Clinical trial NCT02822508
Conditions: Constipation
Sponsor: Braintree Laboratories
Start date: 2016-06-01; Completion date: 2017-04-01
Enrollment: 434 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate multiple doses of BLI801 Laxative for safety and efficacy versus placebo in adults experiencing non-idiopathic constipation.

Detailed description:

Arms: arm 1: BLI801 Laxative (high dose) arm 2: BLI801 Laxative (mid dose) arm 3: BLI801 Laxative (low dose) arm 4: BLI801 Placebo
Interventions: intervention 1: BLI801 Laxative intervention 2: BLI801 Placebo
Intervention descriptions: intervention 1: BLI801 oral laxative intervention 2: BLI801 oral laxative placebo

Protocol documents:
Prot_SAP_000.pdf: 
NCT02822508  
STUDY PROTOCOL 
 
A Safety and Efficacy Evaluation of BLI801 Laxative in Adults 
Experiencing Non-Idiopathic Constipation 
 
DOCUMENT DATE: 04/27/2016 




Braintree Laboratories, Inc. 
 
Confidential 
Protocol Number BLI801-203 
Version dated 4-27-2016 
 
Page 2 of 42 
 
1. 
INTRODUCTION .................................................................................................................. 6 
2. 
STUDY OBJECTIVE .......................................................................................................... 13 
3. 
STUDY PLAN ....................................................................................................................... 13 
3.1. 
STUDY DESIGN ................................................................................................................ 13 
3.2. 
NUMBER OF SUBJECTS ..................................................................................................... 13 
3.3. 
DURATION OF STUDY ...................................................................................................... 13 
3.4. 
STUDY TREATMENTS ....................................................................................................... 14 
3.5. 
SUBJECT SELECTION ........................................................................................................ 16 
3.5.1. 
Inclusion Criteria .......................................................................................... 16 
3.5.2. 
Exclusion Criteria ......................................................................................... 17 
4. 
STUDY PROCEDURES ...................................................................................................... 18 
4.1. 
VISIT 1: SCREENING ........................................................................................................ 18 
4.1.1. 
Informed Consent .......................................................................................... 19 
4.1.2. 
Enrollment and Allocation of Subject Number ............................................ 19 
4.1.3. 
Electronic Subject Diary during Screening Period ...................................... 20 
4.2. 
VISIT 2: RANDOMIZATION ............................................................................................... 20 
4.2.1. 
Randomization ............................................................................................... 21 
4.2.1. 
Study Medication ........................................................................................... 21 
4.3. 
TREATMENT PERIOD ........................................................................................................ 21 
4.3.1. 
Electronic Subject Diary during Treatment Period ..................................... 21 
4.3.2. 
Treatment Day 1 ............................................................................................ 22 
4.3.3. 
Visits 3 – 4 (Day 28 and 56) .......................................................................... 22 
4.3.4. 
Visit 5 – Day 84 .............................................................................................. 22 
4.3.5. 
Day 98 Follow-up Telephone Call: +/- 3 days .............................................. 23 
4.4. 
TABULATED STUDY PROCEDURES ................................................................................... 24 
4.5. 
PREGNANCY .................................................................................................................... 25 
4.6. 
CONCOMITANT MEDICATIONS ......................................................................................... 25 
5. 
ADVERSE EVENTS ............................................................................................................ 26 
5.1. 
ADVERSE EVENT DEFINITION AND REPORTING ............................................................... 26 
6. 
SERIOUS ADVERSE REACTIONS AND DISCONTINUATION OF STUDY ........... 27 
7. 
INSTITUTIONAL REVIEW BOARD AND INFORMED CONSENT ......................... 28 
8. 
MANAGEMENT OF INTERCURRENT EVENTS ......................................................... 29 
8.1. 
MODIFICATION OF PROTOCOL ......................................................................................... 29 
8.2. 
SUBJECTS DISCONTINUED FROM THE STUDY ................................................................... 29 
9. 
DATA ANALYSIS ............................................................................................................... 30 
9.1. 
SAMPLE SIZE ................................................................................................................... 30 
9.2. 
NULL AND ALTERNATIVE HYPOTHESES .......................................................................... 30 
9.3. 
PLANNED ANALYSES ....................................................................................................... 30 
9.3.1. 
Demographic and Baseline Characteristics ................................................. 30 
9.3.2. 
Efficacy Analyses ........................................................................................... 31 


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9.3.3. 
Safety Analyses .............................................................................................. 33 
9.4. 
STUDY POPULATIONS ...................................................................................................... 34 
9.4.1. 
Intention-to-Treat (ITT) Population ............................................................. 34 
9.4.2. 
Modified Intention-to-Treat (mITT) Population .......................................... 34 
9.4.3. 
Per Protocol Population ................................................................................ 34 
10. 
DRUG INVENTORY AND DISPOSITION .................................................................. 35 
11. 
STUDY MONITORING .................................................................................................. 35 
12. 
DOCUMENTS AND NOTIFICATIONS ....................................................................... 35 
12.1.  INFORMED CONSENT ....................................................................................................... 35 
12.2.  INSTITUTIONAL REVIEW BOARD ...................................................................................... 35 
12.3.  AMENDMENTS TO THE PROTOCOL ................................................................................... 36 
12.4.  DATA RECORDS ............................................................................................................... 36 
13. 
PUBLICATION AND AGREEMENT ........................................................................... 36 
14. 
INVESTIGATORS AGREEMENT ............................................................................... 37 
15. 
REFERENCES ................................................................................................................. 38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Braintree Laboratories, Inc. 
 
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Protocol Number BLI801-203 
Version dated 4-27-2016 
 
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CLINICAL PROTOCOL SUMMARY SHEET 
 
STUDY TITLE:  
A Safety and Efficacy Evaluation of BLI801 Laxative in Adults Experiencing 
Non-Idiopathic Constipation 
 
PROTOCOL: 
 
BLI801-203 
 
VERSION DATE:  4-27-2016 
 
IND NUMBER: 
118,906 
 
OBJECTIVE:  
 
To evaluate multiple doses of BLI801 Laxative for safety and efficacy versus placebo in 
adults experiencing opioid induced constipation. 
 
STUDY DESIGN:  
 
This will be a randomized, double-blind, parallel, multi-center, dose-ranging study. 
 
SUBJECTS:   
Approximately 400 male or female constipated adult subjects will be randomized in this 
study after completing a 21 day screening period to confirm constipation status.  
 
STUDY MEDICATIONS:  
 
Group 1: 
 BLI801 High Dose  
Group 2:  
 BLI801 Mid Dose   
Group 3: 
 BLI801 Low Dose  
Group 4:  
 Placebo 
 
 
DURATION OF TREATMENT 
 
Subjects will take one dose of BLI801 Laxative or placebo per day as needed for 12 
weeks for relief of constipation symptoms. Participation in this study will last for 
approximately 15 weeks, including the 21 day Screening Period. 
 
 
 
PRIMARY ENDPOINT 
 
 
The primary endpoint is the proportion of subjects who are weekly responders for at least 9 out 
of 12 weeks, with at least 3 of these weeks occurring in the last 4 weeks of treatment. A weekly 
responder is a subject who has ≥ 3 spontaneous bowel movements (SBMs) and an increase from 
baseline of > 1 SBM in that week. An SBM is a bowel movement that occurs with no rescue 
laxative use in the previous 24 hours. 
 
 
 
 


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SECONDARY ENDPOINT  
 
Secondary endpoints will include but are not limited to the following:  
 
Overall success using a >50% definition (weekly response in at least 6 out of 12 weeks) 
 
SBM and CSBM frequency rates by week 
 
SBM and CSBM frequency rates by month 
 
Stool and symptom ratings (stool consistency, stool straining, abdominal bloating, 
abdominal discomfort) by week  
 
Stool and symptom ratings (stool consistency, stool straining, abdominal bloating, 
abdominal discomfort) by month 
 
Number of study medication doses per week 
 
Rescue bisacodyl doses per week 
 
Safety endpoints will include: 
 
 
Rate of treatment emergent adverse events (assessed at all visits) 
 
Orthostatic vital signs (assessed at all visits) 
 
Changes in laboratory values from Visit 1 to Visits 3, 4 and 5 
 Serum chemistry  
 Hematology 
 Urinalysis – routine urinalysis plus urine electrolytes and osmolality 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. INTRODUCTION 
 
A relatively new bowel cleansing preparation for colonoscopy, SUPREP® Bowel Prep 
Kit, containing about 44 grams of sulfate salts has been approved by the United States 
Food and Drug Administration.  The formulation depends on the osmotic activity of the 
sulfate anion. The formulation has been submitted to FDA as a new drug application 
(NDA 22-372).  Based on its safety and efficacy in Phase I -III studies (1), it is believed 
that an acceptable laxative dose may be achieved by reducing the volume of solution 
administered. Patient tolerance and safety are expected to be superior to over-the-counter 
(OTC) stimulant laxatives which are typically associated with defecation urgency and 
abdominal cramping (e.g. bisacodyl). Stimulant laxatives produce a bowel movement 
within several hours following a single treatment.  Because the sulfate anion is poorly 
absorbed it acts primarily as a osmotic agent, in addition sulfate containing laxatives have 
been reported to increase gastrointestinal transit (2,3).  
 
Early evaluation of a reduced dose of SUPREP for laxative use and its subsequent 
reformulation is described below. 
 
Preliminary Experience with the Experimental Formulation 
SUPREP® Bowel Prep Kit: a sulfate based bowel preparation 
Several unpublished,  IRB approved, studies were carried out by an independent 
investigator (John Fordtran, MD, Baylor University) to determine whether mixtures of 
sulfate salts that omit phosphates (which are avidly absorbed) can be effective to produce 
colonic purgation without producing clinically significant electrolyte and fluid shifts.  
 
A study performed by John Fordtran compared the safety and efficacy of an optimized 
sulfate formulation containing a mixture of sulfate salts yielding about 44 grams of sulfate 
anion (SUPREP), to Fleet Phospho-soda (EZ-Prep) and NuLYTELY in normal volunteers 
(Baylor Study 006-181 and reference 4). The primary efficacy measure was based on total  
 


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stool output, with percentage of stool solids (as described above) serving as a secondary 
measurement. Five normal volunteers completed treatment with SUPREP, NuLYTELY 
and a Fleet Pharmaceuticals sodium phosphate preparation; EZ-Prep. SUPREP induced 
somewhat higher stool output compared to Fleet, yielding 2911g to Fleet’s 1986g. 
Measurement of the quantity of solids in the final bowel movement after preparation 
(expressed as percent stool solids) provided an indication of bowel cleansing efficacy.  
Stool solids also favored SUPREP over Fleet where SUPREP samples produced an 
average stool solids result of 1.6%, lower than the Fleet average of 4.1% and about the 
same as NuLYTELY (1.1%). The Fleet preparation induced significant losses of 
potassium and elevation of phosphate. This increased phosphate absorption contributed to 
a concomitant serum calcium reduction and CaXP elevation, consistent with previous 
literature reports and may be due to calcium phosphate precipitation.  SUPREP study 
subjects absorbed about 4.2g of sulfate but no other clinically significant changes in 
serum or urine electrolytes were observed. Urine from SUPREP volunteers was shown to 
have a reduced tendency to precipitate calcium phosphate compared to urine from Fleet 
subjects.  Subject reported side effects did not show any differences between the 
preparations. No unexpected or serious adverse events were reported. 
 
Studies in rats and dogs (5) demonstrated that the SUPREP formulation did not induce 
soft tissue calcification as occurs for the phosphate based preparations.  These 
observations and the safety of the sulfate formulation were confirmed in studies of 
patients with renal and hepatic failure (6). 
 
Two Phase 3 studies were conducted comparing SUPREP to the FDA approved 
preparation MoviPrep in a total of 751 patients requiring colonoscopy (1). The BLI800-
301 study evaluated SUPREP as a one-day preparation, completed on the day prior to 
colonoscopy. The BLI800-302 study utilized a two-day (or “split-dose”) regimen in which 
half the preparation was taken the evening prior to colonoscopy, and the remaining half 
completed on the morning of the procedure.  
 


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The primary efficacy analysis in both Phase III studies supported the conclusion that 
SUPREP is equivalent to MoviPrep with respect to cleansing efficacy (cumulative data 
shown below in Table 1). 
 
Table 1 
Primary Efficacy Responder Analysis  
BLI800-301/302 Studies 
 
Responder1 
SuPrep 
n (%) 
MoviPrep 
n (%) 
95% CI 
p2 
p3 
All Patients (n) 
      Success  
      Fail 
375 
334 (89.5%) 
39 (10.5%) 
376 
330 (87.8%) 
46 (12.2%) 
 
-2.8, 6.3 
 
0.410 
 
<0.001
301 Patients (n) 
  Success  
  Fail 
194 
159 (82.4%) 
 34 (17.6%) 
193 
155 (80.3%) 
38 (19.7%) 
 
-5.7, 9.8 
 
0.614 
 
<0.001 
302 Patients (n) 
      Success  
      Fail 
181 
175 (97.2%) 
 5 (2.8%) 
183 
175 (95.6%) 
8 (4.4%) 
 
-2.2, 5.4 
 
0.391 
 
<0.001
 
(1) A successful treatment is defined as bowel cleansing graded either excellent or good by the 
blinded colonoscopist (grading score = 3 or 4).                                             
(2) P-value for the difference between treatments  
(3) P-value for the non-inferiority hypothesis using an equivalence margin of 15 percent 
 
The data indicate that a two day preparation regimen, as performed in the 302 study, 
produces markedly superior cleansing results over a one day preparation, as in the 301 
study. In each study and overall, SUPREP achieved a greater number of excellent 
preparations than MoviPrep. This difference resulted in a higher Mean Preparation Score 
for SUPREP, reaching statistical significance (p = 0.049) in the total population.  
 
Adverse events were also evaluated in the Phase 3 studies. The most frequent adverse events 
reported by patients taking both preparations were gastrointestinal, and included the expected 
events of overall discomfort, abdominal pain and distension, nausea, and vomiting. No 
clinically significant differences between groups were seen in laboratory testing of  serum 
chemistry and hematology. At the one month follow-up visit, no change in serum creatinine 
was observed for SUPREP patients. 
 


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            Reduced Dose SUPREP for Laxative Use 
The results described above indicated that a reduced dose of sulfate salts may safely 
provide relief for patients with constipation.  A randomized, open-label pilot study was 
therefore conducted in 60 constipated patients (Braintree Study BLI801-101). SUPREP 
was administered at four different dose levels (1.2g, 3.7g, 6.2g and 8.7 grams of sulfate 
salts) as a single dose of solution to evaluate product efficacy to induce bowel movements 
within 3 hours of ingestion while minimizing patient discomfort and diarrhea. Since it had 
been reported that about 4 grams of sulfate are required to have a laxative effect (5), the 
1.2g dose was chosen as a placebo dose.  Patient tolerance and safety were expected to be 
superior to over-the-counter (OTC) stimulant laxatives (e.g. bisacodyl).  
 
As shown in Table 2 below, most patients in the 6.2g and 8.7g groups had at least one 
bowel movement within 3 hours after ingesting their dose of sulfate salts.  As expected, 
the number having a bowel movement within three hours increased with increasing dose. 
 
Table 2 
Patients with BM<3hrs 
Dose 
n 
# with BM 
10ml (1.2g) 
15 
6 (40%) 
30 ml (3.7g) 
15 
8 (53%) 
50 ml (6.2g) 
14 
12 (86%) 
70 ml (8.7g) 
14 
10 (71%) 
 
Table 3 shows a direct relationship between stool amount and consistency, with the 6.2g 
and 8.7g groups experiencing larger bowel movements of softer consistency. As expected, 
these groups also reported higher Bristol Stool Scores, indicating softer, looser stools.   
 
Table 3 
Mean BM Amount and Consistency 
Dose 
n 
Stool 
Amount1 
Score 
Stool 
Consistency2 
Score 
Mean 
Bristol Stool 
Scale3 
10ml (1.2g) 
15 
1.5 
1.5 
3.0 
30 ml (3.7g) 
14 
1.8 
1.8 
3.8 
50 ml (6.2g) 
14 
2.2 
2.1 
4.5 
70 ml (8.7g) 
15 
2.1 
2.2 
5.0 
 
 
1Amount: 1=a little; 2=some; 3=a lot 
 
 
2Consistency: 1=hard; 2=soft; 3=liquid 
 
 
3Bristol: 1 = separate hard lumps, like nuts – 7 = watery, no solid pieces 


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No significant adverse events were reported. Based on efficacy and stool form results, a 
dose of approximately 6.2 grams appears adequate to achieve laxation without eliciting 
excessive loose stools. 
   
Sulfate Laxative Reformulation 
The sulfate solution was reformulated by Dr. Fordtran in an Investigator-sponsored study 
to exclude magnesium sulfate.  This was evaluated in a single center study comparing 
sulfate salt compositions containing 43.8mM (4.2g) or 80mM (7.7g) sulfate to 10mg 
bisacodyl (Baylor Study 008-211).  The compositions were tested in seven normal 
volunteers for efficacy to induce a rapid, controlled bowel movement without significant 
gains or losses of electrolytes. Volunteers were given a single dose in an in-patient setting 
during which all stool and urine were collected for 24 hours after laxative administration. 
  
A sulfate formula containing 43.8mM sulfate induced less stool and fewer bowel 
movements over a 12 hour period than 10mg bisacodyl.  Sulfate formulas containing 80 
mM sulfate induced about the same amount of stool and bowel movements as 10mg 
bisacodyl, although the stools had a higher water content and tended to be more liquid.  
The 80 mM sulfate formulation, but not the 43.8 mM formula, had a much faster time of 
onset inducing a bowel movement in less than three hours in all patients.   Only one 
bisacodyl volunteer had a bowel movement in less than three hours. No study volunteer 
reported incontinence in association with any of the test laxatives. Gastrointestinal 
symptoms were similar between the 10mg bisacodyl and the sulfate formulations and no 
unexpected adverse events were reported. A formulation providing a 3:1 ratio of sodium 
to potassium minimized sodium and potassium electrolyte absorption or loss from the 
laxative and was considered appropriate for further study in constipated patients at a dose 
of about 60mM (5.8 grams sulfate).  
 
A pilot study of the reformulated sulfate solution (BLI801 Laxative) was conducted to 
evaluate a seven day treatment of the BLI801 Laxative in adult outpatients meeting 
ROME III constipation criteria.  The intent of this multi-center study was to determine the 


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efficacy of the laxative as both a one day and a seven day therapy.  33 patients received 
BLI801 laxative and 19 received placebo (a solution of sodium chloride).   
The primary endpoint of the study was the percentage of patients experiencing a bowel 
movement within 3 hours of the first study medication dose.  The co-primary endpoint 
was the percentage of patients with a successful treatment week, defined as not meeting 
ROME III criteria at the end of the treatment week. Seventy percent of patients that 
received BLI801 Laxative had a bowel movement within 3 hours versus 53% of placebo 
patients (p=0.412).  The rapid effect of BLI801 Laxative was more predictable over the 
treatment week, with significantly more BLI801 Laxative patients having a bowel 
movement within 3 hours on at least 4 out of 7 treatment days, as shown below in Table 4.  
 
Table 4 
Secondary Efficacy Responder Analysis  
Percent of Patients having a BM within 3 hours of Dosing (min. 4 out of 7 days) 
 
Responder 
BLI801 
n (%) 
Placebo 
n (%) 
95% CI 
p 
All Patients (n) 
      Success  
      Fail 
33 
20 (60.6%) 
13 (39.4%) 
19 
4 (21.1%) 
15 (78.9%) 
 
11.4, 62.9 
 
0.008 
 
 
With respect to weekly treatment success, 69.7% of BLI801 Laxative patients no longer 
met the ROME III definition (6) of constipation by the end of the study versus 26.3% of 
placebo recipients (p<0.01).  There was no evidence of tachyphylaxis. 
 
 
There were no statistically significant differences between BLI801 Laxative and placebo 
with respect to treatment emergent adverse events.  Also, there was no significant 
differences seen for the expected patient reported symptoms of gas and cramping (rated 
using a five point scale ranging from “1=None” to “5=Severely Distressing”).  More 
patients experienced watery stools in the BLI801 group, which is expected due to its 
laxative effect. There were no serious adverse events during the study and no on-study 
deaths.  Laboratory results showed no differences between BLI801 Laxative and Placebo 
for serum chemistry data, including sulfate.  
 


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A second Phase 2 study was conducted to evaluate two dose levels of BLI801 Laxative 
taken on an as needed, or “on demand” basis for 4 weeks. Patients were instructed to take up 
to one full dose of BLI801 Laxative if they felt they needed relief of their constipation 
symptoms. Sixty constipated patients meeting ROME III criteria completed the protocol.  
Their average age was 43 years and study participants were predominantly female (88%). 
Subjects in both the high and low dose group averaged 4 doses of BLI801 laxative during 
each treatment week. There was no difference between the two dose groups with respect 
to overall treatment success which was defined as > 3 complete spontaneous bowel 
movements (CSBMs) during a given treatment week with an accompanying increase of at 
least 1 CSBM from baseline for that week for 3 out of 4 weeks of treatment.  The low 
dose group had about 35.5% of study subjects with a successful outcome according to this 
definition versus 38.7% for the higher dose. When a lower success threshold was applied 
(2 out of 4 successful weeks), the high dose group had a success rate of 58% compared to 
42% in the low dose group.  
 
As shown in Table 5, the higher dose was associated with many more patients having a 
BM within three hours of dose ingestion (55%) than the lower dose (29%). This 
difference persisted when a more strict definition of complete, spontaneous BMs was 
applied.  
Table 5 
Day 1 Efficacy Parameters 
 
BLI 801 
Low 
Dose 
BLI801 
High 
Dose 
p1 
Bowel Movement (BM) 
within 3 hrs 
9 (29%) 
17 (55%) 
0.062 
Complete Spontaneous 
BM within 3 hrs 
6 (19%) 
11 (36%) 
0.206 
 
1) P value is from a CMH Chi-square test, controlling for site 
 
 
 
BLI801 Laxative was well tolerated in this study with few side effects other than loose 
stools and diarrhea. There were more reports of treatment emergent diarrhea in the high 
dose group (19% vs 0%).   However, average Bristol stool ratings were similar between 


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the dose groups (average scores about 4) with no effect of “on demand” dosing versus 
daily treatment observed. Other treatment emergent adverse events were infrequent, with 
no significant differences detected between the two treatments.   
 
This study supports the conclusion that BLI801 laxative solution is effective and predictable 
both as a one day “on demand” treatment for chronic idiopathic constipation as well as a 
laxative for daily use. The current study will evaluate the efficacy of BLI801 Laxative in 
subjects whose constipation is caused by treatment with opiate containing medications.  
 
2. STUDY OBJECTIVE 
 
To compare the safety and efficacy of multiple doses of BLI801 Laxative versus placebo in 
adults experiencing opioid induced constipation. 
 
3. STUDY PLAN 
3.1. Study Design 
This is a randomized, double-blind, parallel group, multi-center, dose-ranging study in 
adult subjects with opioid induced constipation receiving chronic opioid therapy for non-
malignant pain. 
3.2. Number of Subjects 
Approximately 400 subjects with opioid induced constipation will be randomized into this 
study. A “completed” subject is defined as one who took the study treatment and 
completed 12 weeks of treatment.  
 
3.3. Duration of Study  
The day after Visit 1, subjects will begin a 21 day Screening Period to confirm their 
constipation status. Qualifying subjects will be randomized at Visit 2 and will begin a 12 
week Treatment Period. Subjects will return for follow up clinic visits every 4 weeks 
during the Treatment Period.   
 


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3.4. Study Treatments 
 
BLI801 Laxative 
BLI801 Laxative will be provided in tablet form and will be packed in blister packs. Each 
dose will consist of 6 tablets as shown below: 
 
Component Amounts 
(anhydrous equivalents) 
 
Na2SO4 
K2SO4 
High Dose 
5.54g 
2.27g 
Mid Dose 
3.69g 
1.51g 
Low Dose 
1.85g 
0.76g 
Placebo 
0g 
0g 
 
A small bottle containing 6 blister packaged tablets will be provided for each potential 
day of dosing (30 bottles per month). The bottles will be provided in boxes, each with a 
clinical label containing a caution statement, study code, study sponsor and kit number. 
Each subject will receive a 30 day supply of tablets (1 box) at Visit 2. Placebo will be 
provided in identical tablets containing normal maltodextrin.   
 
Rescue Bisacodyl 
Subjects will be dispensed bisacodyl (5 mg)  tablets at each study visit. Subjects will be 
instructed 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. During the Treatment Period, subjects 
should not take rescue bisacodyl unless they have taken at least 2 consecutive daily doses 
of study medication. 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. Use of alternative rescue methods (e.g. enemas) must be pre-approved by the Sponsor. 
 


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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). 
Sites can view weekly summaries of subject diary data, including rescue bisacodyl use. 
Investigators should consider discontinuing subjects consistently taking more than 30mg 
of bisacodyl per week. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 between the ages of > 18 and < 85 years 
 
2. 
Constipated, defined  by the following criteria: 
 Fewer than 3 spontaneous defecations per week and at least one of the 
following symptoms for the previous 4 weeks:  
 
o Straining during > 25% of defecations 
o Lumpy or hard stools in > 25% of defecations 
o Sensation of incomplete evacuation for > 25% of defecations 
 
3. 
Receiving a stable maintenance opioid regimen consisting of a total daily dose of 30 
mg to 1000 mg of oral morphine, or equianalgesic amount(s) of 1 or more other opioid 
therapies for a minimum of 8 weeks prior to screening for non-cancer-related pain 
with no anticipated change in opioid dose requirement over the proposed study period 
as a result of disease progression. Patients will be disqualified if their average dose of 
long-acting maintenance opioid dose is modified outside the protocol specified range 
(30mg to 1000mg) at any time during the study.  
 
4. 
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) 
 
5. 
Negative pregnancy test at screening (Visit 1), if applicable 
 
6. 
In the Investigator’s judgment, subject is mentally competent to provide informed 
consent to participate in the study 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5.2. Exclusion Criteria  
Subjects who meet any of the following criteria will be excluded from the study: 
 
1. 
Subjects with known or suspected ileus, gastrointestinal obstruction, gastric retention, 
bowel perforation, toxic colitis ortoxic megacolon 
 
2. 
Subjects who have had major surgery within 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 
 
3. 
Medical conditions associated with diarrhea, intermittent loose stools or constipation, 
which could confound the interpretation of the results, eg, fecal incontinence or 
irritable bowel syndrome. Subjects with irritable bowel syndrome (IBS) that has been 
previously diagnosed by a physician prior to initiation of the constipating therapy and 
that meets the following criteria, are excluded: 
a. Absence of a structural or biochemical explanation for the abdominal pain 
symptom 
 
b.  At least 12 weeks during a period of 12 months, of abdominal discomfort or 
pain with at least 2 of the following 3 features: 
i.  Relieved with defecation, and/or 
ii. Onset associated with a change in frequency of stool, and/or 
iii. Onset associated with a change in form of stool. 
 
4. 
Subjects diagnosed with chronic constipation prior to initiation of opioid treatment 
 
5. 
Subjects taking laxatives (with the exception of fiber supplements), prokinetic agents 
or antidiarrheal drugs and refuse to discontinue these treatments from Visit 1 until 
after completion of Visit 5 
 
6. 
Subjects who are pregnant or nursing, or intend to become  pregnant during the study 
 
7. 
Subjects of childbearing potential who refuse a pregnancy test 
 
8. 
Subjects who are allergic to any BLI801 component  
 
9. 
Subjects taking non-opioid medications or supplements known to cause constipation 
 
10. 
Subjects with an active history of drug or alcohol abuse 
 
11. 
Subjects who have participated in an investigational clinical, surgical, drug, or device 
study within the past 30 days 
 
12. 
Subjects who, in the opinion of the Investigator, should not be included in the study 
for any reason, including inability to follow study procedures. 
 
13. 
Subjects who have had a colonoscopy within 2 weeks of Visit 1 or are scheduled to 
have a colonoscopy during their participation in the study. 
 
14. 
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 4.4, below. 
Acceptable deviations from the visit schedule are indicated.  These variations must not be 
cumulative; i.e. visits should always be scheduled in relationship to Visit 2 (Day 0). 
4.1. Visit 1: Screening  
At the screening visit, the following procedures will be undertaken: 
 Subject is fully informed about the study and gives written agreement to study 
participation in the form of a signed informed consent form (refer to Section 4.1.1) and 
assign a subject number 
 Assess eligibility (refer to inclusion/exclusion criteria) 
 Review of medications 
 Medical history including history of constipation (ROME criteria) 
 Physical examination (including height and body weight) 
 Vital signs: including temperature, weight, heart rate, respiratory rate, and an assessment 
of orthostatic hypotension (while seated and after standing for a minimum of 2 minutes)  
 A 12-lead ECG will be performed by qualified, trained site personnel.  ECG output must 
be reviewed by a physician investigator (MD only). Any clinically significant cardiac 
abnormalities identified on the ECG should disqualify a subject. Data from the ECG will 
be collected in the eCRF. 
 Blood and urine samples will be collected for testing at a central laboratory, as shown 
below.  
Chemistry: alkaline phosphatase, ALT, anion gap, AST, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatine kinase (CK), creatinine, eGFR, GGT, 
HCG,  inorganic phosphate, ionized calcium, magnesium, osmolality, potassium, 
sodium,  sulfate and 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.  
 Provide the subject an electronic diary and review instructions with the subject in detail to 
ensure full understanding (refer to Section 4.1.3). 


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 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 21 full screening days.  
 
Subjects that are ineligible due to prohibited medication use (Exclusion Criteria 5 and 9) 
must be washed out for a period of 14 days prior to beginning the Screening Period. No 
additional procedures should be performed on these patients until after they have 
completed washout (laboratory testing must be repeated after washout if done at Visit 1).  
Subjects will receive a reminder card detailing the washout period.   Rescue bisacodyl will 
not be dispensed at this visit.  When subjects return following washout, concomitant 
medications should be reviewed, physical exam and vital signs should be performed (if 
not done previously).   
4.1.1.  Informed Consent 
Following the informed consent process, study subjects will sign a current IRB approved 
consent form. No study procedures may be performed prior to the subject providing 
informed consent. The subject’s original signed and personally dated Informed Consent 
Form (together with any subsequent IRB approved amended versions) must be retained by 
the Investigator in the subject’s file.  A copy of the original signed and dated Informed 
Consent Form must be given to the subject. 
4.1.2. Enrollment and Allocation of Subject Number 
Subjects will be enrolled into the study only when they have given their written, informed 
consent to participate. 
Subjects enrolled at the screening visit will be assigned a subject number by site personnel.  
This number will consist of:  
 The 3-digit Site Number;  
 A 3-digit subject identifier number (this number is a sequentially allocated number). Each 
site will begin with 001 for the first subject screened, 002 for the second and so on.  For 
example, the third subject screened at Site 015 will become Subject Number 015003.  After 
a subject completes the informed consent process, site personnel will assign a subject 
number.  


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4.1.3. Electronic Subject Diary during Screening Period 
Subjects will be asked to use an electronic subject diary to self-report their bowel 
movement and rescue medication experiences each day. Subjects will be required to enter 
data on each bowel movement as soon as possible following completion. This data will 
include assessments of BM completeness, consistency, straining and urgency.  
Each dosing episode of rescue medication will be entered. Instructions on how to 
complete the diary questions will be supplied in a separate manual.  
4.2. Visit 2: Randomization 
Subjects will return to the study center as soon as possible after the 21 day Screening 
Period for Visit 2.  
 
BM Entry Criteria – to be eligible for randomization, subjects must meet the following 
criteria related to their Screening Period BMs: 
 average of fewer than 3 spontaneous bowel movements (SBMs) per week during 
the last 2 weeks of the 21 day Screening Period. An SBM is defined as a bowel 
movement which has occurred with no rescue laxative use in the prior 24 hours. 
 No more than 1 SBM with a Bristol Stool rating of 6 
 No SBMs with a Bristol Stool rating of 7 
 
Diary Compliance Criterion – to be eligible for randomization, a subject must have 
completed an average of 5 responses in the bowel movement diary entries per week or 
more during the last 2 weeks of the 21 day Screening Period.  
 
Vital signs will be taken. Subjects will be queried for any adverse events or changes to 
their concomitant medications (including ongoing opioid dose). 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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4.2.1. Randomization 
Subjects that meet the BM and Diary Compliance Criteria will be randomized using an 
automated interactive web response system (IWRS). The randomization schedule will be 
implemented in the automated interactive web response (IWR) system prior to kit 
distribution to the site. At the time of randomization the IWRS will assign a drug kit 
number for site personnel to dispense to the subject. Dispensing kits out of order is 
considered a protocol violation.  
4.2.1. Study Medication 
During Visit 2, subjects will be provided with instructions on how to take the study 
medication. A 30 day supply of study medication will be dispensed per subject. Subjects 
will take a daily dose of study medication (6 tablets) as needed to treat constipation 
symptoms. Daily dosing is not required.  
 
Subjects will also be dispensed bisacodyl (5 mg)  tablets at each study visit. Subjects will 
be instructed 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. Subjects should not take rescue 
bisacodyl unless they have taken at least 2 consecutive daily doses of study medication.  
 
Subjects will be instructed to return all medication (including bisacodyl) and components 
at Visit 3.  
4.3. Treatment Period 
4.3.1. Electronic Subject Diary during Treatment Period 
 
Each day during the Treatment Period, subjects will complete their e-diary reporting. 
Subjects will report each bowel movement as it occurs along with related symptoms and 
characteristics (consistency, straining, urgency, completeness). Subjects will also report 
their daily study medication and rescue medication doses (if applicable) as they occur, and 
the reason for taking the dose (eg, subject felt constipated, subject didn’t have a BM 
today, etc). On days in which no dosing was reported, subjects will be prompted to answer 
why they felt like they did not need a dose that day.  


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4.3.2. Treatment Day 1 
Starting on Treatment Day 1 (the day after randomization), subjects will take a daily dose 
of study medication (6 tablets) as needed to treat their symptoms of constipation.  
4.3.3. Visits 3 – 4 (Day 28 and 56)  
Subjects will return to the clinic for Visit 3 (Day 28 +/- 2 days) and Visit 4 (Day 56 +/- 2 
days).  Vital signs will be repeated.  Study personnel will review dosing bottles (including 
blister packs) and count rescue bisacodyl tablets for accountability purposes and for 
consistency with the electronic diary reporting. Study personnel must discuss any 
electronic diary reporting irregularities (e.g. excessive study medication or rescue 
bisacodyl use, reporting compliance). Subjects will complete the PAC-QOL and PAC-
SYM questionnaires. Subjects will be queried for any adverse events or changes to their 
concomitant medications (including ongoing opioid dose). Samples for chemistry, 
hematology and urinalysis will be repeated as outlined in Section 4.1.  
 
A 30 day supply of study medication along with 1 packet of rescue bisacodyl will be 
dispensed at each visit. Unused product will not be redispensed.  No rescue medication 
will be redispensed.  Subjects will be instructed to bring all medication (including 
bisacodyl) and components at each follow up visit. 
4.3.4. Visit 5 – Day 84 
 
Subjects will return at after a full 84 days of dosing (+4 days) for their final clinic visit. 
Vital signs and ECG will be repeated.  A physical examination will be performed 
(including bodyweight). Study personnel will review dosing bottles (including blister 
packs) and count rescue bisacodyl tablets for accountability purposes and for consistency 
with the electronic diary reporting. Study personnel must discuss any electronic diary 
reporting irregularities (e.g. excessive study medication or rescue bisacodyl use, reporting 
compliance). Subjects will complete the PAC-QOL and PAC-SYM questionnaires. 
Subjects will be queried for any adverse events or changes to their concomitant 
medications (including ongoing opioid dose). Samples for chemistry, hematology and 
urinalysis will be repeated as outlined in Section 4.1.  


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4.3.5. Day 98 Follow-up Telephone Call: +/- 3 days 
At Day 98, 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 5 have resolved.  Subjects will also be 
asked about the status of their concomitant medications. 


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4.4. Tabulated Study Procedures 
The following graphically depicts the flow of study procedures at each visit. 
 
Procedures 
Visit 1 
Screening 
Visit 2 
Day 0 
Visits 3 
Days: 28 
Visit 4 
Day 56 
 
Visit 5/ 
ET 
Day 84 
Day 98 
 
 
 
+/-2 days 
+/-2 days 
+4 days 
+/- 3 days 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
 
Vital Signs  
X 
X 
X 
X 
X 
 
Electrocardiogram 
X 
 
 
 
X 
 
Review of Concomitant Medication 
X 
X 
X 
X 
X 
X 
Dispense Electronic Diary 
X 
X 
X 
X 
 
 
Blood Samples for Chemistry & Hematology Testing 
 X 
 
X 
X 
X 
 
Urine Sample for Urinalysis 
 X 
 
X 
X 
X 
 
Dispense Rescue Bisacodyl 
X 
 X 
X 
X 
 
 
Randomize Eligible Subjects 
 
X 
 
 
 
 
Subject to Complete PAC-QOL, PAC-SYM 
 
X 
X 
X 
X 
 
Dispense Study Drug 
 
       X 
X 
X 
 
 
Study Drug and Rescue Bisacodyl Accountability 
 
 X 
X 
X 
X 
 
Assess Safety 
 
     X 
X 
X 
X 
X 
 


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4.5. Pregnancy 
Subjects who are female and of childbearing potential must have a serum pregnancy test 
done at screening. A positive result will rule out the participation of the subject in the 
study. A second serum pregnancy test will be performed at Visit 5. 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 serum 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. 
 
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. 
 
4.6. Concomitant Medications 
 
The use of concomitant medication will be recorded from 14 days prior to Visit 1 until the 
end of the study at the telephone contact on Day 98. Subjects enrolled in this study will 
not be permitted to take any laxatives (other than the sponsor supplied rescue bisacodyl), 
whether prescription or over-the-counter, from Visit 1 until after completion of Treatment 
Day 84. Any restricted laxative use during the study may result in termination of subject’s 
participation. Subjects may not initiate treatment with any constipating medication and 
must remain on a qualifying dose of opioid pain medication (30mg to 1000mg).  


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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 patient providing informed consent to 
participate in the study and will conclude with the end of study participation at Day 98 (2 
week follow-up phone call).  Diarrhea should be reported as an adverse event if a patient 
has more than 3 watery stools per day (Bristol Stool Rating = 7). Patients with clinically 
significant laboratory results at Visit 5 which are classified by the Investigator as adverse 
events should return for a repeat blood draw. Patients 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 Phase 3 studies, adverse events associated with Oral Sodium Sulfate administered at 
doses consistent with colonoscopy preparation have included nausea, vomiting, abdominal 
cramping and bloating. These adverse reactions were transient and subsided rapidly.  
 
In a Phase 2 study of BLI-801 laxative, the most frequently reported adverse events were 
abdominal pain, diarrhea, flatulence and nausea.  These adverse reactions were transient 
and subsided rapidly.    
 
6. SERIOUS ADVERSE REACTIONS AND DISCONTINUATION OF STUDY 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that results in at 
least one of the following outcomes: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 Is a congenital anomaly/birth defect 
 Requires medical or surgical intervention to prevent permanent impairment or damage 


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 SAE collection will coincide with the patient providing informed consent to participate in 
the study and will conclude 30 days after a patient’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. 
 
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. 
 


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8. MANAGEMENT OF INTERCURRENT EVENTS 
8.1. Modification of Protocol 
Neither an Investigator nor Braintree Laboratories will modify the protocol without first 
obtaining the concurrence of the other and the IRB. Investigators that continually violate 
the protocol or commit a serious violation may be subject to termination from the study. 
The study may be halted if at any time an Investigator or Braintree Laboratories deems 
the incidence or severity of adverse events to be unacceptable. 
 
8.2. Subjects Discontinued from the Study 
Subjects may be dropped from the study for any of the following reasons: 
1) Subject did not meet BM Entry Criteria. 
2) Subject did not meet Diary Compliance Criterion. 
3) Subject took prohibited laxatives or non-opioid constipating medications 
during the Screening or Treatment Period 
4) Subject significantly modified their opioid medication dose 
5) An adverse event requiring discontinuation (including failure to tolerate study 
medication). 
6) The Investigator decides that the patient should be dropped from the  
       study (e.g. serious adverse event, protocol violation, non-compliance). 
7) The patient decides to withdraw from the study. Patients 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.  
 
 


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9. DATA ANALYSIS 
9.1. Sample Size 
Four hundred subjects will be randomly assigned to BLI801 Laxative (one of 3 doses) or 
placebo in a ratio of 1:1:1:1 (100 subjects per group).  The definition of a weekly 
responder is based on weekly assessments of spontaneous bowel movements (SBMs).  
Based on data from a previous Phase 2 study, it is anticipated that approximately 50% of 
subjects would be classified as responders in the  BLI801 arm, with a placebo response up 
to 30% (based on placebo response in recent Phase 3 studies with the same endpoint) 
(REF). The proposed study size will have greater than 80% power to detect a difference of 
20% between the active and placebo groups at a one-sided significance level of 0.05. 
 
9.2. Null and Alternative Hypotheses 
The primary objective of this study is to compare the safety and efficacy of BLI801 
Laxative to placebo in patients with opioid induced constipation. To establish this, the 
primary comparison of interest will be on the overall responder percentage based on 12 
weeks of treatment. A weekly responder is a subject who has ≥ 3 SBMs and an increase 
from baseline of > 1 SBM in that week. 
The null hypothesis will be that there is no difference in the response rates between 
BLI801 Laxative and placebo, the alternative hypothesis being that the response rate is 
higher for BLI801 Laxative than for placebo. 
 
9.3. Planned Analyses 
9.3.1.   Demographic and Baseline Characteristics 
Baseline comparability of the following demographic and baseline characteristics for the 
treatment groups will be performed. 
 Age (ANOVA) 
 Gender (CMH Chi square) 
 Race/ethnicity (CMH Chi square) 


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 Constipation History (ANOVA) 
 Screening spontaneous bowel movement frequency (ANOVA) 
 Screening rescue bisacodyl use (ANOVA) 
 
9.3.2. Efficacy Analyses 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be assessed on the basis of a binary outcome of overall 
treatment success or failure. The primary efficacy endpoint will be proportion of subjects 
who are weekly responders for 9 out of the 12 weeks of treatment, with at least 3 of these 
weeks occurring in the last 4 weeks of treatment. A weekly responder is a subject who has 
an average of ≥ 3 SBMs/week and an average increase from baseline of > 1 SBM/week in 
that week. A SBM is a bowel movement that occurs with no rescue laxative use in the 
previous 24 hours. 
 
Superiority Hypothesis: 
The primary endpoint of treatment success will be based upon the difference D=P1-P2, 
where P1 is the observed success fraction in the BLI801 Laxative group (experimental 
group) and P2 is the observed success fraction in the placebo group (control group).  The 
procedure tests the null hypothesis 
H0: π1-π2=0 
versus the alternative hypothesis 
H1: π1-π2 ≠0, 
where π1 is the true underlying probability of successful treatment in the BLI801 Laxative 
group, and π2 is the true underlying success probability in the placebo group.   
 
We will test the null hypothesis of superiority separately for the comparisons of individual 
BLI801 Laxative dose levels versus placebo.  We will preserve the family-wise type I 
error rate at 5% using the Bonferroni approach, conducting each test at the 2.5% two-
sided level.  If multiple comparisons are significant, we will conduct a test comparing the 
two dose levels of BLI800 at the two-sided 5% level.  As we will only perform this test 
conditionally on the other tests being significant, it has no effect on the family-wise type I 
error rate, and so it requires no further multiplicity adjustment. 


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The following equation will be used to calculate the weekly SBM frequency: 
SBM frequency = 7 X (Number of SBMs/number of days with non-missing SBM 
assessments)  
 
If a subject has fewer than four days of data observed for a week, then that subject’s data 
should be considered missing for that entire week and the subject considered a non-
responder. 
The primary efficacy endpoint will be analyzed using the CMH test controlling for the effect 
of study center. The presence of a treatment-by-center interaction will be investigated by the 
Breslow-Day test of homogeneity of odds ratio.  The strategy for pooling centers will be 
based on geographical considerations, with low enrolling centers pooled by geographic 
region.  Details of any pooling performed will be documented prior to database lock and 
unblinding of the study. 
No bowel movements that occur within 24 hours of a rescue bisacodyl (or other prohibited 
laxative) dose will be included in primary or secondary efficacy analyses.  
Secondary endpoints will include the following: 
 Overall response by gender and age group (< 65, > 65 years) 
 Number of study medication doses taken per week (mean) 
 Number of rescue bisacodyl doses taken per week (mean) 
 % of subjects not meeting ROME criteria at the end of each treatment week 
 Mean Time to BM after dose  
 Weekly stool consistency 
 Number of BMs with straining per week (mean) 
 SBM frequency rates during each week (weeks 1 to 12) 
 BM urgency score per week (mean) 
 Bristol Stool Form score per week (mean) 
 Number of BMs per week (mean) 
 Number of diarrhea episodes per week (mean) – diarrhea is defined as > 3 watery 
stools per day  


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 Weekly stool straining 
 Change in PAC-SYM from Baseline by Visit (total and individual scores) 
 Change in PAC-QOL from Baseline by Visit (total and individual scores) 
9.3.3.Safety Analyses 
Analysis of safety will be performed using the Intent to Treat population (see Section 9.4). 
 
Adverse Events 
Adverse Events will be coded using the MedDRA classification to provide a preferred 
term and primary system organ class for each event.  Proportions of subjects with adverse 
events will be presented by treatment group.  Tables of AEs will be presented by system 
organ class and preferred term, and include overall totals for AEs within each system 
organ class.  Counting will be done by subject and not by event.  A table of counts and 
percentages will also be made of those subjects with SAEs or AEs which led to 
withdrawal from the study.  
Treatment-emergent AEs are defined as adverse events that had an onset day and time on 
or after the day and time of the first dose of study drug up to 30 days after the last 
application of treatment.  Adverse Events having missing onset dates will be considered 
as treatment emergent. 
The difference in adverse event rates between study groups will be tested by Chi-Square 
or Fisher’s exact test with 95% confidence intervals. Adverse events will be presented for 
the overall Treatment Period. 
Laboratory Parameters  
Summary statistics (i.e., mean, minimum, maximum, standard deviation, and number of 
subjects) will be presented for each treatment group for each laboratory parameter at each 
visit.  When calculating the summary statistics only, the last observation within a visit 
window will be used if there are multiple observations.  Changes from baseline will be 
presented in a similar format.  An additional listing will be provided of those subjects who 


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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 (Screening) and group differences 
will be tested using ANOVA. 
Vital Signs 
Summary statistics (i.e., mean, minimum, maximum, standard deviation, and number of 
subjects) will be presented for each treatment group for each vital sign at each visit.  
When calculating the summary statistics only, the last observation within a visit window 
will be used if there are multiple observations.  The data will also be presented as shift 
tables and clinically significant abnormalities will be examined. 
ECG variables will be tabulated and presented for data collected at each visit. Data will be 
tabulated and summarized with descriptive statistics (N, mean, SD, CV%, SEM, 
minimum, and maximum) for each of the ECG variables. The differences in ECG 
variables between Visit 2 (pre-dose) and Visits 3 - 5 will be tested using ANOVA.  
 
9.4. Study Populations 
The following populations have been defined for data analyses. 
9.4.1. 
Intention-to-Treat (ITT) Population 
This population includes all subjects randomized to treatment and will be used for the 
primary efficacy analysis and all safety analyses.  
9.4.2. 
Modified Intention-to-Treat (mITT) Population  
This population consists of all randomized subjects that took at least one dose of study 
medication. This population will be utilized for secondary efficacy analyses and 
sensitivity analysis of the primary efficacy endpoint.  
9.4.3. 
Per Protocol Population  
The per protocol (PP) population will consist of all subjects in the mITT population who 
have not violated any major entry criteria and have not deviated significantly from the 


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protocol during the course of the study.  Any efficacy analyses from this population will 
be considered as supportive to the ITT and mITT analyses.  Reasons for exclusion from 
the PP population will be defined prospectively in the statistical analysis plan and prior to 
unblinding of the data. 
 
10. DRUG INVENTORY AND DISPOSITION 
 
At the conclusion of the study, all drug materials will be accounted for.  Federal law 
requires that, at the conclusion of the study, all drug materials must be returned to the 
study sponsor or destroyed according to local regulations.  
 
11. STUDY MONITORING 
 
A Braintree Laboratories Study Monitor or qualified designee will visit the study center 
prior to the commencement of the study and periodically during the course of the study in 
accordance with federal guidelines governing the sponsorship of studies. 
 
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 all 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 
BLI801 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 
 
 
1. DiPalma JA, Rodriguez R, McGowan J, Cleveland, MV.  A Randomized Clinical 
Study Evaluating the Safety and Efficacy of a New, Reduced-Volume, Oral Sulfate 
Colon-Cleansing Preparation for Colonoscopy. Am J Gastroenterol. 2009 Jul 7. [Epub 
ahead of print] 
 
 
2. Heizer WD, Sandler RS, Seal E, Murray SC, Busby MG, Schliebe BG, Pusek SN: 
Intestinal effects of sulfate in drinking water on normal human subjects.  Dig Dis Sci 
1997;42(5):1055-1061. 
 
3. Vu MK, Nouwens AG, Biemond, I, Lamers CBHW, Masclee AAM: The osmotic 
laxativie magnesium sulphate activates the ileal brake. Aliment. Pharmacol. Ther. 
2000;14:587-595. 
 
4. Patel V, Nicar M, Emmett M, Asplin J, Maguire JA, Santa Ana CA, Fordtran JS. 
Intestinal and renal effects of low-volume phosphate and sulfate cathartic solutions 
designed for cleansing the colon: pathophysiological studies in five normal subjects. Am. 
J. Gastro. 2009: 2009 Apr;104(4):953-65. 
 
5. Cocchetto DM, Levy G. Absorption of orally administered sodium sulfate in humans. J 
Pharm Sci. 1981; 70(3):331-3. 
 
6. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. 
Functional bowel disorders. Gastroenterology. 2006 Apr;130(5):1480-91. Review. 
Erratum in: Gastroenterology. 2006 Aug;131(2):688. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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