Constipation – Symptom (PAC-SYM) Questionnaire