Clinical trial NCT03120520
Conditions: Chronic Idiopathic Constipation
Sponsor: Bausch Health Americas, Inc.
Start date: 2017-01-01; Completion date: 2018-09-07
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of efficacy and safety of Plecanatide in pediatric subjects aged 12 to \< 18 years diagnosed with Chronic Idiopathic Constipation.

Detailed description:
The purpose of the study is to evaluate efficacy, safety, and pharmacokinetics (PK) of oral Plecanatide 0.5, 1.0 and 1.5 mg tablets dosed once a day as compared to matching placebo, when administered for 8 weeks in adolescents with chronic idiopathic constipation.

This study will consist of a 4-week screening period, 8 weeks of treatment, and a 2-week follow-up. The study will assess the effects of Plecanatide on bowel movement frequency and other clinical features of CIC.

Arms: arm 1: Taken orally once daily in the morning for 8 weeks arm 2: Taken orally once daily in the morning for 8 weeks arm 3: Taken orally once daily in the morning for 8 weeks arm 4: Taken orally once daily in the morning for 8 weeks
Interventions: intervention 1: Plecanatide intervention 2: Matching placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
A Randomized, Double-blind, Placebo-controlled, 3 Dose Level, Parallel-group Study of the 
Efficacy and Safety of Plecanatide in Adolescents 12 to <18 Years of Age with Chronic 
Idiopathic Constipation (CIC) 
Sponsor: 
Synergy Pharmaceuticals Inc. 
420 Lexington Avenue, Suite 2012 
New York, NY 10170 
T:  +1 212-297-0020 
F:  +1 646-961-4760 
Clinical Research Organization: 
Chiltern International 
1241 Volunteer Parkway 
Bristol, TN 37620 
T:  +1 423-968-9533 
Medical Monitor: 
Sam L. Teichman, MD 
steichman@synergypharma.com 
1-925-437-2067
Sponsor Protocol No.: 
SP304202-13 
IND No.: 
74883 
Study Drug Name:  Phase: 
Plecanatide: Phase 2b 
Date of Protocol (Version 4.0): 
May 18, 2017 
Date of Previous Protocol (Version 3.0): 
April 25, 2017  
Date of Previous Protocol (Version 2.0): 
January 19, 2017  
Date of Previous Protocol (Version 1.0): 
December 28, 2015 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP) and 
with other applicable regulatory requirements. 
This document contains confidential information of Synergy Pharmaceuticals Inc. 
Do not copy or distribute without written permission from the Sponsor. 
NCT03120520


Synergy Pharmaceuticals Inc. 
Clinical Study Protocol 
Protocol SP304202-13 
CONFIDENTIAL 
Final Version 4.0 
Page 2 of 79 
May 18, 2017 
 
SIGNATURE PAGE 
 
Declaration of Sponsor 
 
Title:  A Randomized, Double-blind, Placebo-controlled, 3 Dose Level, Parallel-group 
Study of the Efficacy and Safety of Plecanatide in Adolescents 12 to < 18 Years of Age with 
Chronic Idiopathic Constipation (CIC) 
 
This study protocol was subjected to critical review.  The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as with 
the moral, ethical, and scientific principles governing clinical research as set out in the guidelines 
on Good Clinical Practice. 
 
 
 
 
Renata Tenenbaum, MS  
Clinical Research Scientist 
Synergy Pharmaceuticals Inc. 
T:  +1 212-584-7608 
E-mail:  rtenenbaum@synergypharma.com 
 
Date 
 
 
 
 
 
Statistician 
Henry C. Foehl, PhD 
Principal Statistician 
Foehl Statistics & Analytics LLC 
T:  +1 610-646-0167 
E-mail:  henry.foehl@hcfoehl.com 
 
Date 
 
 
 
 
 
Patrick H. Griffin, MD 
Chief Medical Officer 
Synergy Pharmaceuticals Inc. 
T:  +1 212-297-0020 
E-mail:  pgriffin@synergypharma.com 
 
Date 
 
 
 
 


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Final Version 4.0 
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Declaration of the Investigator 
 
Title:  A Randomized, Double-blind, Placebo-controlled, 3 Dose Level, Parallel-group 
Study of the Efficacy and Safety of Plecanatide in Adolescents 12 to < 18 Years of Age with 
Chronic Idiopathic Constipation (CIC) 
 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence.  This documentation includes this study 
protocol, Investigator's Brochure, electronic Case Report Forms (eCRFs), and other scientific 
data. 
 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB).  No changes will be made to the study protocol without the 
prior written approval of the Sponsor and the IRB, except where necessary to eliminate an 
immediate hazard to the patients. 
I have read and understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
 
Responsible Investigator of the local study center 
 
 
 
Signature 
 
Date 
Name (block letters) 
 
 
Institution (block letters) 
 
 
Phone number 
 
 
 


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Protocol SP304202-13 
CONFIDENTIAL 
Final Version 4.0 
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PROTOCOL SYNOPSIS 
Study Title 
A Randomized, Double-blind, Placebo-controlled, 3 Dose Level, Parallel-group 
Study of the Efficacy and Safety of Plecanatide in Adolescents 12 to < 18 Years of 
Age with Chronic Idiopathic Constipation (CIC) 
Sponsor 
Synergy Pharmaceutical Inc. 
Sponsor Study No. 
SP304202-13 
Phase 
2b 
Study Centers 
The study will be conducted at approximately 40 clinical sites in the United States  
Objectives 
Primary objective:  
To evaluate the safety and efficacy of 3 different doses of oral plecanatide taken 
once daily for 8 weeks as treatment for CIC in adolescents 12 to less than 18 years 
of age 
Secondary objectives: 
• To identify the pharmacokinetic (PK) parameters of plecanatide in this patient 
population (to the extent possible since plecanatide is not expected to be 
absorbed) 
• To evaluate the effect of 3 selected dose levels of plecanatide on stool 
consistency and relief of CIC-related symptoms in adolescents 12 to less than 18 
years of age  
• To assess the effect of 3 selected dose levels of plecanatide on the frequency of 
complete spontaneous bowel movements (CSBMs) 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group 
study of the efficacy and safety of 3 dose levels of plecanatide (0.5, 1.0, or 1.5 mg) 
in adolescent patients 12 to less than 18 years of age with CIC. Patient 
randomization will focus on the balanced enrollment of males and females across 
the 4 treatment groups. 
This Phase 2b study will comprise a 28-day bowel habit Screening/Baseline Period, 
an 8-week Treatment Period, and a 2-week Posttreatment Follow-up Period. Patients 
will visit the clinic 5 times during the study. 
Screening/Baseline Period: Patients’ legally authorized representatives (e.g., parent 
or guardian) will provide informed parental permission and patients will provide 
written assent before they undergo any protocol-specified procedures or 
assessments. At the Screening visit, patients will undergo a review of medical 
history, a review of prior and concomitant medications, a brief dietary history, and 
physical examination. During the 28-day Screening/Baseline Period prior to 
randomization, patients will record - through an electronic diary - daily assessments 
of bowel movements (BMs), stool consistency (using the Bristol Stool Form Scale 
[BSFS]), abdominal pain, abdominal discomfort, abdominal bloating, straining and 
pain when passing stools, fecal incontinence, excessive flatulence, and feeling of 
incomplete evacuation following bowel movement. Data from the electronic diary 
will be used to confirm study eligibility immediately prior to the randomization 
visit, as well as to characterize the patient’s baseline chronic constipation status with 
which the change from Baseline across and at the end of the 8-week treatment 
period will be compared. 
Treatment Period: Patients who meet all entry criteria will be randomly assigned to 
1 of 4 treatment groups (3 active, 1 placebo) in a 1:1:1:1 ratio on Day 1 of the 
Treatment Period. Randomization will be stratified to ensure gender balance across 
treatment groups. Patients will take an oral dose of the study drug once daily for 
8 weeks and continue to complete their daily electronic diaries with recording of 


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BMs, rescue medication use for constipation, abdominal pain, and other symptoms. 
At Weeks 1, 4, and 8 of the Treatment Period, patients will return to the clinic to 
undergo safety and efficacy assessments. 
Posttreatment Follow-up Period: For 2 weeks after the last dose of study drug, 
patients will continue to complete their daily electronic diaries. Patients will then 
return to the clinic for a final Follow-up visit at the end of Week 10. 
The planned duration of participation in this study will be approximately 14 weeks 
from signing of informed consent/assent through posttreatment. 
Study Drug 
Plecanatide 0.5, 1.0, or 1.5 mg tablets and matching placebo for oral administration 
Treatment 
Following a 28-day Screening Baseline Period, patients will be randomly assigned 
to 1 of 3 plecanatide doses (0.5, 1.0, or 1.5 mg) or to matching placebo. Study drug 
will be provided as a 4-week supply of tablets in blister packs. It will be distributed 
on Day 1 and replenished at Week 4. Patients will take the assigned dose of study 
drug each morning approximately at the same time for 8 weeks. 
Dulcolax® will be provided as a rescue laxative that can be used if a patient has not 
had a bowel movement for at least 72 hours. Patients will be advised that it is 
preferred that they NOT take rescue medication for the period from 24 hours before 
to 72 hours after Day 1 of dosing.  
Number of Patients and 
Population 
Approximately 120 adolescents with CIC will be randomized (~30 in each treatment 
group) into the study.  Eligibility for study enrollment (2 or fewer SBMs per week, 
adequate diary entry compliance and proper use of rescue medication) will be 
confirmed by electronic diary entries made during each week of the two-week 
baseline diary assessment. 
Key Inclusion Criteria 
Male or female adolescents 12 to less than 18 years of age diagnosed with CIC 
based on the Rome III criteria for child/adolescent functional constipation. 
Key Exclusion Criteria 
(abbreviated) 
• 
Medical history or conditions that may be affecting GI motility or defecation 
• 
Lack of willingness to use Dulcolax® as the only laxative. 
• 
Non-compliance with eDiary and rescue medication use. 
Criteria for Evaluation of 
Efficacy and Safety 
Efficacy endpoints 
The primary efficacy endpoint is:   
Proportion of responders for the last 2 weeks of the Treatment Period (responder = a 
child who experiences >3 SBMs per week for each of the last two weeks of the 
treatment period) compared to placebo and across treatment groups.   
The key secondary efficacy endpoints are: 
• 
Change from Baseline in stool consistency (as assessed by BSFS) 
• 
Change from Baseline in frequency of SBMs 
• 
Change from Baseline in frequency of CSBMs 
Additional efficacy endpoints are:   
• 
Change from Baseline in CIC-related symptoms (abdominal pain, abdominal 
bloating, abdominal discomfort, straining with a bowel movement and pain 
with defecation) 
• 
Frequency/severity of excessive flatulence  
• 
Frequency of fecal incontinence 
• 
Patient Reported Global Assessments (PGA, PAC-SYM and PAC-QOL) 
 
Pharmacokinetic endpoints 
Single dose and steady state of plasma plecanatide (population modeling): 


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• 
Plasma concentration of plecanatide (Note:  measurable plecanatide levels 
have not been observed in the adult population) 
• 
PK parameters, including Cmax, Tmax, and Cmin (only if a sufficient number of 
plecanatide levels can be measured to allow computation of these parameters) 
Safety endpoints 
• 
Frequency of treatment-emergent adverse events (TEAEs) 
• 
Significant shifts from Baseline values in laboratory analytes and vital signs 
Statistical Methods 
Analysis Populations 
Analysis populations include the Safety population, the Intent-to-treat (ITT) 
population, and the Per-Protocol (PP) population. The Safety population will include 
all patients who were randomly assigned to a treatment group and received at least 1 
dose of study drug. The ITT population will include all patients who were 
randomized to receive study drug. The PP population will be used for sensitivity 
analyses, and will consist of all patients in the ITT population without any 
significant protocol violations. The ITT population will be the primary population 
for efficacy analyses. 
 
Patient Characteristics and Disposition 
Demographic characteristics (including age, gender, race, weight, height, and body 
mass index) and characteristics of patients’ CIC history will be summarized by 
descriptive statistics for each treatment group. 
Efficacy Analyses 
Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of responders for the last 2 weeks of 
the Treatment Period (responder = a child who experiences >3 SBMs per week for 
each of the last two weeks of the treatment period) compared to placebo and across 
treatment groups.  The change from baseline in mean weekly SBM rate will be 
analyzed using a linear mixed-effects model with fixed effects for gender 
(stratification variable), treatment, week, and the corresponding baseline value; a 
random intercept for patient will also be specified.  The least squares (LS) mean 
change from baseline will be presented, by treatment group, and the difference in LS 
means for each plecanatide treatment group compared to placebo will be presented, 
with 95% confidence intervals and corresponding statistical p-values. 
 
Secondary Efficacy Analysis 
The secondary efficacy endpoints are: 
• 
Change from baseline in weekly average stool consistency (BSFS) score over 
the 8-week treatment period, and by study week 
• 
Change from baseline in the weekly rate of SBMs, by study week 
• 
Change from baseline in the weekly rate of CSBMs over the 8-week treatment 
period, and by study week 
The mean in each period and the change from baseline will be summarized in each 
treatment group. Differences between treatment groups will be analyzed with an 
analysis of covariance, including fixed effects for gender (stratification variable) and 
treatment and corresponding baseline value as a covariate. A least squares mean 
with 95% confidence intervals will be presented for the difference between each 
plecanatide group and placebo.  
 
Pharmacokinetic Analyses 
Plasma plecanatide (and its major metabolite SP-338) concentrations will be 
assessed for all patients pre-dose on Day 1, and at Week 4 and Week 8 visits. 


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Intensive PK sampling (30, 60, 90 and 120 min post-dose on Day 1) will be done in 
a subset of approximately 40 patients at selected sites. Descriptive PK parameters 
will be presented and to the extent possible will be analyzed.  
Safety Analyses 
The Medical Dictionary for Regulatory Activities (Version 14.1 or higher) will be 
used to classify all AEs with respect to system organ class and preferred term. 
Adverse events, changes in clinical laboratory parameters, and vital signs will be 
analyzed descriptively. Shifts in key laboratory parameters will be summarized from 
Baseline to the end of the study. Similarly, shifts in toxicity of key laboratory 
parameters and proportion of patients with abnormal clinical and vital sign results 
will be summarized. 
 


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Final Version 4.0 
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LIST OF STUDY PERSONNEL 
 
Sponsor: 
Patrick H. Griffin, MD 
Chief Medical Officer 
Synergy Pharmaceutical Inc. 
420 Lexington Avenue, Suite 2012 
New York, NY 10170 
T:  +1 212-297-0020 
 
Medical Monitor: 
Sam L. Teichman, MD 
steichman@synergypharma.com 
1-925-437-2067 
 
SAE Reporting: 
Chiltern International  
PV Global SAE Fax number: +1 888-726-8416    
PV email: Global.SAEInbox@chiltern.com 
Central Laboratory: 
ACM Medical Laboratory, Inc.  
160 Elmgrove Park  
Rochester, New York 14624  
 
Pharmacokinetic Laboratory: 
Pyxant Labs  
4720 Forge Rd # 106  
Colorado Springs, CO 80907 
Tel: +1 719-593-116 
 
Drug Manufacturer: 
UPM Pharmaceuticals, Inc. 
501 Fifth Street 
Bristol, TN 37620 
 
Drug Packaging and Distribution: 
Sharp Corporation  
7451 Keebler Way and 
7339 Industrial Blvd.  
Allentown, PA 18106 
 
 


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Table of Contents 
1 
OVERALL DESIGN AND PLAN OF THE STUDY .................................................................................... 16 
2 
INTRODUCTION ............................................................................................................................................ 17 
2.1 
BACKGROUND AND RATIONALE ..................................................................................................................... 17 
2.1.1 
Chronic Idiopathic Constipation in Adults ............................................................................................ 17 
2.1.2 
Chronic Idiopathic Constipation in Children ......................................................................................... 17 
2.1.3 
Plecanatide Mechanism of Action and Pharmacology ........................................................................ 18 
2.1.4 
Clinical Experience in Adults................................................................................................................. 18 
2.2 
OBJECTIVES ................................................................................................................................................... 20 
2.2.1 
Primary Objective ................................................................................................................................. 20 
2.2.2 
Secondary Objectives ........................................................................................................................... 20 
2.2.3 
Rationale for Dose Selection ................................................................................................................ 21 
2.3 
RISK-BENEFIT ASSESSMENT .......................................................................................................................... 21 
2.4 
CRITERIA FOR EVALUATION OF THE STUDY ................................................................................................... 21 
2.4.1 
Efficacy Endpoints ................................................................................................................................ 21 
2.4.1.1 
Primary Efficacy Endpoint .......................................................................................................................... 21 
2.4.1.2 
Secondary Efficacy Endpoints .................................................................................................................... 22 
2.4.1.3 
Additional Efficacy Endpoints .................................................................................................................... 22 
2.4.1.4 
Patient Reported Outcomes ...................................................................................................................... 22 
2.4.1.5 
Exploratory Efficacy Endpoints .................................................................................................................. 22 
2.4.2 
Pharmacokinetic Endpoints ................................................................................................................. 22 
2.4.3 
Safety Endpoints .................................................................................................................................. 22 
2.5 
JUSTIFICATION OF THE STUDY DESIGN ........................................................................................................... 23 
2.6 
PLANNED SAMPLE SIZE AND NUMBER OF STUDY CENTERS ........................................................................... 23 
3 
STUDY POPULATION................................................................................................................................... 24 
3.1 
INCLUSION CRITERIA ..................................................................................................................................... 24 
3.2 
EXCLUSION CRITERIA .................................................................................................................................... 24 
3.3 
PREVIOUS AND CONCOMITANT MEDICATIONS ............................................................................................... 25 
3.3.1 
Permitted Concomitant Medications ................................................................................................... 26 


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3.3.2 
Prohibited Prior and Concomitant Medications and Supplements ...................................................... 26 
3.4 
DIETARY INTAKE ........................................................................................................................................... 28 
4 
VARIABLES AND METHODS OF ASSESSMENT .................................................................................... 29 
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...................................................................................... 29 
4.1.1 
Patient Demography ............................................................................................................................ 29 
4.1.2 
Disease and Medical History ................................................................................................................ 29 
4.1.3 
Previous Medications and Diet ............................................................................................................ 29 
4.2 
EFFICACY VARIABLES .................................................................................................................................... 29 
4.2.1 
Data Collected via the Electronic Diary ................................................................................................ 29 
4.2.2 
Variables Assessed by Questionnaires Administered at the Study Site ................................................ 31 
4.3 
SAFETY VARIABLES ....................................................................................................................................... 32 
4.3.1 
Collection of Adverse Events ................................................................................................................ 32 
4.3.2 
Laboratory Variables ............................................................................................................................ 32 
4.3.3 
Immunogenicity and Pharmacokinetic (PK) Assessments .................................................................... 33 
4.3.4 
Vital Signs ............................................................................................................................................ 34 
4.3.5 
Electrocardiograms .............................................................................................................................. 34 
4.3.6 
Physical Examinations .......................................................................................................................... 34 
4.3.7 
Concomitant Medications and Diet ..................................................................................................... 35 
4.3.8 
Rescue Medication ............................................................................................................................... 35 
5 
STUDY CONDUCT ......................................................................................................................................... 36 
5.1 
SCHEDULE OF ASSESSMENTS ......................................................................................................................... 36 
5.2 
PROCEDURES BY VISIT ......................................................................................................................................... 38 
5.2.1 
Visit 1: Screening (Day-28) ................................................................................................................... 38 
5.2.2 
Visit 2:  Randomization / Day 1 of Treatment Period .......................................................................... 39 
5.2.3 
Visit 3:  Week 4, Day 28 (± 3 days) of Treatment Period ...................................................................... 40 
5.2.4 
Visit 4:  Week 8, Day 56 (+ 3 days) of Treatment Period ...................................................................... 41 
5.2.5 
Visit 5:  Week 10, Day 70 (+ 3 days) – Posttreatment Follow-up (End of Study) .................................. 41 
5.2.6 
Early Withdrawal Visit (EW) ................................................................................................................. 42 


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6 
STUDY DRUG ................................................................................................................................................. 43 
6.1 
IDENTITY OF PLECANATIDE AND PLACEBO .................................................................................................... 43 
6.2 
ADMINISTRATION ........................................................................................................................................... 43 
6.3 
PACKAGING, LABELING AND STORAGE .......................................................................................................... 45 
6.3.1 
Packaging............................................................................................................................................. 45 
6.3.2 
Label ..................................................................................................................................................... 45 
6.3.3 
Storage ................................................................................................................................................. 45 
6.4 
BLINDING AND BREAKING THE BLIND ........................................................................................................... 46 
6.5 
DRUG ACCOUNTABILITY ................................................................................................................................ 46 
6.6 
COMPLIANCE ................................................................................................................................................. 47 
7 
ASSESSMENT, REPORTING, RECORDING AND FOLLOW UP OF ADVERSE EVENTS .............. 48 
7.1 
DEFINITION .................................................................................................................................................... 48 
7.2 
EVENT OF SPECIAL INTEREST – DIARRHEA .................................................................................................... 48 
7.3 
ASSESSMENT OF ADVERSE EVENTS ............................................................................................................... 49 
7.3.1 
Seriousness........................................................................................................................................... 49 
7.3.2 
Intensity (Severity) ............................................................................................................................... 50 
7.3.3 
Causality .............................................................................................................................................. 50 
7.4 
RECORDING ADVERSE EVENTS ...................................................................................................................... 51 
7.5 
REPORTING SERIOUS ADVERSE EVENTS ................................................................................................................... 51 
7.6 
FOLLOW-UP OF ADVERSE EVENTS ................................................................................................................. 53 
7.7 
PREGNANCY ................................................................................................................................................... 53 
8 
STATISTICAL METHODS ........................................................................................................................... 54 
8.1 
RANDOMIZATION AND TREATMENT ASSIGNMENT ......................................................................................... 54 
8.2 
SAMPLE SIZE AND POWER CONSIDERATIONS ................................................................................................. 54 
8.3 
ANALYSIS POPULATIONS ............................................................................................................................... 54 
8.4 
GENERAL CONSIDERATIONS .......................................................................................................................... 55 
8.4.1 
Missing Data Conventions ................................................................................................................... 55 
8.4.2 
Diary Data Visit Windows .................................................................................................................... 56 


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8.4.3 
Baseline Definition ............................................................................................................................... 56 
8.5 
DISPOSITION OF PATIENTS ............................................................................................................................. 57 
8.6 
TREATMENT COMPLIANCE ............................................................................................................................. 57 
8.7 
DEMOGRAPHICS, MEDICAL HISTORY, BASELINE CHARACTERISTICS, AND CONCOMITANT MEDICATIONS .... 57 
8.8 
EFFICACY ANALYSES ..................................................................................................................................... 57 
8.8.1 
Primary Efficacy Endpoint .................................................................................................................... 57 
8.8.1.1 
Analysis of the Primary Efficacy Endpoint .................................................................................................. 57 
8.8.2 
Secondary Efficacy Endpoints .............................................................................................................. 58 
8.8.2.1 
Change from Baseline in Weekly Average Stool Consistency (BSFS) Score Over the 8-week Treatment 
Period, and by Study Week ............................................................................................................................................. 58 
8.8.2.2 
Change from Baseline in the Weekly Rate of SBMs, by Study Week ......................................................... 58 
8.8.2.3 
Change from Baseline in Weekly Rate of CSBMs Over the 8-week Treatment Period, and by Study Week
 
59 
8.8.3 
Additional Efficacy Endpoints .............................................................................................................. 59 
8.8.3.1 
Analysis of the Additional Efficacy Endpoints ............................................................................................ 59 
8.8.4 
Exploratory Efficacy Endpoints ............................................................................................................ 60 
8.8.4.1 
Analysis of Exploratory Efficacy Endpoints ................................................................................................ 60 
8.8.5 
Patient Reported Outcomes ................................................................................................................. 60 
8.8.6 
Adjustments for Multiple Comparisons ............................................................................................... 60 
8.9 
PHARMACOKINETIC ANALYSIS ...................................................................................................................... 60 
8.10 
SAFETY ANALYSES.................................................................................................................................... 61 
8.11 
INTERIM ANALYSES .................................................................................................................................. 61 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ....................................................................... 62 
9.1 
DATA QUALITY ASSURANCE .......................................................................................................................... 62 
9.1.1 
Database Management and Quality Control ....................................................................................... 62 
9.2 
ELECTRONIC CASE REPORT FORMS AND SOURCE DOCUMENTATION ............................................................. 62 
9.2.1 
Data Collection ..................................................................................................................................... 62 
9.3 
ACCESS TO SOURCE DATA ............................................................................................................................. 63 
9.4 
DATA CODING ................................................................................................................................................ 63 


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9.5 
ARCHIVING STUDY RECORDS ........................................................................................................................ 64 
9.6 
GOOD CLINICAL PRACTICE ............................................................................................................................ 64 
9.7 
INFORMED CONSENT ...................................................................................................................................... 64 
9.8 
PROTOCOL APPROVAL AND AMENDMENT ...................................................................................................... 64 
9.9 
DURATION OF THE STUDY .............................................................................................................................. 65 
9.10 
PREMATURE TERMINATION OF THE STUDY ............................................................................................... 65 
9.11 
CONFIDENTIALITY ..................................................................................................................................... 65 
9.12 
OTHER ETHICAL AND REGULATORY ISSUES .............................................................................................. 65 
9.13 
LIABILITY AND INSURANCE ....................................................................................................................... 65 
9.14 
PUBLICATION POLICY ................................................................................................................................ 66 
10 
REFERENCE LIST ......................................................................................................................................... 67 
11 
APPENDICES .................................................................................................................................................. 69 
A. 
ROME III DIAGNOSTIC CRITERIA FOR CONSTIPATION IN CHILD/ADOLESCENT .............................................. 70 
B. 
PREGNANCY REPORTING ................................................................................................................................ 71 
C. 
BRISTOL STOOL FORM SCALE ................................................................................................................................ 72 
D. 
ELECTRONIC DAILY DIARY ............................................................................................................................ 73 
E. 
PATIENT QUESTIONNAIRES ............................................................................................................................ 74 
F. 
REGULATIONS AND GOOD CLINICAL PRACTICE GUIDELINES ......................................................................... 79 
List of Tables 
TABLE 1 
LABORATORY ASSESSMENTS .................................................................................................................... 33 
TABLE 2 
SCHEDULE OF ASSESSMENTS ..................................................................................................................... 36 
TABLE 3 
TREATMENT ARMS .................................................................................................................................... 43 
TABLE 4 
INDIVIDUAL PATIENT STOPPING CRITERIA ................................................................................................ 44 
List of Figures 
FIGURE 1 
STUDY DESIGN ..................................................................................................................................... 16 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AGA 
American Gastroenterological Association 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
ATC 
Anatomical Therapeutic Chemical [Classification System] 
ß-HCG 
Beta-Human Chorionic Gonadotropin 
BM 
Bowel movement 
BMI 
Body mass index 
BSFS 
Bristol Stool Form Scale 
CFR 
Code of Federal Regulations 
CFTR 
Cystic Fibrosis Transmembrane Conductance Regulator 
CI 
Confidence interval 
CIC 
Chronic Idiopathic Constipation 
cGMP 
Cyclic guanosine monophosphate 
CMH 
Cochran-Mantel-Haenszel (test) 
CRO 
Contract Research Organization 
CSBM 
Complete spontaneous bowel movement 
CTCAE 
Common Terminology Criteria for Adverse Events 
DRE 
Digital rectal examination 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EOS 
End of Study 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GC-C 
Guanylate cyclase C 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
IBS 
Irritable Bowel Syndrome 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web-based Response System 
LAR 
Legally authorized representative 
LLN 
Lower limit of normal 
LOCF 
Last observation carried forward 
LS 
Least Squares 
MCG 
Microgram 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
Milligram 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
PDUFA 
Prescription Drug User Fee Act 


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PE 
Physical examination 
PGA 
Patient Global Assessment 
PI 
Principal Investigator 
PIN 
Personal Identification Number 
PP 
Per-Protocol (Population) 
PRO 
Patient Recorded Outcome 
PV 
Pharmacovigilance 
QD 
Once daily 
QoL 
Quality of Life 
RM 
Rescue medication 
RTSM 
Randomization and Trial Supply Management 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBM 
Spontaneous bowel movement 
SD 
Standard deviation 
SOC 
System organ class 
SP-304 
Previous designation for Plecanatide 
TEAE 
Treatment emergent adverse event 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WHODD 
World Health Organization Drug Dictionary 
 
Definition of Terms 
Spontaneous bowel 
movement (SBM) 
A bowel movement that occurs in the absence of laxative use within the 
preceding 24 hours 
Complete spontaneous 
bowel movement (CSBM) 
A spontaneous bowel movement with the sense of complete evacuation 


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1 
OVERALL DESIGN AND PLAN OF THE STUDY 
This is an exploratory, randomized, double-blind, placebo-controlled, multicenter, parallel-group 
study of the efficacy and safety of 3 dose levels of plecanatide (0.5, 1.0, or 1.5 mg) in adolescent 
patients 12 to less than 18 years of age with CIC. Approximately 120 patients will be enrolled at 
approximately 40 study sites in the United States. Patient randomization will focus on the 
balanced enrollment of males and females across the 4 treatment groups. 
The overall study plan is presented in Figure 1. 
 
Figure 1 
Study Design 
 
 
 
 
 
Visit 1  
 
              Visit 2 
     Visit 3            Visit 4 
                   Visit 5       
 
                             Randomization 
 
 
     EOT 
 
        EOS 
After written informed consent/assent is obtained at Visit 1, patients will be screened for study 
eligibility. Qualifying patients will be instructed on the use of an electronic diary that will serve 
to record information on their daily bowel habits, rescue medication use and symptoms 
associated with CIC. 
 
Patient will begin diary entries following Visit 1 and continue daily diary entries for the 
remainder of the study. The information recorded by the patient in the diary during the 2 
weeks just prior to Visit 2 will confirm study eligibility, confirm diary compliance and 
establish baseline values for primary and secondary efficacy endpoints. The interval between 
Visit 1 (Screening) and Visit 2 (Randomization) should ideally be 28 days to ensure 2 weeks of 
‘diary practice’ experience and 2 weeks for baseline diary recording. A minimum of 1 week of 
‘diary practice’ is required prior to the 2-week baseline diary recording.  
 
At Visit 2 (Day 1 of Treatment Period), patients who meet all study entry criteria will be 
randomly assigned to 1 of 4 treatment groups (3 active, 1 placebo) in a 1:1:1:1 ratio. The 
patients will take their first dose of study drug at the clinical site, and continue to take a 
single oral dose daily for 8 weeks. Supplies of the study drug will be replenished at the Week 
4 Visit. At Weeks 4 and 8, patients will return to the clinic to undergo safety and efficacy 
assessments.  
 
For 2 weeks after the last dose of study drug, patients will continue to complete their daily 
electronic diaries. Patients will return to the clinic for a final Follow-up visit at the end of    
Week 10. 
 
The planned duration of participation in this study will be approximately 14 weeks (98 days) 
from signing of informed consent/assent through posttreatment. 
TREATMENT PERIOD  
(56 days) 
Plecanatide (0.5, 1.0, 1.5 mg) 
or Placebo 
POST-TREATMENT 
FOLLOW-UP 
(14 days) 
SCREENING PERIOD  
(up to 28 days, includes 2-wk 
Baseline Diary Assessment)  


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2 
INTRODUCTION 
2.1 
BACKGROUND AND RATIONALE 
2.1.1 
Chronic Idiopathic Constipation in Adults 
Idiopathic or functional constipation is a common disorder, affecting approximately 15% of the 
adult population of the United States (US), depending on demographic factors and the definitions 
used (Higgins, 2004). Internationally, similar prevalence rates have been reported in most 
geographic areas (Suares, 2011; Pare, 2001; Peppas, 2008). Constipation is a symptom of many 
diseases and is a collective term used to imply infrequent stools, incomplete bowel movements 
(BMs), straining, bloating, and hard lumpy stool (Cash, 2007).  Treatment for constipation is 
usually based on increased dietary fiber and supplementation with bulking agents; exercise; and 
habit training.  However, often only partial relief is obtained, and many patients use non-bulking 
laxatives on a regular basis without medical supervision.  Chronic use of laxatives is often 
inappropriate, and may lead to side effects, such as dependency and progressive tolerance, 
electrolyte imbalance, and, for the anthraquinones, melanosis coli.  In addition, stimulant 
laxatives may damage the myenteric plexus, resulting in cathartic colon.  Laxatives available 
over the counter are, in general, approved for episodic and not chronic use. 
2.1.2 
Chronic Idiopathic Constipation in Children 
Although a lack of a uniform and consistent definition (or definitions) for “chronic constipation” 
make it difficult to estimate the prevalence of constipation, several published reports confirm that 
it is a prevalent condition worldwide in children as well as adults. It is important to recognize 
that while clinical trial populations are generally defined using Rome Criteria (Appendix A), it 
is not as common to apply them in clinical practice and therefore they are not used uniformly as 
the basis for epidemiology studies of chronic constipation across adult populations or studies 
among the various pediatric age groups. 
 
A recent comprehensive review of the published literature on the epidemiology of pediatric 
constipation concludes that the median value of reported prevalence rates among 19 published 
articles was in a range from 0.7% to 29.6%, with a median of 12% (Mugie, 2011). No consistent 
gender differences for constipation in children have been noted. However, similar to adults, high 
body mass index (BMI) and low socioeconomic status appear to be associated with a higher 
prevalence of constipation in the pediatric population. A positive family history has been found 
in 28% to 50% of children with constipation and a higher incidence has been reported in 
monozygotic than in dizygotic twins. Approximately 40% of children with functional 
constipation develop symptoms during the first year of life (Davidson, 1963; Benninga, 1993) 
while 16% of parents of 22-month old children report constipation in their child (Cash, 2007). 
Peak incidence occurs at the time of toilet training (2-4 years of age), with an increased 
prevalence in boys. 
 
Constipation in children is recognized as having a significant impact on the overall health care 
system, with constipation representing 3% to 5% of general pediatric outpatient visits and up to 
25% of pediatric gastroenterology consultations (Partin, 1992; Caplan, 2005). 
 
Two drugs are approved in the US for treatment of chronic idiopathic constipation in adults - 
linaclotide and lubiprostone. There is still unmet need for treatment of constipation in children.  


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Plecanatide as a member of the guanylate cyclase (GC-C) agonist class of oral therapeutic agents 
is expected to improve the current therapy for CIC. 
2.1.3 
Plecanatide Mechanism of Action and Pharmacology 
Plecanatide (SP-304) is a peptide discovered and synthesized by Synergy Pharmaceuticals Inc. 
(hereinafter referred to as Synergy). 
Plecanatide binds to the GC-C receptor expressed on epithelial cells that line the intestinal 
lumen.  This binding of drug to the GC-C receptor stimulates the intracellular production of 
cyclic guanosine monophosphate, resulting in decreased Na+ reabsorption through Na+/H+ 
exchange and activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) 
(Sindic, 2006). Activation of CFTR in turn enhances transepithelial efflux of chloride and 
bicarbonate ions and as a consequence fluid secretion into the intestinal lumen is stimulated.  
This fluid secretion is expected to facilitate BMs.  Nonclinical data (in human colon carcinoma 
T84 cells and in animals) suggested potential therapeutic utility of orally dosed plecanatide in the 
treatment of CIC. 
2.1.4 
Clinical Experience in Adults 
In clinical trials completed to date, plecanatide has been found to be safe and well-tolerated.  
Plecanatide has been shown to increase the frequency of bowel movements (BMs) in patients 
with Chronic Idiopathic Constipation (CIC); effects on stool consistency and reduction of the 
time to first bowel movement were also seen.  
 
SP304101-08 was a Phase 1 single-dose escalation study in 71 healthy adult subjects receiving 
doses of 0.1, 0.3, 0.9, 2.7, 5.4, 8.1, 16.2, 24.3, or 48.6 mg plecanatide (n=53) or placebo (n=18) 
(IB for Plecanatide).  The study reported no systemic absorption at any dose and no serious 
adverse events (SAEs) or withdrawals due to adverse events (AEs).  Diarrhea was the most 
common AE in the study, reported by 8 of 53 (15.1%) plecanatide subjects and 3 of 18 (16.7%) 
placebo subjects.  The occurrence of diarrhea did not appear to be dose related.  Other AEs 
occurring in 2 or more subjects included abdominal discomfort, nausea, and vomiting 
(Shailubhai, 2009). 
 
SP304201-09 was a Phase 2a 14-day, repeat-dose, placebo-controlled, oral dose-escalation study 
to determine the safety of plecanatide in adult patients with CIC (Shailubhai, ACG 2010 Poster). 
Seventy-eight patients were enrolled in this study and randomized to receive 1 of 4 plecanatide 
doses  (0.3 mg, 1.0 mg, 3.0 mg, or 9.0 mg) or placebo.  Each dose cohort consisted of 20 patients 
(15 active; 5 placebo).  After each cohort was completed, a safety review was conducted prior to 
initiating the next dose cohort.  No SAEs or withdrawals due to AEs occurred for any of the 
patients who received plecanatide during this study.  None of the 58 patients treated with 
plecanatide in this study had diarrhea.  The majority of AEs were mild or moderate in severity 
and transient in nature. 
 
SP304-20210 was a large, 12-week, double-blind, placebo-controlled, multicenter, dose-ranging 
study in adult patients with CIC (study data on file). A total of 951 patients were randomized at 
113 clinical sites in the US.  Randomization was 1:1:1:1 to plecanatide (0.3, 1.0, or 3.0 mg) or 
placebo.  In this study, 948 patients received study drug (712 plecanatide) and 946 patients had at 
least 1 study assessment and were included in the modified Intent-to-Treat (ITT) population.  In 
the high-dose group (3.0 mg, n=237), the proportion of patients who were overall responders 


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(19%) was statistically significantly greater than in patients treated with placebo (10.7%) 
(p=0.009). 
 
Among secondary endpoints for Protocol SP304-20210, there were statistically significant 
changes from baseline (as compared to placebo) in the frequency of complete spontaneous bowel 
movements (CSBMs), stool consistency (higher Bristol Stool Form Scale [BSFS] score), and 
straining that were dose-related, with the greatest change and degree of statistical significance at 
the 3.0-mg dose group.  The median times to first SBM were statistically significantly shorter for 
all doses of plecanatide compared to placebo (27.3 hours) with the shortest median time to first 
spontaneous bowel movement (SBM) of 12.5 hours at the 3.0-mg dose.  In addition, the 
proportion of patients who had a SBM in the first 24 hours was 41.5% with placebo as compared 
to 55.7% (0.3 mg), 53.8% (1.0 mg), and 67.5% (3.0 mg) in plecanatide-treated patients.  
Statistically significantly different (from placebo) changes in patient global assessments and the 
PAC-SYM© and PAC-QOL© scales were also observed over the 12 weeks of treatment at the 
1.0- and 3.0-mg doses.  In general, plecanatide was safe and well tolerated. 
 
Diarrhea was the most common AE, which increased with increasing dose to an incidence of 
9.7% in the 3.0-mg dose group.  Of the cases of diarrhea in patients treated with plecanatide, 
0.7% overall were considered severe and in patients receiving 3.0 mg, only one case (0.4%) was 
considered severe.  The other most common treatment-emergent AEs (TEAEs) occurring in at 
least 2% of patients were headache, abdominal pain, nausea, abdominal distension, urinary tract 
infection, flatulence, and upper respiratory infection.  Serious AEs were uncommon, occurring in 
only 9 study patients, and none were considered to be related to study drug.  Overall, 
approximately 5.5% of patients on 3.0 mg of plecanatide withdrew due to AEs compared to 3.4% 
on placebo.  Three percent of patients at the 3.0-mg dose withdrew participation due to diarrhea 
compared to 0.4% on placebo.  There were no clinically significant changes in laboratory tests, 
electrocardiograms (ECGs), or vital signs.  Further details on plecanatide can be found in the 
investigator’s brochure (IB). 
 
The most recently completed clinical trials in population of patients with CIC were two Phase 3 
studies SP304203-00 and SP304203-03.  The objectives of these double-blind, placebo-
controlled, parallel-group studies were to evaluate the safety and efficacy of 3 mg and 6 mg 
doses of plecanatide administered once daily for 12 weeks in a population of patients with CIC – 
male and female patients ages 18 to 80 years. Overall, safety findings were consistent with 
earlier observations from previous studies and indicate that 12 weeks of plecanatide 
administration at doses up to 6 mg are generally well tolerated by patients with CIC. 
 
In the SP304203-00 study, a total of 1394 patients were randomized, and 1389 patients received 
at least one dose of study drug at 164 clinical sites in the US and Canada. The two doses of 
plecanatide (3 mg and 6 mg) that were evaluated over 12 weeks of treatment in CIC patients in 
this study were generally well tolerated and provided safety observations similar to those 
associated with exposure to placebo. The percentage of patients (34.3%) in the plecanatide 
groups reporting at least one TEAE was not substantially different from the percentage of 
patients in the placebo group (32.8%).  
 
Overall, 469 of the 1389 (33.8%) patients in the Safety Population reported at least one TEAE. A 
total of 818 TEAEs were reported across all treatment groups. Of the 469 patients, 150 patients 
(32.8%) were in the placebo group, 168 patients (35.4%) were in the 3-mg plecanatide group, 


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and 151 patients (33.0%) were in the 6-mg plecanatide group. The highest rate of patients 
reporting a TEAE (35.4%) and the largest number of reported TEAEs (290) occurred in the 3-mg 
plecanatide group. The percentage of patients in the plecanatide groups reporting at least one 
TEAE, however, was not substantially different from the percentage of patients in the placebo 
group.  
 
Treatment-emergent AEs experienced by ≥ 2.0% of patients (in any treatment group) included 
diarrhea (5.9%, 5.5% − 3-mg and 6-mg plecanatide groups, respectively); nasopharyngitis (2.4% 
− 6 mg plecanatide); sinusitis (2.1% − 3 mg plecanatide); and in the placebo group, urinary tract 
infection (2.2%), and back pain and headache (2.0% each). Diarrhea (59 [4.2%]) and 
nasopharyngitis (23 [1.7%]) were reported by the highest percentage of patients overall.  
 
In the SP304203-03 study, a total of 1410 patients were randomized and 1402 patients received 
at least one dose of study drug at 162 clinical sites in the US. The two doses of plecanatide (3 mg 
and 6 mg) that were evaluated over 12 weeks of treatment in CIC patients in this study were 
generally well tolerated and provided safety observations similar to those associated with 
exposure to placebo. The percentage of patients (26.5%) in the plecanatide groups reporting at 
least one TEAE was not substantially different from the percentage of patients in the placebo 
group (24.7%).  
 
Overall, safety findings were consistent with earlier observations from previous studies and from 
the other phase 3 study of identical design and indicate that 12 weeks of plecanatide 
administration at doses up to 6 mg are generally well tolerated by patients with CIC. 
Overall, 372 of the 1402 (26.5%) patients in the Safety Population reported at least one TEAE. A 
total of 618 TEAEs were reported across all treatment groups. Of the 372 patients, 115 patients 
(24.7%) were in the placebo group, 120 patients (25.7%) were in the 3-mg plecanatide group, 
and 137 patients (29,2%) were in the 6-mg plecanatide group. The highest rate of patients 
reporting a TEAE (29.2%) and the largest number of reported TEAEs (226) occurred in the 6-mg 
plecanatide group. The percentage of patients in the plecanatide groups reporting at least one 
TEAE, however, was not substantially different from the percentage of patients in the placebo 
group.  
 
Treatment-emergent AEs experienced by ≥ 2.0% of patients (in any treatment group) included 
diarrhea (3.2%, 4.5% − 3-mg and 6-mg plecanatide groups, respectively) and headache (2.1 % − 
3 mg and 6 mg plecanatide groups each). The percentage of patients who reported diarrhea 
appeared to correlate with dose of plecanatide treatment.  
 
2.2 
OBJECTIVES 
2.2.1 
Primary Objective 
The primary objective is to evaluate the safety and efficacy of 3 different doses of oral 
plecanatide taken once daily for 8 weeks as treatment for CIC in adolescents 12 to less than 18 
years of age. 
2.2.2 
Secondary Objectives 
Secondary objectives are: 


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• To estimate the pharmacokinetic (PK) parameters of plecanatide in this patient population (to 
the extent possible, since plecanatide is not expected to be absorbed) 
• To evaluate the effect of 3 selected dose levels of plecanatide on stool consistency and relief 
of CIC-related symptoms in adolescents 12 to less than 18 years of age 
• To assess the effect of 3 selected dose levels of plecanatide on the frequency of complete 
spontaneous bowel movements (CSBMs)  
2.2.3 
Rationale for Dose Selection 
Safety and efficacy data with plecanatide in adult CIC clinical trials performed to date has 
defined a safe and effective dose roughly in the range of 0.05 mg/kg to 0.1 mg/kg. Data suggest 
that children aged 4 years through 16 years appear to have a GC-C receptor density more 
reflective of a “mature” intestine (Cohen, 1988). Although safety of a particular dose cannot be 
taken for granted, it is more likely that children in this age group will respond to a GC-C agonist 
similarly to adult patients. Thus, the expectation is that ≤ 0.05 mg/kg should represent safe and 
effective doses for treatment of CIC in adolescents ages 12 to 17 years under study in this 
protocol. There are few data that might shed light on potential physiological differences between 
adults and children in terms of pharmacological dose-responsiveness to GC-C agonists.  
 
Based on considerable PK experience in the adult population it is known that plecanatide is 
essentially unabsorbed from the human GI tract in the dose range proven effective for the 
treatment of adult CIC. There is no expectation that pediatric patients will differ in this respect. 
Therefore, the doses selected for an adolescent population are anticipated to be safe and well 
tolerated. 
 
2.3 
RISK-BENEFIT ASSESSMENT 
The most common TEAEs in adult patients treated with plecanatide have been diarrhea and other 
gastrointestinal (GI)-related symptoms such as abdominal cramps, gas, and bloating Investigator 
Brochure (IB) Ed. 8.0 for Plecanatide, 1/2016. It is expected that the plecanatide safety profile 
observed in the 12 to < 18-year old pediatric population will be similar to that observed in adult 
patients with CIC.  
 
The amount of blood to be drawn during the course of this study (approximately 57 mL for the 
majority of patients, and 81 mL for patients participating in the intensive PK analysis) is not 
considered to be a risk to adolescent patients qualified for enrollment in this study. 
 
2.4 
CRITERIA FOR EVALUATION OF THE STUDY 
The efficacy and safety endpoints are described below. For information concerning the analyses 
of these endpoints, see Section 8.8 and Section 8.10 respectively. 
2.4.1 
Efficacy Endpoints 
2.4.1.1 Primary Efficacy Endpoint  
The primary efficacy endpoint is the proportion of responders for the last 2 weeks of the 
Treatment Period (responder = a child who experiences >3 SBMs per week for each of the last 
two weeks of the treatment period) compared to placebo and across treatment groups.   


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2.4.1.2 
Secondary Efficacy Endpoints  
The secondary efficacy endpoints are:  
• Change from baseline in weekly average stool consistency (BSFS) score over the 8-week 
treatment period, and by study week 
• Change from baseline in the weekly rate of SBMs, by study week 
• Change from baseline in the weekly rate of CSBMs over the 8-week treatment period, and by 
study week 
2.4.1.3 Additional Efficacy Endpoints 
Additional efficacy endpoints related to CIC symptoms are:  
• Change from baseline in abdominal pain, by study week 
• Change from baseline in abdominal bloating, by study week 
• Change from baseline in straining during a BM, by study week 
• Change from baseline in pain with defecation, by study week  Change from baseline in 
excessive flatulence, by study period 
• Change from baseline in frequency of fecal incontinence, by study period 
2.4.1.4 Patient Reported Outcomes  
The following patient reported outcomes will be assessed (see Appendix E for the assessment 
instruments used for these endpoints): 
• 
PGA 
• 
PAC-SYM 
• 
PAC-QOL 
2.4.1.5 Exploratory Efficacy Endpoints 
The following exploratory endpoints will be assessed (see Section 8.8.4 for definitions of these 
endpoints): 
 
• 
4/8 Week SBM 3 + 1 Responder 
• 
6/8 Week SBM 3 + 1 Responder 
• 4/8 Week CSBM 3 + 1 Responder 
• 6/8 Week CSBM 3 + 1 Responder 
2.4.2 
Pharmacokinetic Endpoints  
Single dose and steady state PK of plecanatide and its major metabolite SP-338 (population 
modeling): 
 
• Plasma concentration of plecanatide and SP-338 (Note: measurable plecanatide/SP-338  
levels have not been observed in the adult population)  
• PK parameters, including Cmax, Tmax, and Cmin (only if sufficient number of plecanatide levels 
can be measured to allow computation of these parameters) 
2.4.3 
Safety Endpoints 
The following safety endpoints will be assessed: 
• Frequency of treatment-emergent adverse events (TEAEs) 
• Withdrawals due to adverse events and serious adverse events 


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Clinically important changes in laboratory tests, vital signs, and ECGs will be presented. 
 
2.5 
JUSTIFICATION OF THE STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, parallel group, Phase 2b study evaluating 
plecanatide 8-week treatment in adolescent patients with CIC.  
 
Randomization and double-blind components of the study design are used to minimize bias in 
treatment group assignment and investigator/study personnel/patient bias, respectively, during 
the study. The fixed dose and time on study drug are the most objective ways to assess the 
therapeutic effect and safety of an investigational agent relative to placebo. The treatment period 
is 8 weeks, which is sufficient time to test the durability of response. 
2.6 
PLANNED SAMPLE SIZE AND NUMBER OF STUDY CENTERS 
Approximately 120 patients (~ 30 patients per treatment group) will be recruited for this study at 
approximately 40 clinical sites in the USA. The patients will be enrolled in this multi-center 
outpatient study by gastroenterologists, internists, and general medicine practitioners who have 
been qualified as Investigators. 
 


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3 
STUDY POPULATION 
Patients must meet all of the inclusion criteria and none of the exclusion criteria listed below to 
be enrolled in the study. 
3.1 
INCLUSION CRITERIA 
A patient will be eligible for study participation if he or she meets all of the following criteria: 
1. Male or female adolescents 12 to less than 18 years of age. 
2. Diagnosed with CIC based on the Rome III criteria for child/adolescent functional 
constipation (Appendix A). 
3. Patient is able to voluntarily provide written, signed, and dated (personally and via a legally 
authorized representative [LAR]) assent/informed consent as applicable to participate in the 
study. 
4. Patient and patient’s parent/LAR demonstrates an understanding, ability, and willingness to 
fully comply with study procedures (e.g., acceptance of venipuncture, patient willing and 
able to swallow tablets, acceptance of urine drug screen for opiates) and restrictions. 
3.2 
EXCLUSION CRITERIA  
A patient will be excluded from the study if he or she meets any of the following criteria: 
1. The patient has a mental age <4 years in the investigator’s opinion. 
2. The patient has previously been diagnosed with anorectal malformations, neurological 
deficits, or anatomical anomalies that would constitute a predisposition to constipation. 
3. The patient currently requires iron supplements, amitriptyline, or other tricyclic 
antidepressants for depression, opioid-containing medications or compounds for pain, or has 
other conditions that require medications known to cause constipation. A patient with an 
onset of constipation prior to the use of these medications and who has been on a stable dose 
for at least 8 weeks prior to Screening might be considered eligible for this study if the 
investigator deems these medications do not significantly contribute to the patient’s 
constipation. Screening of these patients needs to be approved by the medical monitor and 
the sponsor. 
4. The patient is pregnant or lactating. 
5. The patient, if female of childbearing potential (defined as postmenarche), does not agree to 
practice 1 of the following medically acceptable methods of birth control throughout the 
study: 
• Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal 
contraceptives for a minimum of 1 full cycle (based on the patient’s usual menstrual 
cycle period) before study drug administration. 
• Total abstinence from sexual intercourse since the last menses before study drug 
administration. 
• Intrauterine device. 


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• Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or 
cream. 
6. The patient follows a diet not considered normal by the investigator for the patient’s age, 
relative to variety of food, caloric content, and quantity. The patient must have been on a 
stable diet for at least 30 days weeks prior to Screening. 
7. The patient’s mobility or normal exercise tolerance is compromised in the investigator’s 
opinion. 
8. The patient has a history of an eating disorder.   
9. The patient has clinical or laboratory signs and symptoms of significant cerebral, respiratory, 
renal, hepatobiliary, pancreatic, intestinal (including acute appendicitis, inflammatory bowel 
disease, or undiagnosed abdominal pain), endocrinologic, or infectious disease that in the 
investigator's judgment could interfere with study assessments or completion of the study.  
(Note: A patient with a history of thyroid disease may be enrolled if he or she has normal T3 
and T4 at Screening. If the patient is taking medication for active thyroid disease, his or her 
T3 and T4 level must be within normal limits and the dose of any medication used to treat it 
must be stable for at least 30 days prior to Screening.) 
10. The patient has any other medical condition or is receiving concomitant medication or 
therapy that would in the investigator’s opinion compromise his or her safety or compliance 
with the study protocol or compromise data collection. 
11. The patient has a history or evidence of drug or alcohol abuse in the 12 months before 
Screening. 
12. The patient has a hypersensitivity, allergy, or contraindication to plecanatide. 
13. The patient has received any experimental drug, including linaclotide and lubiprostone, or 
experimental therapy within 30 days of study start. 
14. The patient is unable to tolerate protocol-prescribed rescue medication (Dulcolax®), or 
unwilling to use it as the only laxative for the duration of the trial. 
15. The patient has taken a protocol-prohibited medication prior to randomization. 
16. The patient and his or her parent/guardian are unable to communicate well with the study 
staff and comply with the study requirements (restrictions, appointments, and examination 
schedule). (The patient must be able to complete all required Daily BM and Symptom 
electronic diary entries during the Screening/Baseline period and for the duration of the 
study.  The patient must also agree to receive a reminder daily via phone should he or she not 
complete the daily electronic diary entries.)   
Exclusion Criteria Based on Baseline Diary Entries 
17. Completion of < 5 of the 7 required daily diary entries in each week of the 2-week baseline 
diary assessment. 
18. Use of rescue medication (Dulcolax®, bisacodyl) for more than 2 days during either of the 
two weeks of the 2-week baseline diary assessment. 
19. ≥ 3 SBM per week for either week of the 2-week baseline diary assessment.  
3.3 
PREVIOUS AND CONCOMITANT MEDICATIONS 
Any medication the patient takes other than the study drug, including herbal and other non-
traditional remedies, is considered a concomitant medication.  The following information must 


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be recorded in the eCRF for each concomitant medication:  generic name, route of 
administration, start date, stop date, dosage, and indication.  Any changes in the dose or regimen 
of a concomitant medication must also be recorded in the eCRF. 
 
At the Screening visit, patients will be asked what medications they have taken during the last 30 
days.  At each subsequent study visit, patients will be asked what concomitant medications they 
are currently taking.  Use of rescue medication will be recorded daily in the BM Diary and 
should not be included under concomitant medications. 
3.3.1 
Permitted Concomitant Medications 
Rescue Medication (RM) – Dulcolax®  
 
Dulcolax® 5 mg tablets will be dispensed to patients at Visit 1, and re-supplied at the study visits 
as needed. From Visit 1 and for the duration of the trial, only protocol supplied Dulcolax® is to 
be used as the “rescue medication” (laxative) - no other laxatives are allowed. As per Dulcolax® 
package insert (directions for use), Dulcolax® “may be taken 1 to 2 tablets as a single dose per 
day”. 
 
Patients are instructed to take rescue medication only if it has been at least 72 hours since 
their last bowel movement. A patient is therefore expected to have no more than two days of 
RM use in any given week. 
  
Rescue medication usage will be recorded daily via the electronic diary. Sites will review rescue 
medication use with patients during their study visits and have the option to discontinue 
participation of patients who do not adhere to rescue medication guidelines. 
Patients are advised NOT to take rescue medication for the period from 24 hours before to 72 
hours after Day 1 of dosing.  This avoids confounding the data collected in the first week of 
study drug administration and allows for accurate determination of the time to first BM.   
Dulcolax® will be distributed to sites by Sharp Corporation.  Sites may order additional bulk 
supplies of rescue medication by submitting a Dulcolax® Request Form. Supplies of Dulcolax® 
will not be reconciled at the completion of the study.  Sites must track inventory of rescue 
medication supplies for the purpose of ensuring adequate quantities for re-supplying patients as 
needed.  The site’s supply of rescue medication will not be managed nor automatically re-
supplied. 
3.3.2 
Prohibited Prior and Concomitant Medications and Supplements 
The following medications, laxatives, and supplements are prohibited within 15 days prior to 
the Screening visit and for the duration of the study, unless otherwise indicated: 
• Oral anticholinergic agents (topical and inhaled anticholinergics are allowed) 
• Drugs with activity at the 5-HT4, 5-HT3, and 5-HT2b receptors 
• Antidiarrheal agents including Pepto Bismol™, kaolin, and opiates 
• Drugs known to cause diarrhea such as orlistat, acarbose, misoprostol, and colchicine 
• Bile acid sequestrants (cholestyramine and colestipol) 
• Amitiza® (lubiprostone) 


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• Linzess®/Constella® (linaclotide) 
• Resolor® (prucalopride)Antibiotics, including rifaximin, and opioids, including tramadol or 
opiate antidiarrheals (diphenoxylate, and loperamide) are generally prohibited.  However, 
short-term (<15 days) use of opioids or antibiotics for the treatment of AEs or intercurrent 
illness may be administered during the Screening Period prior to Visit 2 (Day 1) or after 
randomization in the study as long as they are reported.  If a patient needs to be started on an 
antibiotic or a narcotic during the screening period, the patient’s Visit 2 may be delayed to 
allow for discontinuation of these medications at least 3 days before randomization. 
 
Prohibited drugs when required and used to treat TEAEs are allowed. 
The following drugs are allowed only if the patient has been on a stable dose for the 8 weeks 
prior to the Screening/Baseline Period and the patient agrees to remain on this dose for the 
duration of the study. 
• Anticonvulsants 
• Antidepressants  
• Calcium channel blockers 
• Proton pump inhibitors and H2 antagonists 
• Antihistamines that have primarily anti H1 activity (eg, cetirizine, loratadine, and 
chlorpheniramine) 
• Bulking agents (eg, psyllium [Metamucil®] methylcellulose [Citrucel®], calcium 
polycarbophil) 
Thyroid hormone supplementation: levothyroxine (T4) or natural desiccated thyroid hormone or 
liothyronine (T3) are allowed only if the patient has been on a stable dose for the 30 days prior to 
the 2-week Screening/Baseline Period and remains on this dose for the duration of participation 
in the study. 
 
Prohibited Laxatives 
All laxatives (except for rescue medication as described in the following list) will be prohibited 
from the Screening Visit (Visit 1) and onward for the duration of the study (including 2 weeks 
posttreatment).  This includes the following: 
• Lactulose 
• Stimulant laxatives, including senna (Ex-Lax®) and sennosides (eg, Senokot®), cascara 
sagrada, anthraquinones, castor oil, aloe, or other 
• Osmotic laxatives (eg, polyethylene glycol 3350 [MiraLAX®], magnesium hydroxide [Milk 
of Magnesia®], magnesium sulfate [Epsom Salts®] sodium biphosphate [Phospho-Soda®], 
saline laxatives [magnesium citrate], glycerine suppositories, glucitol [Sorbitol®] lactulose) 
 


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• Bisacodyl (eg, Dulcolax®, Carter’s Little Pills®, Alophen®, Correctol®) and other 
diphenylmethane laxatives (phenolphthalein). Note:  See rescue medication exception in 
Section 3.3.1 
• Stool softeners (docusate sodium, eg, Colace®) 
 
3.4 
DIETARY INTAKE 
A stable dietary intake should be maintained including high fiber diet, fiber supplements, 
vitamins and minerals, probiotics, fish oil, during the study.  Patients must have been on a stable 
dietary regimen for at least 30 days before Visit 1, and are expected to remain on that diet, 
including all supplements, for the duration of the study. 


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4 
VARIABLES AND METHODS OF ASSESSMENT 
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
4.1.1 
Patient Demography 
Patient demography consists of: 
• Age at screening (date of birth) 
• Race 
• Ethnicity 
• Sex (Gender) 
• Height (m), without shoes  
• Weight (kg) and BMI 
BMI will be calculated by measuring the patient’s height (without patient wearing shoes) and 
weight and using these measurements (in meters and kilograms) in the formula:  BMI (kg/m²) = 
weight (kg) ÷ height² (m²) 
4.1.2 
Disease and Medical History 
A complete medical history, including history of GI diseases, should be recorded for all patients.  
Source documentation for diagnoses, previous treatments and interventions, where available, 
should be included in the patient’s medical record to facilitate source documentation verification.  
Confirmation of diagnosis of CIC is required as part of evaluation for this study; if not 
previously documented in the patient’s medical history, the diagnosis must be included in the 
patient’s medical record for the purpose of source document verification. 
4.1.3 
Previous Medications and Diet 
At the Screening Visit (Visit 1), the clinical site will ensure the patient is not or has not been on 
prohibited medications, supplements or investigational agents during the specified time (see 
Section 3.3.2).  If the patient has used a prohibited medication within the proscribed time period 
prior to Visit 1, the site needs to assure that the required washout period for the medication is 
completed before commencement of the 2-week baseline diary assessments. Previous 
medications will be documented as described in Section 3.3. 
 
The diet history of each patient will be reviewed at Screening (Visit 1) to determine if the patient 
has been on a stable diet for the last 30 days, and whether the patient agrees to remain on that 
diet for the duration of the study.     
4.2 
EFFICACY VARIABLES 
4.2.1 
Data Collected via the Electronic Diary 
At the Screening Visit (Visit 1), patients will be instructed on the use of the electronic diary and 
the importance of daily diary reports. Episodic or “real time” calls should be made at the time of 
each bowel movement or use of rescue medication during the course of the day. End of Day calls 
should be made only once per day (between 7 pm to 11:59 pm each day). Patients will begin 
using the electronic diary following training at Visit 1 and will continue using it through 
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The electronic diary will be activated at the Screening Visit (Visit 1) in order for the patient to 
become familiar with its daily use to record their BMs, rescue medication intake and constipation 
symptoms.  Note that any data entered prior to the beginning of the 2-week baseline diary 
assessment will be utilized for assessment of compliance only and will not be saved. 
The electronic diary is designed for: 
 
• Episodic reporting of each bowel movement (BM) and rescue medication (RM) use in 
“real-time” as they occur throughout a 24-hour period (Patients may report BMs and RM use 
as often as necessary); 
• End-of-Day daily reporting constipation-related symptoms (and BM/RM if not already 
reported as an ‘episodic report’) at a specific time each evening.  Patients who have not 
completed the prompted evening call will receive an automated reminder (via phone) each 
evening. 
 
To remain eligible for the study, patients must complete at least 5 of the 7 days of electronic 
End-of-Day diary entries for each of the 2 weeks of Baseline diary period.  
 
Compliance with diary entries should be a focus for patient education at all study visits. 
 
The following endpoints will be assessed using data collected via the electronic diary: 
 
Frequency and Completeness of Bowel Movements 
Patients will be asked to report in “real time” the numbers of BMs they experienced each day, 
the time of each BM, and the completeness of evacuation in the daily BM Diary.  Frequency of 
BMs is one aspect of the primary endpoint for evaluation of study drug efficacy. 
 
Stool Consistency—Bristol Stool Form Scale (BSFS) 
Patients will be asked to rate their stool consistency according to the BSFS (see Appendix C), 
which will be provided to them in the form of a laminated card (and will appear on the 
appropriate electronic hand-held device screen) at the Screening Visit (Visit 1), and may be 
referred to as often as necessary throughout the Screening, Treatment and Posttreatment Periods.  
The BSFS is a validated measure of stool consistency commonly used in clinical trials. 
 
Use of Rescue Medication (RM)  
As part of the daily diary, the patient will be questioned concerning the use of provided rescue 
medication (Dulcolax®), including time of use, frequency of use, and amount of rescue 
medication used.  Use of rescue medication will determine whether a BM was spontaneous, but 
only this aspect of rescue medication use is part of the primary endpoint. 
 
Constipation-related Symptoms 
The patient will also record in the electronic diary the frequency and severity of several CIC-
related gastrointestinal symptoms. These symptoms include abdominal pain, abdominal bloating, 
abdominal discomfort, straining during bowel movement and pain with defecation.  Patients will 
be asked to rate their symptoms on an 11-point Numeric Rating Scale from 0 (NO) to 10 
(WORST POSSIBLE) (See Appendix D). 


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4.2.2 
Variables Assessed by Questionnaires Administered at the Study Site 
NOTE:  Standard definitions for flatulence and fecal incontinence will be included in the 
study procedure manual  
Excessive Flatulence 
Excessive flatulence (NOTE:  the term “excessive” is meant to be interpreted by each patient in 
terms of what he/she perceives as “more than normal” either for him or herself or as compared to 
his peers/friends) will be assessed via the IWRS at each study visit.  Patients will be asked to rate 
their “excessive flatulence” using the IWRS on a scale from 0 to 4, where 0 = none, 1 = mild, 2 = 
moderate, 3 = severe, and 4 = very severe.  
Fecal Incontinence 
The following question will be asked at each study visit using the IWRS as follows: 
Visit 1: 
Have you ever experienced fecal incontinence?  YES 
NO 
If YES, Approximately how many episodes of fecal incontinence did you experience over the 
last two weeks? 
0                1                2                  3                    more than 3 
 
Visits 2 through 5: 
Approximately how many episodes of fecal incontinence did you experience over the last two 
weeks? 
0                1                2                  3                    more than 3 
 
Three standardized patient questionnaires (see Appendix E) will also be administered during the 
scheduled study site visits to assess the severity of constipation and impact of the disease on the 
patient’s quality of life.  
 
Patient Assessment of Constipation—Symptoms (PAC-SYM) 
The PAC-SYM is a previously validated questionnaire which is made up of 12 questions 
addressing specific symptoms of constipation.  The patient will be asked to rate each symptom 
on a scale of 0 (“absent”) to 4 (“very severe”).  
Patient Assessment of Constipation—Quality of Life (PAC-QOL) 
The PAC-QOL is a previously validated questionnaire is made up of 28 questions which assess 
how the patient has been impacted by constipation over the specified period.  The questions 
measure worries and concerns, physical discomfort, psychosocial discomfort, satisfaction, and 
overall effects on the patient’s quality of life.  Patients will be asked to give their response on a 
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Patient Global Assessment (PGA) Questionnaire 
The Patient Global Assessment (PGA) questionnaire is designed to provide an assessment of 
constipation severity before, during, and after treatment. The PGA is reproduced in Appendix E.  
 
4.3 
SAFETY VARIABLES 
4.3.1 
Collection of Adverse Events 
It is the responsibility of the Investigator to ensure that all AEs are collected.  This includes both 
serious and non-serious AEs derived by spontaneous, unsolicited reports of patients, by 
observation, and by routine open questionings e.g., “How have you felt since I last saw you?” 
NOTE:  Specific GI symptoms are recorded daily in the GI symptom diary (abdominal bloating, 
abdominal pain, abdominal discomfort, straining with a bowel movement and pain with 
defecation) in response to standardized questions. The frequency and severity ratings recorded 
for these symptoms are both an efficacy and safety record and therefore these events should 
generally NOT be recorded elsewhere as adverse events.  
For Definitions, Assessments of AEs, Causality, Severity, Recording and Reporting of Adverse 
Events and Follow Up, see Section 7. 
4.3.2 
Laboratory Variables 
Laboratory assessments will be performed by a central laboratory, as identified in the List of 
Study Personnel.  Please see the Laboratory Manual for detailed instructions regarding the 
collection, processing, and handling of laboratory samples. 
The laboratory variables presented in Table 1 will be assessed in accordance with the Schedule 
of Assessments (Table 2).  Routine laboratory tests (serum chemistry [including electrolytes], 
hematology, and urinalysis) will be performed at each study visit, from Screening to 
Posttreatment.  A 6- to 12-hour fast is advised for Visit 1 and is highly recommended prior to all 
visits when blood sampling is scheduled. The timing of other safety tests (e.g., pregnancy tests 
and drug screen) is presented in the Schedule of Assessments (Table 2). 
 
 
 


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Table 1 
Laboratory Assessments 
Hematology: 
Erythrocytes, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
neutrophils, eosinophils, basophils, lymphocytes, monocytes, platelets, leukocytes, 
hemoglobin, and hematocrit 
Urinalysis: 
Specific gravity, pH, protein, glucose, ketones, blood, and microscopic examination of 
sediment 
Serum chemistry: 
Alanine aminotransferase, aspartate aminotransferase, creatinine, alkaline phosphatase, total 
bilirubin, direct bilirubin, blood urea nitrogen, total protein, albumin, uric acid, glucose, and 
cholesterol. 
Hormone: 
TSH at screening to determine eligibility (T3 and free T4 if TSH is out of range) 
Electrolytes: 
Sodium, potassium, chloride, magnesium, phosphorus, calcium 
Pregnancy test: 
Urine pregnancy tests via dip sticks (performed on-site) 
Immunogenicity: 
Anti-plecanatide antibody serum assessment 
PK: 
Plecanatide (and SP-338) plasma assessment 
Urine screen for 
select opioids:  
Methadone, morphine, and oxycodone. 
At Screening, any laboratory abnormality considered clinically significant by the Investigator or 
the Medical Monitor will render the patient ineligible for study enrollment. 
Approximately 2.0 mL of blood will be drawn for each hematology sample and approximately 
5.0 mL of blood will be drawn for each serum chemistry sample.  The volume of blood that will 
be required for these laboratory tests during the duration of the study, not including possible 
repeat tests, will be approximately 28 mL. 
4.3.3 
Immunogenicity and Pharmacokinetic (PK) Assessments 
Approximately 3.5 mL of blood for immunogenicity testing – measurement of serum 
concentration of anti-plecanatide antibodies, will be collected (and banked) from all patients, as 
specified in the Schedule of Assessments. The total volume of blood required for 
immunogenicity testing during the study will be approximately 11 mL. 
Blood samples (6 mL each) for measurement of plecanatide and SP-338 concentration will be 
collected from all patients on Day 1 of the Treatment Period (15 min prior to dosing) and at the 
Week 4 and Week 8 visits. Intensive sampling for formal PK analysis will be conducted in a 
subgroup of approximately 40 patients (10 patients per each treatment group) who consent to the 
additional blood sampling at 30, 60, 90, and 120 minutes following study drug administration on 
Day 1 of treatment.  The actual sampling times will be recorded on the eCRF for each PK 
sample. The total blood volume collected for PK analysis will be about 18 mL for the majority of 
patients, and 42 mL for patients participating in the intensive PK analysis. Only samples from 
patients randomized to active treatment will be analyzed. 


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Orally delivered plecanatide is not absorbed in the adult population nor is it expected to be 
absorbed in the 12 to <18-year-old age group.  However, should any measurable levels of 
plecanatide or its primary metabolite (SP-338) be observed, to the extent possible, 
pharmacokinetic parameter estimates (Cmax, Cmin, tmax) will be undertaken.  Nominal sampling 
time will be used for all parameter estimation. 
In order to maintain the double-blind status of the study, results of the pharmacokinetic assay 
will be blinded to the investigators, to the sponsor, and monitors during the course of the study.  
The procedure for the collection, handling, storage, and shipment of the samples for PK and 
immunogenicity analysis are specified in the site reference laboratory manual. 
4.3.4 
Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of Assessments 
(Table 2).  Measurements should be performed after the patient has been seated for at least 
5 minutes. A clinically significant abnormality at screening may result in the patient being 
excluded from the study. 
• Blood pressure (systolic and diastolic; mmHg) 
• Heart rate (beats per minute) 
• Oral body temperature (°C) 
• Respiration rate (breaths per minute) 
4.3.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed in accordance with the Schedule of Assessments 
(Table 2).  A clinically significant abnormality at Screening, as determined by the PI, will result 
in the patient being excluded from the study. 
4.3.6 
Physical Examinations 
Physical examinations (PEs) will be performed in accordance with the Schedule of Assessments 
(Table 2). A clinically significant abnormality at Screening may result in the patient being 
excluded from the study. 
The PE will be based on the following body systems:  general appearance, head (ear, eyes, nose, 
and throat), cardiovascular, respiratory system, abdomen, musculoskeletal, neurological, lymph 
nodes, and skin.   
Neither a urogenital exam nor a digital rectal examination is required for the study but should 
take place at Screening if the Investigator feels that there may be a confounding factor for 
constipation symptoms e.g., anal pathology, or a rectocele in a female patient. 
NOTE:  The presence of other alarm symptoms (lower GI bleeding, iron-deficiency anemia, 
unexplained clinically-significant weight loss and systemic signs of infection or colitis) preclude 
patient eligibility for this trial, unless the PI has adequately assessed each alarm symptom and 
has discussed their medical relevance with the Medical Monitor, including the potential need for 
colonoscopic evaluation of the symptoms. 


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Height will be measured at the Screening Visit only.  Weight will be measured as part of all 
physical examinations; the same calibrated scale should be used for each measurement.  BMI 
calculation will use the height and weight recorded at Visit 1 (Screening Visit).     
4.3.7 
Concomitant Medications and Diet 
Concomitant medications or supplements will be reviewed and documented at each study visit to 
ensure prohibited/restricted substances are not being taken. Concomitant medication will be 
documented as described in Section 3.3. 
Drugs required to be at a stable dose prior to screening including thyroid hormone replacement 
(30-day stabilization) should not be initiated or dose adjusted during the study.   
Diet will be reviewed at each study visit to ensure that each patient is maintaining an acceptable 
and stable diet throughout the study.  Any change in diet considered clinically significant by the 
Investigator will be documented in the eCRF.   
4.3.8 
Rescue Medication 
Use of rescue medication will be reported in the electronic diary.  Patients will be instructed to 
take rescue medication only if 72 hours have elapsed since their last BM and reminded of this 
instruction at each visit.   


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5 
STUDY CONDUCT 
5.1 
SCHEDULE OF ASSESSMENTS 
Patients will provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of 
Assessments Table 2. Throughout the study, every reasonable effort should be made by study 
personnel to follow the timing of assessments and procedures in the Schedule of Assessments for 
each patient. If a patient misses a study visit for any reason, the visit should be rescheduled as 
soon as possible. 
Table 2 
Schedule of Assessments 
Study Period 
Screening/ 
Baseline 
Treatment 
Post-treatment 
Follow-up 
Visit 
Study Week 
Visit 1  
Week -4  
Visit 2 
Week 1 
Visit 3 
Week 4 
Visit 4     
Week 8(EOT)  
or EW 
Visit 5 
Week 10(EOS)  
Visit Day (Window) 
Day -28 
Day 1 
Day 28±3 
Day 56 +3 
Day 70 +3 
Informed Consent/Assent 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
Demography 
X 
 
 
 
 
Medical History (including GI and bowel habits) 
X 
X 
 
 
 
Prior and Concomitant Medications/Diet 
X 
X 
X 
X 
X 
Physical Examination a 
X 
X 
X 
X 
X 
Vital Signs b 
X 
X 
X 
X 
X 
Pregnancy Test (urine)c 
X 
X 
X 
X 
X 
Urine Drug Screen for Opioids d 
X 
X 
 
 
 
Serum Chemistry, Hematology, Urinalysis 
X 
X 
X 
X 
 
TSH (include T3 and T4 only if TSH is 
abnormal) 
X 
 
 
 
 
Immunogenicity Test (serum collection) 
 
X 
X 
X 
 
Plecanatide/SP-338 Concentratione (plasma 
collection)  
 
X e 
X 
X 
 
PK Sampling (30, 60, 90 and 120 mins post-dose 
in a subset of patients)  
 
X 
 
 
 
12-lead Electrocardiogram f 
X 
X* 
 
X 
 
Electronic Diary Training and Activation g 
X 
 
 
 
 
Diary Eligibility h / Compliance Check  
 
X h 
X 
X 
 
Randomization 
 
X 
 
 
 
Study Drug Dispensation and Administrationi 
 
X 
X 
 
 


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Study Period 
Screening/ 
Baseline 
Treatment 
Post-treatment 
Follow-up 
Visit 
Study Week 
Visit 1  
Week -4  
Visit 2 
Week 1 
Visit 3 
Week 4 
Visit 4     
Week 8(EOT)  
or EW 
Visit 5 
Week 10(EOS)  
Visit Day (Window) 
Day -28 
Day 1 
Day 28±3 
Day 56 +3 
Day 70 +3 
At Visit PRO Assessmentsj 
X 
X 
X 
X 
X 
Study Drug Collection and Accountability 
 
 
X 
X 
X 
Rescue Medication Dispensation 
X 
X 
X 
X 
 
Adverse Events k 
X 
X 
X 
X 
X 
 
 
 
 
 
 
EOT = end of treatment; EW = early withdrawal; EOS = end of study; GI = gastrointestinal; PK = pharmacokinetic; TSH = 
thyroid-stimulating hormone. 
a. Physical examination, including body weight measurement, will be performed at Visits 1 to 4 and EW; height is measured 
(and body mass index calculated) at the Screening Visit only.  
b. Seated blood pressure (after patient has been seated for at least 5 minutes), heart rate, respiration, temperature. 
c. Urine pregnancy test will be performed on-site for female patients; negative result must be confirmed at Screening and Day 1 
prior to randomization. 
d. Urine drug screen for selected opioids (screen includes methadone, morphine and oxycodone) will be performed on-site; a 
negative result must be confirmed prior to dispensing the study medication.  
e. 15 mins before study drug dosing. 
f. The standard 12-lead ECG will be performed in the semi-recumbent or supine position. (*) At Visit 2 (Week 1/Day 1), ECG 
will be performed prior to study drug dosing and again one hour after the study drug administration.    
g. Clinical site personnel will train patients on the use of electronic diaries at the Screening visit and remind them to make daily 
entries throughout the study, with retraining as needed. The interactive voice or web response system will provide daily 
reminders to improve compliance.  
h. Baseline diary results will be reviewed programmatically and a “Diary Eligible” or “Not Diary Eligible” report will be 
provided to the site immediately prior to randomization.  
i. Patients will take their first dose of study drug at the site on Day 1; it is recommended that for dosing at home, patients take it 
once daily at approximately the same time in the morning. 
j. Details on timing of each PRO Assessments will be included in the Study Procedure Manual. 
k. Adverse Event collection begins immediately after informed consent is signed. A symptom-directed physical examination 
should be performed as appropriate at discretion of the investigator. 
 


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5.2 
PROCEDURES BY VISIT 
5.2.1 
Visit 1: Screening (Day-28) 
Patients are often pre-screened for the study. Pre-screening information is generally obtained 
through customary practice of routine medical intake for the patients. Of note, patients who have 
completed pre-screening are not pre-qualified for participation in the study, therefore the site is 
still responsible for completing all required screening assessments in accordance with the study 
protocol. 
The patient must be screened, ideally, within 28 days before the randomization visit in the study.  
A 3-day window is allowed to complete the Day 1 visit.  The last 14 days prior to randomization 
will be used as the patient’s baseline electronic diary assessment. 
The following will be completed at the Screening Visit: 
• Obtain informed consent/assent.  The patient must provide written assent and parent or 
caregiver must provide written informed consent.  
• Assign a unique patient number.  Unique patient numbers will begin with the clinical site 
number, eg, 001 followed by a 3-digit number.  Unique patient numbers will be assigned 
sequentially by clinical site personnel accessing the EDC system.  This unique patient 
number will be kept for the duration of the study.  Patients who discontinue from the study 
before randomization will retain their unique patient number (ie, numbers from screen fail 
patients will NOT be reassigned). 
• Assess willingness and ability to maintain a stable diet and fiber supplements (if applicable) 
for the study period and to comply with not using laxatives with the exception of the rescue 
medication provided as part of the study. 
• Determine eligibility, based on Rome III criteria for child/adolescent functional constipation 
(Appendix A) 
• Verify inclusion/exclusion criteria. 
• Collect demographic information. 
• Record medical history, including GI and bowel habit history. 
• Record prior and concomitant medications and dietary history. 
• Perform a physical examination, including measurement of body weight and height.  
• Measure vital signs (seated blood pressure, heart rate, respiration, and body temperature). 
• Perform urine screen for opioids (see Section 4.3.2 for details). 
• Perform a urine pregnancy test for female patients (a negative result must be confirmed at 
Screening and on Day 1 prior to randomization). 
• Collect blood and urine samples for safety laboratory tests (serum chemistry, including 
thyroid-stimulating hormone [TSH], hematology, and urinalysis). 
• Perform 12-lead ECG in the semi-recumbent position. 


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• Have the patient complete the Excessive Flatulence and Fecal Incontinence questionnaires 
(Per Study Procedure Manual). 
• Train patients how to use the electronic diary to record their responses about BM and CIC-
related symptoms and activate the diary. 
• Distribute a laminated card with the BSFS to patients and explain how to use it to record 
stool consistency in their daily electronic diaries.   
• Ensure patients understand the importance of entering data in their diaries on daily basis for 
all questions. 
• Dispense rescue medication to patients and instruct them on the appropriate use. 
Patients who fail to qualify for randomization during the Screening Period will be considered 
Screen Failures and the reason for failure will be documented.  
Patients who screen-failed may be allowed to re-screen under certain circumstances upon review 
and approval by the Medical Monitor. 
5.2.2 
Visit 2:  Randomization / Day 1 of Treatment Period 
Study eligibility must be confirmed prior to randomization, including the following: 
• Confirm that patient has used only study-supplied rescue medication laxative (Dulcolax®) 
since Visit 1 
• Urine drug screen (see Section 4.3.2 for details) 
• Urine pregnancy test, if applicable 
• Update medical history and concomitant medications, as necessary 
The last 14 days of daily diary entries prior to randomization will be used for determination of 
baseline data.  Only patients who meet the protocol criteria for confirmation of CIC and 
demonstrate diary and RM compliance are eligible for randomization.  This eligibility 
determination will include: 
• A review of the baseline diary entries to ensure patients have completed at least 5 of the 7 
days of diary entries in each of the 2 weeks of baseline assessments  
• A review of the BM frequency data to ensure < 3 SBMs in each of the 2 weeks of the 
baseline diary assessment period 
• A review of rescue medication use to ensure patients have not used RM for more than 2 days 
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The eligibility determination based on these criteria will be programmed into the IWRS and the 
system will report out eligibility (the PI or site staff will not be responsible for evaluating diary 
data to make the diary-based eligibility determination). 
The following procedures will be performed only for patients eligible for randomization: 
Procedures prior to study drug dosing: 
• Physical examination (including body weight) and vital signs (seated blood pressure, heart 
rate, respiration, and body temperature) 
• 12-lead ECG (semi-recumbent) 
• Assess adverse events 
• Safety laboratory assessments (hematology, serum chemistry, urinalysis) 
• Confirm that patient is on a stable diet and has no significant changes in their consumption of 
liquids or fiber or their level of activity  
• Blood samples for plecanatide/SP-338 concentration and immunogenicity assessments (see 
Section 4.3.3 for details) 
• Have the patient complete all baseline PRO questionnaires (Per Study Procedure Manual).    
 
The first dose of study drug will be administered at the clinical site under supervision.  The time 
of dosing will be recorded. 
 
The following procedures will be performed after study drug dosing: 
• At selected sites and in a subgroup of patients who consented to an additional PK analysis, 
blood samples will be obtained for PK assessment 30, 60, 90 and 120 minutes after study 
drug administration 
• At one hour post dosing, the patient will have a standard 12-lead ECG performed;  clinically 
significant findings will be assessed as an adverse event 
• Dispense 4-week supply of study drug with the instructions for use and storage (as described 
in Section 6.3) 
• Distribute additional rescue medication (Dulcolax® tablets), if needed 
• Re-emphasize  the need for diary compliance, as necessary 
• Confirm the next visit and explain the importance of meeting the 3-day window for 
completion of study visits  
5.2.3 
Visit 3:  Week 4, Day 28 (± 3 days) of Treatment Period 
The following will be completed at Visit 3: 
• Collect/record unused study drug from the supply dispensed at the previous visit 
• Review the electronic diary compliance reports and re-emphasize the need for diary 
compliance, as necessary 
• Have the patient complete the PRO questionnaires (per Study Procedure Manual) 


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• Assess/record changes in concomitant medications and diet 
• Physical examination (including body weight) and vital signs (seated blood pressure, heart 
rate, respiration, and body temperature) 
• Safety laboratory assessments (hematology, serum chemistry, urinalysis) 
• Collect blood samples for immunogenicity assessments 
• Urine pregnancy test, if applicable 
• Assess adverse events 
• Dispense 4-week supply of study drug 
• Distribute additional rescue medication (Dulcolax® tablets), if needed 
5.2.4 
Visit 4:  Week 8, Day 56 (+ 3 days) of Treatment Period 
The following will be completed at Visit 4: 
• Collect/record unused study drug from the supply dispensed at the previous visit 
• Review the electronic diary compliance reports and re-emphasize the need for diary 
compliance, as necessary 
• Have the patient complete the PRO questionnaires (per Study Procedure Manual) 
• Assess/record changes in concomitant medications and diet 
• Physical examination (including body weight) and vital signs (seated blood pressure, heart 
rate, respiration, and body temperature) 
• 12-lead ECG (semi-recumbent) 
• Safety laboratory assessments (hematology, serum chemistry, urinalysis) 
• Urine pregnancy test, if applicable 
• Collect blood samples for plecanatide/SP-338 concentration and immunogenicity 
assessments 
• Assess adverse events 
• Distribute additional rescue medication (Dulcolax® tablets), if needed 
5.2.5 
Visit 5:  Week 10, Day 70 (+ 3 days) – Posttreatment Follow-up (End of Study) 
The following will be completed at Visit 5: 
• Assess/record changes in physical examination, vital signs, concomitant medications and diet 
• Perform urine pregnancy test, if applicable 
• Assess adverse events 
• Collect/record unused study drug, if not collected (per protocol) at Visit 4 
• Have the patient complete the PRO questionnaires ((per Study Procedure Manual ) 


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5.2.6 
Early Withdrawal Visit (EW) 
Patients are free to withdraw from participation in the study at any time.  Investigators may 
choose to discontinue a patient’s participation in the study if they believe it is in the patient’s 
best interest clinically.  If a patient’s post-randomization compliance is of concern, contact the 
medical monitor to discuss.  If the patient has an intervening illness that requires discontinuation 
of study participation, the patient and Investigator will follow procedures for early withdrawal.  
The following are examples of AEs that qualify for Early Withdrawal (EW): 
• A positive pregnancy test will require discontinuation from the study (see Section 7.7). 
• Changes in laboratory values, PE findings, or other assessments considered by the 
Investigator (or designee) to be clinically significant will require discontinuation from the 
study. 
• Clinically significant TEAEs, including clinically significant laboratory test abnormalities or 
SAEs regardless of relatedness to study treatment that cause the patient, investigator, or 
Sponsor to feel it is not in the patient’s best interest to continue. 
 
A patient may also be withdrawn from study drug/study by the Sponsor, regulatory authorities, 
or the institutional review board (IRB).  Patients will also be withdrawn if the entire study is 
terminated prematurely as described in Section 9.10. 
Patients who discontinue early from the study should, if possible, have an Early Withdrawal 
Visit.  The Investigator must make every effort (with proper documentation) to have the patient 
complete this final visit.  This visit should take place as soon as possible (and within 5 days) 
after the patient stops taking study drug. 
The following procedures will be performed at the Early Withdrawal Visit: 
• Collect/record unused study drug from the supply dispensed at the previous visit 
• Review the electronic diary compliance reports and re-emphasize the need for diary 
compliance, as necessary 
• Have the patient complete the PRO questionnaires (see Study Procedure Manual) 
• Assess/record changes in concomitant medications and diet 
• Physical examination (including body weight) and vital signs (seated blood pressure, heart 
rate, respiration, and body temperature) 
• 12-lead ECG (semi-recumbent) 
• Safety laboratory assessments (hematology, serum chemistry, urinalysis) 
• Perform urine pregnancy test, if applicable 
• Collect blood samples for plecanatide/SP-338 and immunogenicity assessments 
• Assess adverse events. 
• Distribute additional rescue medication (Dulcolax® tablets), if needed 
In all cases, a single, primary reason for withdrawal must be recorded on the eCRF. 
The End of Study assessments should be performed 2 weeks following the last study drug 
administration.  Patients withdrawn after randomization will not be replaced.  


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6 
STUDY DRUG 
6.1 
IDENTITY OF PLECANATIDE AND PLACEBO 
Plecanatide is a synthetic hexadecapeptide that is an analog (identical, with the exception of a 
single amino acid) of uroguanylin, a natural hormone. The chemical name, molecular formula, 
molecular weight, and amino acid sequence of plecanatide can be found in the IB provided to 
each clinical site.   
The drug product is a tablet comprised of plecanatide, microcrystalline cellulose, and magnesium 
stearate.  Matching placebo composition is identical but does not contain plecanatide.  Both 
plecanatide and placebo tablets are manufactured by UPM Pharmaceuticals (Bristol, TN) and 
packaged by Sharp Packaging Solutions (Allentown, PA).  Study supplies will be retested as 
required by the sponsor. 
6.2 
ADMINISTRATION 
Study drug will be administered for 8 consecutive weeks according to the randomization scheme 
displayed in Table 3. Each patient will take one tablet orally (by mouth) daily preferably at the 
same time each day—in the morning—with approximately 240 mL (~8 oz.) of liquid, with or 
without food. 
No dose adjustments will be allowed on this study. 
Table 3 
Treatment Arms 
Table 3: Treatment Arms 
Treatment Arm 
Treatment 
Number of Patients 
1 
0.5 mg plecanatide 
30 
2 
1.0 mg plecanatide 
30 
3 
1.5 mg plecanatide 
30 
4 
Matching placebo 
30 
  
Overdose 
Plecanatide has minimal systemic absorption, therefore standard treatment measures for the 
symptomatology being exhibited should be provided.  Notable, plecanatide was generally well-
tolerated after single doses up to 48.6 mg and multiple doses up to 9.0 mg for 12 weeks in prior 
studies. 
Individual Patient Stopping Criteria 
Adverse events due to study drug that affect individual patient safety may necessitate dose 
interruptions or early discontinuation as described in this section.   


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Plecanatide therapy in adults with CIC has caused diarrhea in 5% of patients with severe diarrhea 
occurring in 0.6% of patients.  Severe diarrhea may cause dehydration.  Pediatric patients may be 
at increased risk for diarrhea and dehydration with plecanatide therapy. 
In general, study drug dosing should not be modified for mild diarrhea (Grade 1: increase of <4 
stools per day over baseline) or mild dehydration (Grade 1: dry mucous membranes, diminished 
skin turgor) (Guidance for Industry, FDA, 2007).  If study drug is not well tolerated by an 
individual patient, treatment will be permanently discontinued for that patient.   
The following guidelines should be used in the case of moderate or severe diarrhea or 
dehydration: 
Table 4 
Individual Patient Stopping Criteria 
 
Worst Observed Toxicity Grade  
(Guidance for Industry, FDA, 2007) 
Dose Modification for Study Drug 
Diarrhea 
 
Grade 2: Increase of 4-6 stools per day over 
baseline 
No intervention required 
Grade 3: Increase of ≥7 stools per day over 
baseline, incontinence, hospitalization 
indicated 
Interrupt study drug for <7 days until resolved 
to less than Grade 2 severity. If diarrhea was 
study drug-related, permanently discontinue 
study drug.  If diarrhea was not study drug-
related, eg, viral gastroenteritis, then consider 
resuming treatment after consultation with 
Sponsor’s Medical Monitor 
Grade 4: Life-threatening consequences, 
urgent intervention indicated 
Permanently discontinue study drug 
Dehydration 
 
Grade 2: IV fluids indicated <24 hour 
Interrupt study drug for <7 days until resolved 
to less than Grade 2 severity. If dehydration 
was 
study 
drug-related, 
permanently 
discontinue study drug.  If dehydration was 
not study drug-related, consider resuming 
treatment after consultation with Sponsor’s 
Medical Monitor 
Grade 3: IV fluids or hospitalization indicated Permanently discontinue study drug 
Grade 4: Life-threatening consequences, 
urgent intervention indicated 
Permanently discontinue study drug 
 
Study Stopping Criteria 
Dosing of all patients in the study will be interrupted for at least one week if ≥2 patients 
receiving study drug develop drug-related Grade 3 diarrhea and/or dehydration or if one patient 


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develops drug-related Grade 4 diarrhea and/or dehydration.  This will allow the Sponsor to 
assess whether the trial should be stopped or modified. 
6.3 
PACKAGING, LABELING AND STORAGE 
All study centers will be provided with adequate supplies of study medication—plecanatide 
tablets at 3 dose strengths (see Table 3) and identically appearing placebo tablets, by Sharp 
Corporation.   
6.3.1 
Packaging 
Each investigational drug kit will contain a 4-week supply in blister packaging—a total of 32 
tablets, including 4 extra tablets to allow for a 3-day window extension for a study visit. 
Individually blister packaged tablets will be provided in four connected strips (each per 1 week) 
as a 4-panel key-pack that folds into a carton. The two bottom panels fold up into the two top 
panels, nesting blister cavities. Instructions for releasing a tablet from the blister dome are 
printed on the outside of the carton. 
At each dispensing visit, each patient will be given a numbered drug kit corresponding to the 
treatment group into which the patient was randomized. At the randomization visit (Day 1 of the 
Treatment Period), the eligible patient will receive one drug kit for the first 4 weeks of dosing 
(weeks 1, 2, 3 and 4).  At the Week 4 Visit, the patient will receive a new drug kit for their weeks 
5, 6, 7 and 8 of dosing.  Patients are instructed to bring their kits at the following study visit to 
allow for determination of compliance and reconciliation of supplies.  
Save all empty packaging or packaging containing unused tablets for final disposition by the 
sponsor or contract pharmacy. 
6.3.2 
Label 
Each of the investigational drug kits will have a unique label containing the following 
information:  protocol number, drug kit number, contents, directions for use, storage conditions, 
Sponsor name, address and the statements:  “Caution:  New Drug - Limited by Federal Law to 
Investigational use.  Investigational Drug – To be used by Qualified Investigator Only.  For 
Clinical Trial Use Only. Keep Out of Reach of Children under the age of 12”.  
The label will include the following fields to be completed by site personnel:  Investigator name 
and phone number, patient number and treatment weeks.  When dispensing a kit to a patient, 
complete and remove the tear off portion of the label and keep this in the source documents. At 
each monitoring visit, the source document records will be verified against the IWRS 
assignment. 
There will also be a smaller label on the carton spine that identifies the study number and drug 
kit number and Sponsor. 
6.3.3 
Storage 
The Investigator, or qualified designee, is responsible for the proper storage of the study 
medications according to the Sponsor’s recommendations and all applicable federal/state 
regulatory guidelines.  At the clinical site, plecanatide should be stored at controlled room 
temperature 20 to 25°C (68 to 77°F) in a secure area with Min / Max Temperature Recording 


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with restricted access.  Deviations from Sponsors recommendations / guidelines should be 
reported, as directed in the Site Level Temperature Excursion Reporting Form. 
Patients will be instructed to store their study drug at room temperature defined for this study as 
20 to 25°C (68 to 77°F). 
The Investigator must agree not to dispense or store the investigational drug at any location other 
than that listed on the Form FDA 1572. 
6.4 
BLINDING AND BREAKING THE BLIND 
The study will be performed in a double-blind manner.  All study drugs will be supplied in 
identical blister packs and tablets will be similar in color, smell, taste, and appearance, thereby 
assuring double-blind conditions. 
In the event of a need to break the blind, the Investigator at the clinical site will have the ability 
to break the treatment code using the IWRS.  The blind should only be broken following 
discussion on a case-by-case basis, with the Sponsor/Medical Monitor (except in a medical 
emergency). The Sponsor’s Medical Monitor will also be granted emergency code-break 
privileges using the IWRS.  All telephone calls resulting in an un-blinding event will be 
documented.  The Sponsor and CRO, as applicable, will specify who in each company is able to 
review unblinded treatment in a blinded trial. 
In the event of a treatment code-break, the time, date, reason, name, and signature of the person 
responsible for breaking the code must be fully documented in the patient’s source documents 
and any associated AE recorded.  The breaking of the blind will result in the withdrawal of the 
patient from study participation, and the patient should follow the procedures detailed for Early 
Withdrawal Visit study assessment (see Section 5.2.6).  
The overall randomization code for the study will be broken at study completion.  This will 
occur once all final clinical data have been entered into the database, data queries have been 
resolved, and the assignment of patients to the analysis sets has been completed. 
6.5 
DRUG ACCOUNTABILITY 
Acknowledgement of receipt of drug shipments and distribution of all investigational drug kits 
will be recorded using the IWRS.  The drug inventory log can be generated from IWRS at the 
site level as a standard report. 
In addition, accurate records of study drug dispensed to patients will be kept by the Investigator, 
or qualified designee, specifying the kit number, the patient number assigned, and the amount 
dispensed to each patient and the date dispensed.  This information will be available in the IWRS 
and the drug accountability log for the overall study.  At each visit after Visit X, the patient is 
asked to return their previously dispensed drug kit and the number of remaining tablets is entered 
into the eCRF for drug accountability. 
A blinded drug accountability log can also be generated from IWRS and must be available for 
inspection at each monitoring visit and at the completion of the study.  At the completion of the 
study, the Investigator will provide copies of this accountability log to the Sponsor. 


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The Investigator is responsible for assuring the retrieval of all study supplies from patients.  At 
the completion of the study, all unused investigational drug kits will be returned to a third party 
in accordance with the Sponsor’s (or designee’s) written instructions.  The Investigator must 
verify that all unused or partially used study drug supplies have been returned by the patient and 
that no remaining supplies are in the Investigator’s possession. 
6.6 
COMPLIANCE 
Patients will be advised as to how to take their daily medication and will return all unused study 
drug to the clinical site at each visit during the Treatment Period.  The number of remaining 
tablets will be counted and entered into the appropriate eCRF page for that patient.  Patients 
unwilling or unable to maintain compliance with study drug administration or procedures may be 
discontinued from the study at the discretion of the investigator in conjunction with the medical 
monitor. 


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7 
ASSESSMENT, REPORTING, RECORDING AND FOLLOW UP OF 
ADVERSE EVENTS 
7.1 
DEFINITION 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered to be drug related.  An AE can therefore be any unfavorable and unintended 
sign (including abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an investigational product or study procedure whether or not considered related to the 
product or procedure. 
NOTE:  Specific gastrointestinal symptoms related to CIC are recorded daily in the electronic 
Diary in response to standardized questions, and are BOTH efficacy AND safety response 
variables.  These symptoms are abdominal bloating, abdominal pain, abdominal discomfort, 
straining with bowel movement and pain with defecation.  The diary is a “real-time” patient 
reported outcome record that is based on “within 24 hours” patient recall.  Because these 
symptoms are considered adequately recorded in the CIC Symptom Diary, they should generally 
not also be reported in the adverse event database that relies on a much longer patient recall 
period.    In order to prevent double-recording of a single specific event, the daily CIC Symptom 
Diary record is considered the highest quality record of an event and should therefore be the only 
record of the same event. 
All AEs, including intercurrent illnesses and regardless of the source of identification (e.g., 
physical examination, laboratory assessment, electrocardiogram (ECG), reported by patient), 
occurring during the study will be documented in the eCRF.  Concomitant illnesses that existed 
before entry into the study will not be considered AEs unless they worsen during the treatment 
period. 
Adverse events occurring from the time of signing the informed consent form (ICF) up to the 
intake of the first dose of study medication will be classified as pre-existing conditions for the 
study and therefore will be recorded in the Medical History page of the electronic case report 
form (eCRF).  Serious adverse events (as defined below) occurring after the signing of informed 
consent but before randomization (i.e., during screening) will be collected and reported as such.  
A treatment emergent adverse event (TEAE) is defined as an AE that begins or worsens in 
frequency and/or severity after at least one dose of study drug has been administered. 
Minor fluctuations in laboratory values for standard monitoring (abnormal values) that the 
investigator does not consider clinically significant or related to study drug will not be recorded 
as AEs.  However, if the laboratory abnormality is associated with a diagnosis, then the AE term 
for that diagnosis will be reported. 
7.2 
EVENT OF SPECIAL INTEREST – DIARRHEA 
An increase in the frequency of BMs and loosening of the stool consistency from baseline are 
expected pharmacodynamic effects of plecanatide.  These same attributes (increased stool 
frequency and looser stool consistency) are often used to define “diarrhea’; however, in light of 
significant inter-patient variability in bowel habit “phenotype” and wide differences in the 
perception of a “normal” bowel habit there is no standard definition of “diarrhea” for this patient 
population.  An increase in frequency or consistency for one person is a welcome event while for 
another patient it might be bothersome “diarrhea”.  In all cases, as mentioned in the NOTE 


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above, the frequency and consistency of each bowel movement is recorded in the electronic 
diary. However, this objective record often does not go far enough to characterize any change in 
bowel frequency or consistency as clinically important or impactful for the patient (whether 
beneficial or harmful). 
One mechanism to introduce a level of consistency across patients, sites and the trial is to code 
an event as diarrhea only if it is characterized by a specific patient-reported and clinically 
relevant attribute such as “bothersomeness”.  Therefore, for this trial, for any event associated 
with a significant increase from baseline in BM frequency and/or loosening of BM consistency -  
that would otherwise be coded as diarrhea - the site is instructed to record it as an AE only if the 
patient reports that it was bothersome (as defined by each patient). 
7.3 
ASSESSMENT OF ADVERSE EVENTS 
Each AE will be assessed by the Investigator with regard to the following categories. 
7.3.1 
Seriousness 
An SAE is defined as any untoward medical occurrence that at any dose is one of the following: 
• Results in death 
• Is life threatening (an adverse event or suspected adverse reaction is considered “life 
threatening” if, in the view of either the investigator or sponsor, its occurrence places the 
patient or subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly or birth defect 
• Is a medically important event (examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse) 
 
The FDA has recently defined additional “Medically Important Events” that should also be 
reported as SAEs (Guidance for Industry, FDA, July 2009).  These include cases where: 
• Aminotransferases (ALT or AST) are > 3 times the upper limit of normal (ULN) with an 
associated elevation of total bilirubin > 2 times ULN without evidence of hemolysis or with 
alkaline phosphatase < 2 times ULN or not available, or 
• ALT or AST activity that is > 5 times ULN 
All subjects with the above abnormalities should return as soon as possible or within 48 hours to 
the site for further evaluation of the abnormalities, including repeat ALT and AST 
measurements; total and direct bilirubin; alkaline phosphatase; and related laboratory 
assessments of albumin, PT and PTT, creatinine kinase, and GGTP or 5’nucleotidase.  Hepatitis 
A, B, and C, hemolysis, and biliary obstruction should be ruled out.  A detailed medical and drug 


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use history should be taken to exclude all potential causes.  All such laboratory tests should be 
performed locally if they are not listed in Section 4.3.2; Table 1. 
Medical and scientific judgment should be exercised in deciding whether a case is serious and 
whether expedited reporting is appropriate as in the example above for “Medically Important 
Event.”  The medical monitor should be consulted. 
7.3.2 
Intensity (Severity) 
Investigators should assess the severity of AEs according to the following general categorical 
descriptors: 
Mild: 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Moderate: 
Minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL) (instrumental ADL 
includes preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.) 
Severe: 
Medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL (self-care ADL includes bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity, 
whereas seriousness is a regulatory definition as per Section 7.3.1.  An AE of severe intensity 
may not necessarily be considered serious (by definition) or a mild AE (mild stroke) may be 
considered an SAE. 
7.3.3 
Causality 
The investigator will assess the causality/relationship between the study drug, or study 
procedure, and the AE and record that assessment in the eCRF. 
The causal relationship of the AE to study drug will be described in terms of: 
Reasonable Possibility: 
There is evidence to suggest a causal relationship between 
the drug and the AE (e.g., the AE is uncommon and known 
to be strongly associated with drug exposure or is uncommon 
in the study population but not commonly associated with 
drug exposure) 
No Reasonable Possibility: 
There is no evidence to suggest a causal relationship between 
the drug and the AE 
The study conduct relatedness for AEs and SAEs will also be assessed and documented.  The 
most likely cause of an AE or SAE (e.g., disease under treatment, concomitant disease, 


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concomitant medication, other) will be indicated in the eCRF system with details of the 
concomitant disease or medication or other cause. 
7.4 
RECORDING ADVERSE EVENTS 
Adverse event assessment and reporting will extend from signing of ICF until completion of the 
final visit (End of the Posttreatment Period).  Adverse events occurring from the time of ICF 
signing up to the intake of the first dose of study medication will be classified as pre-existing 
conditions for this study and therefore will be recorded in the Medical History page of the eCRF. 
If, however, an event is considered a Serious Adverse Event (as defined below), and occurs after 
the signing of informed consent but before randomization (i.e., during screening), this will be 
collected and reported as non-treatment-emergent Serious Adverse Events, and will be recorded 
in the Adverse Event page of the eCRF. Events that occur from time of first dose of study drug 
until completion of the final study visit will be considered Treatment-Emergent Adverse Events, 
and recorded on the AE page of the eCRF. Adverse events occurring after the end of the study 
should be reported to the Sponsor by the Investigator only if the event meets at least one  
seriousness criterion and the Investigator considers the causal relationship to the study drug as 
‘reasonably possible’. 
All AE reports should contain a brief description of the event, date of onset, date  of resolution, 
intensity, treatment required, relationship to study drug, action taken with the study drug, 
outcome, and whether the event is classified as serious. 
All AEs experienced by patients who are randomized to treatment, regardless of the relationship 
to study drug, will be recorded in the eCRF.  For patients who are screen failures, only SAEs (if 
any) will be reported on the AE page of the eCRF. 
7.5 
 REPORTING SERIOUS ADVERSE EVENTS 
All SAEs that occur during the study, as defined by the protocol, must be reported by the 
Investigator to the designated SAE Safety Contact by submitting (faxing or emailing) the SAE 
Form within 24 hours from the point in time when the Investigator becomes aware of the SAE. 
In addition, all SAEs including any deaths, which occur up to and including 30 days after the 
administration of the last dose of the study medication, must be reported to the designated Safety 
Contact within 24 hours.   
All SAEs will be collected and reported from signing of informed consent/assent until the end of 
the study.  All SAEs that occur from signing of the ICF/assent to 30 days after the last dose of 
study medication must be reported whether or not considered causally related to the study 
medication.  Any SAE that occurs beyond 30 days after last dose of study medication must be 
reported to the designated safety contact only if the event is considered (in the opinion of the 
Investigator) causally related to the study drug. 
SAE forms will be provided to each clinical site.  The information collected will include a 
minimum of the following: protocol number, Investigator information, patient number, event 
term, a narrative description of the event including its start date, and an assessment by the 
Investigator as to the intensity and possible relatedness to study medication.  A sample of the 
SAE form can be found in the study manual. The Medical Monitor or Synergy may request 
follow up information regarding the SAE. 


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The Investigator will prepare or directly oversee preparation of each SAE report and the Medical 
Monitor will evaluate and confirm the seriousness and the causal relationship of the event to 
study treatment. In addition, the Investigator and Medical Monitor will evaluate the expectedness 
according to the reference document (Investigator Brochure).  Based on the Medical Monitor’s 
and Sponsor’s assessment of the event, a decision will be made concerning the need for further 
action. 
The initial SAE Report Form must be faxed or emailed by the Investigator to the 
designated Safety Contact (below) within 24 hours of becoming aware of the event:  
 
 
SAE REPORTING SAFETY CONTACT INFORMATION 
Chiltern Safety and Pharmacovigilance 
 
• PV fax number:  888-726-8416 
 
• PV email:  Global.SAEInbox@chiltern.com 
 
• PV Hotline: 888-723-2445    
 
 
For any questions related to the reporting of an SAE, sites should call the PV Hotline and include 
the following information: Sponsor (Synergy Pharmaceuticals), protocol number (SP304202-13), 
and contact information. 
The minimum information required for an initial report is: 
- 
Name of person sending the report (i.e., name and address of Investigator) 
- 
Patient identification (site number, patient number, initials, NOT patient name) 
- 
Protocol number 
- 
Description of SAE 
- 
Causality assessment, if possible 
However, as far as possible all points on the SAE form should be covered in the initial report, or 
the completed SAE form itself must be faxed to the designated Safety Contact. In addition, the 
event must be documented in the eCRF. 
After receipt of the initial report, the Safety Contact and safety center will review the information 
and, if necessary, contact the Investigator, to obtain further information for assessment of the 
event. Acknowledgement of receipt of the SAE report will be sent to the site within 24 hrs.  In 
the event acknowledgement is not received, the site should contact Chiltern Safety. 


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All SAEs must be reported by the Investigator to their IRB/IEC in writing, as well as appropriate 
regulatory authorities, as required by law. The designated Chiltern Safety Contact will be 
responsible for all information processing and reporting according to local legal requirements. 
7.6 
FOLLOW-UP OF ADVERSE EVENTS 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored until 
the AE (including abnormal laboratory values) has resolved or has returned to baseline or 
stabilized at a level acceptable to the investigator and medical monitor; until there is a 
satisfactory explanation for the changes observed; until the patient is lost to follow-up; or until 
the patient has died.   The recording of a stop date is required for all reported adverse events.  
The handling of a missing AE stop date when a patient is lost to follow-up or when an adverse 
event is considered stable but ongoing at the end of study visit will be outlined prior to database 
lock. 
7.7 
PREGNANCY 
Female patients enrolled in the study should make every effort to avoid becoming pregnant 
during their participation in the study.  Female patients should be reminded at every visit to use 
appropriate birth control methods.  However, if a female patient should become pregnant during 
the study (i.e., from the date the ICF was signed until the patient’s last visit), the investigator (or 
authorized delegate) should notify the designated safety contact and Synergy Pharmaceuticals, 
Inc., on the initial Pregnancy Report form within 24 hours of the investigator (or authorized 
delegate) first becoming aware of the pregnancy.  Pregnancy itself is not an AE, unless there is 
suspicion that the investigational product may have interfered with the effectiveness of a 
contraceptive medication.  Pregnancy reports, however, are tracked and reported in the safety 
(SAE) database but will be reported separately from SAEs.  Pregnancy occurring in the patient 
between the date of the ICF was signed until 30 days after the last dose of study medication will 
fall under the expedited reporting procedure for serious adverse events.  The pregnant patient 
will be immediately discontinued from the study, but will be followed for the duration of the 
pregnancy.  Details of the outcome of the pregnancy (e.g., full term normal delivery, stillbirth, 
congenital anomalies, or miscarriage) will be collected and reported by the site. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  However, elective abortion without complications should 
not be handled as SAEs. 
All outcomes of pregnancy, if known, must be reported by the Investigator to the Medical 
Monitor or designated safety contact on the pregnancy outcome report form within 30 days after 
he/she has gained knowledge of the facts. See Section 11, Appendix B for additional details on 
pregnancy reporting requirements. 


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8 
STATISTICAL METHODS 
The objectives of the study are to assess the safety and efficacy of plecanatide 0.5, 1.0, and 1.5 
mg dosed daily, compared with placebo. 
 
Before database lock and un-blinding, a formal statistical analysis plan (SAP) will be written and 
will include details of all statistical methods to be used to analyze the efficacy and safety data. 
The SAP will supersede the protocol with respect to the analyses specified, although the primary 
analysis described in this section will remain unchanged.  
 
8.1 
RANDOMIZATION AND TREATMENT ASSIGNMENT 
This is a double-blind, placebo-controlled study with four treatment arms that will be conducted 
at approximately 40 clinical sites. Approximately 120 patients will be randomized to receive 
plecanatide 0.5, 1.0, and 1.5 mg, or the placebo equivalent, in a 1:1:1:1 ratio using an Interactive 
Web-based Response System (IWRS). 
 
Central, block randomization will be performed with stratification by gender. 
 
8.2 
SAMPLE SIZE AND POWER CONSIDERATIONS 
Based on data from two phase 3 trials conducted by the sponsor in adults with CIC, assume a 
mean change from baseline in weekly SBM rate for placebo-treated subjects of 1.2 with a 
standard deviation of 2.6; similarly, for plecanatide-treated subjects, assume a mean change from 
baseline of 3.1 with a standard deviation of 4.0.  Then, a t-test for the difference in means of two 
independent samples with unequal variances, at a two-sided level of significance of 0.05 and 
80% power to detect the assumed difference in means, would require 51 subjects per treatment 
group.  Since study SP304202-13 is being conducted in adolescents with CIC, and the primary 
analysis of the primary endpoint will be an ANCOVA using a linear mixed-effects model, the 
sponsor believes that 30 subjects per treatment group (placebo and 3 dose levels of plecanatide), 
yielding a planned target enrollment of a total of 120 subjects, will prove sufficient for achieving 
the primary objective of this phase 2 study. 
 
8.3 
ANALYSIS POPULATIONS 
The following populations will be assessed: 
 
Safety Population: 
All randomized patients who receive at least one dose of the study drug.  
Patients will be analyzed according to the treatment received.  All safety 
analyses will be based on the Safety Population. 
Intent-to-Treat (ITT) 
Population : 
All patients randomized to study treatment.  Patients will be analyzed 
according to the treatment to which they are randomized.  The ITT 
Population is the main population for assessments of efficacy. 
Per Protocol (PP) 
Population: 
All patients in the ITT population who complete the 8-week Treatment 
Period or discontinue from study treatment due to adverse event(s) or 
lack of efficacy, with the exception of major protocol violators.  Criteria 
to identify the PP population will be detailed in the SAP.  Decisions 
regarding exclusion from the PP Population will be made prior to 
unblinding the database. 
Efficacy analyses will be based on the ITT Population.  Efficacy analyses will be repeated for the 
PP Population to assess the sensitivity of the analyses to the choice of analysis set. 


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Deviations from the study protocol, including violations of inclusion/exclusion criteria, will be 
assessed as “minor” or “major” in cooperation with the Sponsor.  Major deviations from the 
protocol will lead to the exclusion of a patient from the PP Population and will be determined 
prior to unblinding the study database. 
 
8.4 
GENERAL CONSIDERATIONS 
Categorical variables will be summarized by the number and percentage of patients in each 
category level.  Continuous variables will be summarized by number of observations, mean, 
standard deviation (SD), median, minimum, and maximum values.  Where data are collected 
over time, both the observed data and change from Baseline will be summarized at each time 
point. 
 
Summaries will be presented by treatment group (placebo, and plecanatide 0.5 mg, 1.0 mg, and 
1.5 mg), and combined active doses.  All data collected in the eCRF will be presented in listings. 
 
All statistical tests will be two-sided at the 5% level of significance, unless stated otherwise. 
 
No interim analyses are planned. 
 
8.4.1 
Missing Data Conventions 
In general, data will not be imputed for safety analyses. 
 
The weekly SBM (CSBM) rate is the sum of the SBMs (CSBMs) recorded for the days in the 
week for which a BM response is recorded in the daily diary.  Note that this is equivalent to a 
“worst case” analysis in that the SBM (CSBM) rate for the week is the sum of the SBMs 
(CSBMs) recorded for the days in the week for which BMs were reported, plus 0 SBMs (0 
CSBMs) for each day in the week for which the BM response is missing.  In any week in which 
no BM response is recorded, the weekly SBM (CSBM) rate will be set to 0 in any summary or 
linear mixed-effects model analysis involving the weekly SBM (CSBM) rate.  In particular, for a 
randomized patient who withdraws from study participation prior to the end of the study, the 
patient is considered to have a weekly SBM (CSBM) rate equal to 0 for any weeks remaining in 
the planned duration of the study for which the patient has no BM responses recorded. 
 
The weekly average CIC-related abdominal pain score is the average of the non-missing, 
abdominal pain scores recorded in that week, i.e., the weekly average is the sum of the 
abdominal pain scores recorded in the diary in the given week, divided by the number of pain 
scores recorded in the week.  In any week in which a patient has no diary days for which an 
abdominal pain score is recorded, the weekly average abdominal pain score will be set to 
missing.  In any linear mixed-effects model analysis involving the weekly average abdominal 
pain score, if the average score is set to missing in a given week, it will be left as missing in the 
linear model.  In particular, for a randomized patient who withdraws from study participation 
prior to the end of the study, the weekly average abdominal pain score will be set to missing for 
any weeks remaining in the planned duration of the study for which the patient has no abdominal 
pain data. 
 


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In any analysis involving abdominal bloating, abdominal discomfort, straining during a bowel 
movement or pain with defecation, the determination of weekly averages will follow the same 
methodology as described above for the abdominal pain score.  That is, the weekly average item 
score is the sum of the non-missing scores recorded during the week, divided by the total number 
of non-missing scores recorded.  In any week in which a patient has no non-missing item score 
recorded, the weekly average score will be set to missing in any summary or linear mixed-effects 
model analysis involving the weekly average item score. 
 
In any analysis involving stool consistency (BSFS scores), the determination of weekly averages 
will follow the same methodology as presented above for abdominal pain.  However, since stool 
consistency cannot be assessed if the patient does not have at least one SBM during the week in 
question (i.e., stool consistency is based on SBMs only), the weekly average will also be set to 
missing if no SBMs are recorded for any days in the week.  Also, it is possible that a patient has 
no baseline weekly average stool consistency score because of the SBM criterion; in that case the 
patient will be excluded from any change from baseline analyses of stool consistency. 
 
For the exploratory Responder analyses, in any given week, a patient must have at least 4 
compliant diary days in that week.  A compliant diary day means that the patient has responded 
to the BM and rescue medication use questions in the daily diary for that day.  Patients who have 
fewer than 4 compliant diary days in a given week will be considered “non-responders” for that 
week.  Note that this implies that for any week for which a patient has no BM or rescue 
medication use data, the patient is considered a non-responder; in particular, for a randomized 
patient who withdraws from study participation prior to the end of the study, the patient is 
considered a non-responder for any weeks remaining in the planned duration of the study for 
which the patient has no BM or rescue medication use data. 
 
8.4.2 
Diary Data Visit Windows 
The daily electronic diary entries reported during the Treatment Period will be classified into 8 
weeks as follows:  
 
Day 1-7 = Week 1 
Day 8-14 = Week 2  
Day 15-21 = Week 3  
Day 22-28 = Week 4 
Day 29-35 = Week 5  
Day 36-42 = Week 6  
Day 43-49 = Week 7  
Day 50-56 = Week 8 
 
Non-diary data, such as vital signs, clinical laboratory assessments, and ECGs, will be displayed 
and analyzed according to the nominal visit date on the eCRF.  Assessments taken outside of 
protocol allowable windows for nominal visits will be displayed according to the slotting scheme 
presented in the SAP for unscheduled or out-of-window visits. 
 
8.4.3 
Baseline Definition 
For each safety parameter, the most recent valid assessment recorded before randomization will 
be used as the baseline for all analyses of that safety parameter. 


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For efficacy parameters, the baseline values will be derived from data collected in the 2-week 
electronic diary assessment at the end of the Screening Period (baseline).  The last 14 days of 
diary entries prior to Day 1 will be the default standard for derivation of these values. 
 
The baseline SBM (CSBM) weekly rate will be the weekly average number of SBMs (CSBMs) 
recorded during the 2-week baseline assessment period.  Baseline stool consistency, severity of 
straining during a BM, and abdominal symptoms will be calculated as follows: for each week of 
the baseline assessment, the weekly average is the sum of the non-missing scores recorded 
during the week divided by the total number of non-missing scores recorded during that week; 
the baseline is then equal to one-half of the sum of the two weekly average scores.. 
  
8.5 
DISPOSITION OF PATIENTS 
Patient disposition and reasons for discontinuation from the Treatment Period of the study will 
be summarized by treatment group for all randomized patients. 
 
8.6 
TREATMENT COMPLIANCE 
Dosing compliance will be defined by the dosing compliance ratio: the number of doses actually 
taken by the patient divided by the number of doses that were expected to be taken during the 
same period multiplied by 100.  Treatment compliance is defined as taking equal to or greater 
than 80% of the drug dosage prescribed.  Otherwise, the patient will be considered noncompliant 
with study treatment.  Rates of treatment compliance as defined above will be compared between 
treatment groups using the Chi-square test. 
 
Patient compliance with making daily electronic diary entries is monitored by the IWRS system; 
patients non-compliant in making daily diary entries will be withdrawn from the study. 
 
8.7 
DEMOGRAPHICS, MEDICAL HISTORY, BASELINE CHARACTERISTICS, AND 
CONCOMITANT MEDICATIONS 
Demographic data and other baseline characteristics, medical history, and concomitant 
medications will be summarized by means of descriptive statistics.  Where applicable, 
comparisons among treatment groups will be performed using an analysis of variance (ANOVA) 
model for continuous variables and a Cochran-Mantel-Haenszel (CMH) test for categorical 
variables 
8.8 
EFFICACY ANALYSES 
8.8.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of responders for the last 2 weeks of the Treatment 
Period (responder = a child who experiences >3 SBMs per week for each of the last two weeks of the 
treatment period) compared to placebo and across treatment groups.   
8.8.1.1 Analysis of the Primary Efficacy Endpoint 
The weekly SBM rate for each patient will be computed, as described in Section 8.4.1, for each 
week of the 8-week treatment period.  The change from baseline in mean weekly SBM rate will 
be analyzed using a linear mixed-effects model with fixed effects for gender (stratification  


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variable), treatment, week, and the corresponding baseline value; a random intercept for patient 
will also be specified.  The least squares (LS) mean change from baseline will be presented, by 
treatment group, and the difference in LS means for each plecanatide treatment group compared 
to placebo will be presented, with 95% confidence intervals and corresponding statistical p-
values. 
 
8.8.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints, and methods of analysis for each, are: 
 
8.8.2.1 Change from Baseline in Weekly Average Stool Consistency (BSFS) Score Over 
the 8-week Treatment Period, and by Study Week 
The weekly average stool consistency (BSFS) score for each patient will be computed, as 
described in Section 8.4.1, for each week of the 8-week treatment period.  The change from 
baseline in mean weekly average BSFS score over the 8-week treatment period will be analyzed 
using a linear mixed-effects model with fixed effects for gender (stratification variable), 
treatment, week, and the corresponding baseline value; a random intercept for patient will also be 
specified.  The least squares (LS) mean change from baseline will be presented, by treatment 
group, and the difference in LS means for each plecanatide treatment group compared to placebo 
will be presented, with 95% confidence intervals and corresponding statistical p-values. 
 
As a supplement to the above analysis, the weekly average stool consistency (BSFS) score for 
each patient will be computed, as described in Section 8.4.1, for each week of the 8-week 
treatment period and for the two weeks of the follow-up period.  A summary, by treatment 
group, of the mean weekly average BSFS score, and change from baseline in mean weekly 
average BSFS score, for each of the 10 study weeks will be presented.  The change from baseline 
in mean weekly average BSFS scores will be analyzed using a linear mixed-effects model with 
fixed effects for gender (stratification variable), treatment, week, the interaction of treatment and 
week, and the corresponding baseline value; a random intercept for patient will also be specified.  
The least squares (LS) mean change from baseline will be presented, by treatment group, and the 
difference in LS means for each plecanatide treatment group compared to placebo will be 
presented, with 95% confidence interval and corresponding statistical p-value, for each week of 
the 8-week treatment period and for the two follow-up weeks. 
 
8.8.2.2 Change from Baseline in the Weekly Rate of SBMs, by Study Week 
The weekly SBM rate for each patient will be computed, as described in Section 8.4.1, for each 
week of the 8-week treatment period and for the two weeks of the follow-up period.  A 
summary, by treatment group, of the mean weekly SBM rate, and change from baseline in mean 
weekly SBM rate, for each of the 10 study weeks will be presented.  The change from baseline in 
mean weekly SBM rate will be analyzed using a linear mixed-effects model with fixed effects 
for gender (stratification variable), treatment, week, the interaction of treatment and week, and 
the corresponding baseline value; a random intercept for patient will also be specified.  The least 
squares (LS) mean change from baseline will be presented, by treatment group, and the 
difference in LS means for each plecanatide treatment group compared to placebo will be 
presented, with 95% confidence interval and corresponding statistical p-value, for each week of 
the 8-week treatment period and for the two follow-up weeks. 


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8.8.2.3 Change from Baseline in Weekly Rate of CSBMs Over the 8-week Treatment 
Period, and by Study Week 
The weekly CSBM rate for each patient will be computed, as described in Section 8.4.1, for each 
week of the 8-week treatment period.  The change from baseline in mean weekly CSBM rate 
over the 8-week treatment period will be analyzed using a linear mixed-effects model with fixed 
effects for gender (stratification variable), treatment, week, and the corresponding baseline value; 
a random intercept for patient will also be specified.  The least squares (LS) mean change from 
baseline will be presented, by treatment group, and the difference in LS means for each 
plecanatide treatment group compared to placebo will be presented, with 95% confidence 
intervals and corresponding statistical p-values. 
 
As a supplement to the above analysis, the weekly CSBM rate for each patient will be computed, 
as described in Section 8.4.1, for each week of the 8-week treatment period and for the two 
weeks of the follow-up period.  A summary, by treatment group, of the mean weekly CSBM rate, 
and change from baseline in mean weekly CSBM rate, for each of the 10 study weeks will be 
presented.  The change from baseline in mean weekly CSBM rate will be analyzed using a linear 
mixed-effects model with fixed effects for gender (stratification variable), treatment, week, the 
interaction of treatment and week, and the corresponding baseline value; a random intercept for 
patient will also be specified.  The least squares (LS) mean change from baseline will be 
presented, by treatment group, and the difference in LS means for each plecanatide treatment 
group compared to placebo will be presented, with 95% confidence interval and corresponding 
statistical p-value, for each week of the 8-week treatment period and for the two follow-up 
weeks. 
 
8.8.3 
Additional Efficacy Endpoints 
 
Additional efficacy endpoints related to CIC symptoms are:  
 
• Change from baseline in abdominal pain, by study week 
• Change from baseline in abdominal bloating, by study week 
• Change from baseline in abdominal discomfort, by study week 
• Change from baseline in straining during a BM, by study week  
• Change from baseline in pain with defecation, by study week 
 
8.8.3.1 Analysis of the Additional Efficacy Endpoints 
The weekly average of each additional efficacy endpoint score (abdominal pain, abdominal 
bloating, abdominal discomfort, straining during a bowel movement, or pain with defecation) for 
each patient will be computed, as described in Section 8.4.1, for each week of the 8-week 
treatment period and for the two weeks of the follow-up period.  A summary, by treatment 
group, of the mean weekly average symptom score, and change from baseline in mean weekly 
average symptom score, for each of the 10 study weeks will be presented.  The change from 
baseline in mean weekly average symptom score will be analyzed using a linear mixed-effects 
model with fixed effects for gender (stratification variable), treatment, week, the interaction of 
treatment and week, and the corresponding baseline value; a random intercept for patient will 
also be specified.  For each abdominal symptom score, the least squares (LS) mean change from 


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 baseline will be presented, and the difference in LS means for each plecanatide treatment group 
compared to placebo will be presented, with 95% confidence interval and corresponding 
statistical p-value, for each week of the 8-week treatment period and for the two follow-up 
weeks. 
 
8.8.4 
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be assessed: 
• 
4/8 Week SBM 3 + 1 Responder 
• 
6/8 Week SBM 3 + 1 Responder 
• 4/8 Week CSBM 3 + 1 Responder 
• 6/8 Week CSBM 3 + 1 Responder 
 
8.8.4.1 Analysis of Exploratory Efficacy Endpoints 
A weekly SBM (CSBM) 3 + 1 Responder is a patient who has at least 3 SBMs (CSBMs) in a 
given week and an increase of at least 1 SBM (CSBM) from baseline during that week.  A 4/8 
Week SBM (CSBM) 3 + 1 Responder meets these criteria for at least 4 of the 8 weeks of the 
treatment period; a 6/8 Week SBM (CSBM) 3 + 1 Responder meets these criteria for at least 6 of 
the 8 weeks of the treatment period. 
 
The responder rate for each of the four exploratory efficacy endpoints will be analyzed.  In each 
of these responder analyses, for each plecanatide group, the proportion of responders will be 
compared to the proportion of responders in the placebo group using the CMH test stratified by 
gender.  The number and percentage of responders for each treatment group (and 95% 
confidence intervals), the difference in responder rates between each plecanatide group and the 
placebo group (and 95% confidence intervals), and the two-sided p-value associated with the 
CMH test will be presented. 
 
8.8.5 
Patient Reported Outcomes 
PRO questionnaire data for fecal incontinence, excessive flatulence, PGA, PAC—SYM, and 
PAC—QOL will be included in the patient listings.  Summary analyses of these data will also be 
provided as described in the SAP. 
 
8.8.6 
Adjustments for Multiple Comparisons 
Since this is a Phase 2 clinical trial for exploratory purposes, no adjustments for multiple 
comparisons will be undertaken. 
8.9 
PHARMACOKINETIC ANALYSIS 
Plasma concentrations of Plecanatide and its major metabolite (SP-338) will be listed by patient 
and summarized by treatment group. 


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8.10 SAFETY ANALYSES 
Evaluation of the safety of once daily plecanatide over 8 weeks of dosing will be based on the 
occurrence of TEAEs, vital signs, clinical laboratory assessments, and ECGs and as compared 
with those noted in the placebo group. 
 
The safety analyses will use the Safety Population defined in Section 8.3. 
 
The frequency of SAEs, AEs leading to withdrawal from study participation, and TEAEs will be 
included in the primary safety tables. 
 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
classifications with reference to system organ classes (SOCs) and preferred terms.  Only TEAEs 
will be included in summary tables.  Summaries of TEAEs will be presented by SOC and 
preferred term, by treatment.  Summaries will include the frequency of TEAEs, SAEs, and AEs 
leading to withdrawal from study participation, by dose as well as by intensity and relationship to 
study drug. 
Out of range laboratory tests, ECGs, and vital signs of potential clinical importance will also be 
summarized; a listing of patients with at least one out of range value will be presented by visit 
for that test. 
 
Laboratory tests (hematology, serum chemistry, and urinalysis), vital signs, and ECG will be 
summarized as changes from baseline.  Laboratory shift tables will also be produced, where 
applicable.  Listings of laboratory tests, vital signs, and ECGs will also be provided. 
 
Physical examination and medical history listings will be provided but not summarized. 
 
Concomitant medications will be auto-encoded using the WHODD coding system with reference 
to Anatomical Therapeutic Classification (ATC) text and preferred terms.  Summaries of 
concomitant medication will be presented by ATC text and preferred terms.  Prior, concomitant, 
prior and concomitant, and post-treatment medications will be presented separately. 
 
 
8.11 INTERIM ANALYSES 
No interim analyses are planned. 
 


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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
DATA QUALITY ASSURANCE 
The sponsor or sponsor’s designee will inform the investigator of the responsibilities and 
procedures for ensuring adequate and correct documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant.  All information recorded in the eCRF for this study must be consistent with the 
patients’ source documentation (i.e., medical records and charts). 
9.1.1 
Database Management and Quality Control 
All data will be captured electronically at each clinical site using eCRFs and the interactive web 
response system (IWRS).  Patient diary and questionnaire data will be collected using the IWRS.   
Once the eCRF clinical data have been submitted, corrections to the data fields will be captured 
in an audit trail.  The reason for change, the name of the person who performed the change, 
together with the time and date will be logged to provide an audit trail. 
Computerized data check programs and manual checks will identify any clinical data 
discrepancies for resolution.  If additional corrections are needed, the responsible monitor or data 
manger will raise a query in the electronic data capture (EDC) application.  The appropriate staff 
at the clinical site will answer queries sent to the investigator.  The name of the staff member 
responding to the query, and time and date stamp, will be captured to provide an audit trail.  
Once all source data verification is complete and all queries are closed, the monitor will freeze 
the eCRF page. 
The specific procedures to be used for data entry and query resolution using the EDC and/or 
IWRS will be provided to study sites in training manuals and/or guidelines.  In addition, clinical 
site personnel will receive training on the EDC system, including the eCRF, and the IWRS 
systems. 
9.2 
ELECTRONIC CASE REPORT FORMS AND SOURCE DOCUMENTATION 
All data obtained during this study should be entered into the EDC system promptly, or entered 
by the patient or site in the IWRS interface.  All source documents from which eCRF entries are 
derived should be placed in the patient’s medical records/charts.  Reports/documents for which 
source documents are usually available include laboratory assessments and ECG recordings. 
The original eCRF entries for each patient may be checked against source documents at the 
clinical site by the site monitor.  Instances of missing or un-interpretable data will be discussed 
with the investigator for resolution. 
9.2.1 
Data Collection 
The investigators (and appropriately authorized staff) will be given access to an online web-
based EDC system that is 21 Code of Federal Regulations (CFR) Part 11 compliant.  This system 
is specifically designed for the collection of the clinical data in electronic format.  Access and 
rights to the EDC system will be carefully controlled and configured according to each 


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individual’s role throughout the study.  In general, only the investigator and authorized staff will 
be able to enter data and make corrections in the eCRFs. 
The eCRF should be completed for each patient included in the study and should reflect the latest 
observations on the patient’s participating in the study.  Therefore, the eCRFs are to be 
completed as soon as possible during or immediately after the patient’s visit or assessment.  The 
expectation is that study sites will complete data entry within 48 hours of a patient visit.  
The investigator must ensure that all data entries in the eCRF are accurate and correct.  If some 
assessments cannot be done, or if certain information is unavailable, not applicable, or unknown, 
the investigator should indicate this in the eCRF. 
Computerized data-check programs and manual checks will identify any clinical data 
discrepancies for resolution.  Corresponding queries will be loaded into the system and the 
clinical site will be informed about new issues to be resolved online.  All discrepancies will be 
resolved online directly by the investigator or by authorized staff.  Data managers and clinical 
site monitors will be available to assist sites in resolving queries.  Offline edit checks will be 
done to examine relationships over time and across panels to facilitate quality data. 
After completion of data entry and cleaning, the investigator will be required to electronically 
sign off on the clinical data collected in the eCRF. 
Data concerning all study drug dispensed to the patient will be tracked in the IWRS system. 
Study drug return will be tracked in the eCRF. 
9.3 
ACCESS TO SOURCE DATA 
During the study, a monitor will make clinical site visits to review protocol compliance, compare 
eCRF entries and individual patient medical records, assess drug accountability, and ensure that 
the study is being conducted according to pertinent regulatory requirements.  eCRF entries will 
be verified using source documentation.  The review of medical records will be performed in a 
manner to ensure that patient confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study.  Moreover, regulatory 
authorities, IRBs, and/or the sponsor’s clinical quality assurance group (or designee) may wish to 
carry out such source data checks and/or on-site audit inspections.  Direct access to source data 
will be required for these inspections and audits; they will be carried out giving due 
consideration to data protection and medical confidentiality.  The investigator and authorized site 
staff will assure that auditors or monitors and the sponsor have full access to study data and files 
and the necessary support of site personnel at all times. 
9.4 
DATA CODING 
Previous and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary (WHODD), which employs the anatomical therapeutic chemical (ATC) 
classification system.  Medical history/current medical conditions and AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 


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The versions of the coding dictionaries used will be provided in the statistical analysis plan and 
the clinical study report. 
9.5 
ARCHIVING STUDY RECORDS 
According to International Council for Harmonisation (ICH) guidelines, essential documents 
should be retained for a minimum of 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region, or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product.  Ten years is the recommended storage duration to ensure 
compliance with ICH requirements.  However, these documents should be retained for a longer 
period if required by applicable legal requirements. 
9.6 
GOOD CLINICAL PRACTICE 
The procedures set out in the study protocol are designed to ensure that the sponsor and 
investigator abide by the principles of the Good Clinical Practice guidelines of the ICH.  The 
study also will be carried out in keeping with local legal requirements (Appendix F). 
9.7 
INFORMED CONSENT 
Before each patient is admitted to the study, informed consent will be obtained from the patient 
(or his/her legally authorized representative) according to the regulatory and legal requirements.  
The informed consent form (ICF) must be dated and retained by the investigator as part of the 
study records.  The investigator will not undertake any investigation specifically required only 
for the clinical study until valid consent has been obtained.  The date of the consent must also be 
documented in the EDC system. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol.  If the ICF is revised, it must be reviewed and approved by the appropriate IRB, and 
signed by all patients subsequently screened for the study as well as those currently enrolled in 
the study. 
9.8 
PROTOCOL APPROVAL AND AMENDMENT 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRB in accordance with local legal requirements.  The sponsor must ensure that all ethical 
and legal requirements have been met before the first patient is screened in the study. 
The protocol is to be followed exactly.  To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel at Synergy Pharmaceuticals, and receive IRB 
approval prior to implementation (if appropriate).  Following approval, the protocol 
amendment(s) will be submitted to the Investigational New Drug (IND) application under which 
the study is being conducted. 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment but must be submitted to the applicable IRB/ethics committee.  All 
amendments will be distributed to all protocol recipients, with appropriate instructions. 


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9.9 
DURATION OF THE STUDY 
For an individual patient, the planned duration of the study will be 98 days (including 28 days for 
screening, 56 days of treatment and 14 days of follow-up.  
9.10 PREMATURE TERMINATION OF THE STUDY 
If the investigator, the sponsor, or the medical monitor becomes aware of conditions or events 
that suggest a possible hazard to patients if the study continues, the study may be terminated 
after appropriate consultation between the relevant parties.  The study may also be terminated 
early at the sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in 
the study 
• Failure to enroll patients at an acceptable rate 
• A decision on the part of the sponsor to suspend or discontinue development of the study 
drug 
9.11 CONFIDENTIALITY 
All study findings and documents will be regarded as confidential.  The investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the sponsor. 
The anonymity of participating patients must be maintained.  Patients will be identified in eCRFs 
and other documents submitted to the sponsor and CRO by their patient number, initials, and/or 
birth date, not by name. 
9.12 OTHER ETHICAL AND REGULATORY ISSUES 
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the sponsor will issue prompt notification to all parties – regulatory 
authorities, investigators, and IRBs. 
A significant safety issue is one that has a significant impact on the course of the clinical study or 
program (including the potential for suspension of the development program or amendments to 
protocols) or warrants an immediate update of informed consent form. 
9.13 LIABILITY AND INSURANCE 
The sponsor will take out reasonable third-party liability insurance coverage in accordance with 
all local legal requirements.  The civil liability of the investigator, the persons instructed by him 
or her, and the hospital, practice, or institute in which they are employed and the liability of the 
sponsor with respect to medical costs for physical injury and other damage that may arise as a 
result of the carrying out of this study are governed by applicable law(s). 
The sponsor will arrange for patients participating in this study to be insured against medical 
costs for physical injury caused by the pharmaceutical products being tested or by medical steps 
taken in the course of the study. 


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9.14 PUBLICATION POLICY 
By signing the study protocol, the investigator agrees with the use of results of the study for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals.  If necessary, regulatory authorities will be notified of the 
investigator's name, address, qualifications, and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted 
with the Sponsor in advance.  Details are included in the Clinical Study agreement completed for 
each investigational site. 
 


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10 
REFERENCE LIST 
1. Higgins PD, Johanson JF. Epidemiology of constipation in North America:  a systematic 
review. Am J Gastroenterol. 2004 99:750-759. 
2. Suares NC, Ford AC. Prevalence of, and Risk Factors for, Chronic Idiopathic Constipation 
in the Community: Systematic Review and Meta–analysis.  Am J Gastroenterol. 2011 
106:1582–1591. 
3. Pare P, Ferrazzi S, Thompson WG, Irvine EJ, Rance L. An epidemiological survey of 
constipation in Canada: definitions, rates, demographics, and predictors of health care 
seeking. Am J Gastroenterol. 2001 96:3130-3137. 
4. Peppas G, Alexiou VG, Mourtzoukou E, Falagas M. Epidemiology of constipation in 
Europe and Oceania: a systematic review. BMC Gastroenterol. 2008 8:5. 
5. Cash BD, Chang L, Sabesin SM, Vitat P. Update on the management of adults with chronic 
idiopathic constipation. J Fam Pract. 2007 56: S13-19. 
6. Mugie SM, Benninga MA, Di Lorenzo C. Epidemiology of constipation in children and 
adults: a systematic review. Best Pract Res Clin Gastroenterol. 2011 25:3-18. 
7. Davidson M, Kugler MM, Bauer CH. Diagnosis and management in children with severe 
and protracted constipation and obstipation. J Pediatr. 1963 62:261-275. 
8. Benninga MA, Büller HA, Taminiau JA. Biofeedback training in chronic constipation. Arch 
Dis Child. 1993 68:126-129. 
9. Cash BD, Chang L, Sabesin SM, Vitat P (). Update on the management of adults with 
chronic idiopathic constipation. J Fam Pract. 2007  96: 513-519. 
10. Partin JC, Hamill SK, Fischel JE, Partin JS. Painful defecation and fecal soiling in children. 
Pediatrics. 1992 89:1007-1009. 
11. Caplan A, Walker L, Rasquin A. Validation of the pediatric Rome II criteria for functional 
gastrointestinal disorders using the questionnaire on pediatric gastrointestinal symptoms. J 
Pediatr Gastroenterol Nutr. 2005 41:305-316. 
12. Sindic A, Schlatter E. Cellular effects of guanylin and uroguanylin. J Am Soc Nephrol. 2006 
17:607–616. 
13. Shailubhai K, Gerson W, Talluto C, Jacob G. SP 304 to Treat GI Disorders:  Effects of a 
Single, Oral Dose of SP304 on Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics in Healthy Volunteers. Gastroenterology. 2009 136 (Issue 5 Supplement 
1):A-641. 
14. Shailubhai K, Talluto C, Comiskey S, Foss J, Joslyn A, Jacob G. A Ph IIa Randomized, 
Double-blind, Placebo-controlled, 14-day Repeat, Oral, Range-finding Study to Assess the 
Safety, Pharmacokinetic and Pharmacodynamic Effects of Plecanatide (SP 304) in Patients 
with CIC. American College of Gastroenterology (ACG) Annual Scientific Meeting.  
October 15-20, 2010 Poster no 762. 
15. SP304-20210. A Randomized, 12-Week, Double-Blind, Placebo-Controlled, Repeat-Dose, 
Oral, Dose-Ranging Study to Assess the Safety and Efficacy of Plecanatide in Patients with 
Chronic Idiopathic Constipation. June 26, 2013 (data on file). 


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16. Investigator Brochure for Plecanatide: for Chronic Idiopathic Constipation (CIC) Program 
and for Irritable Bowel Syndrome with Constipation (IBS-C). Edition 8.0 dated January 21, 
2016. 
17. Cohen MB, Guarino A, Shukla R, and Gianella RA. 1988. Age-related differences in 
receptors for escherichia coli heat-stable enterotoxin in the small and large intestine of 
children. Gastroenterology 94:367-373. 
18. US Department of Health and Human Services. Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine 
Clinical Trials; 2007.  
19. Guidance for Industry Safety Reporting Requirements for INDs and BA/BE Studies.  DHHS 
FDA December 2012. 
20. National Research Council: The Prevention and Treatment of Missing Data in Clinical 
Trials.  Panel on Handling Missing Data in Clinical Trials. Committee on National 
Statistics, Division of Behavioral and Social Sciences and Education.  Washington, DC: The 
National Academies Press; 2010. 
 
 
 


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11 
APPENDICES 
A. 
Rome III Diagnostic Criteria for Constipation in Child /Adolescent 
B. 
Pregnancy Reporting 
C. 
Bristol Stool Form Scale 
D. 
Electronic Diary 
E. 
Patient Questionnaires 
F. 
Regulations and Good Clinical Practice Guidelines 
 
 
 


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A. 
ROME III DIAGNOSTIC CRITERIA FOR CONSTIPATION IN CHILD/ADOLESCENT 
 
H3a. Functional Constipation 
Diagnostic criteria*  
Must include two or more of the following in a child with a developmental age of at least 4 years 
with insufficient criteria for diagnosis of IBS: 
1. Two or fewer defecations in the toilet per week  
2. At least one episode of fecal incontinence per week  
3. History of retentive posturing or excessive volitional stool retention  
4. History of painful or hard bowel movements 
5. Presence of a large fecal mass in the rectum 
6. History of large diameter stools which may obstruct the toilet  
* Criteria fulfilled at least once per week for at least 2 months prior to diagnosis 
 


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B. 
PREGNANCY REPORTING 
If a female patient should become pregnant during the course of the study (i.e., from the date the 
informed consent was signed until the patient’s last visit), the Investigator (or authorized 
delegate) should notify the designated Safety Contact within 24 hours of the Investigator (or 
authorized delegate) first becoming aware of the pregnancy.  The notification of pregnancy 
should be submitted using the initial Pregnancy Report Form.  The initial Pregnancy Report 
Form should be completed with study patient’s details (eg, patient number, initials, date of birth, 
and investigational product information.).  Whenever possible, the initial notification of 
pregnancy should include detailed information on the pregnancy, including last menstrual period 
and/or expected date of delivery.  If pregnancy is to be terminated, the anticipated date of 
termination should be provided.  If a maternal AE is reported during the initial notification of 
pregnancy, the details of the AE should also be described in the narrative field of the initial 
Pregnancy Report Form. 
 
The Sponsor, Medical Monitor, or designated Safety Representative will request permission to 
follow the patient’s progress with the doctor medically responsible for the pregnancy.  If 
additional information on the progress of the pregnancy and/or any maternal AE is received 
“spontaneously” by the clinical site, the Investigator (or authorized delegate) should submit a 
follow-up Pregnancy Report Form to the Sponsor within 24 hours of becoming aware of the 
information. 
 
If additional information on the outcome of the pregnancy and/or the details of the birth/delivery 
is received “spontaneously” by the clinical site, the Investigator (or authorized delegate) should 
also submit a pregnancy outcome report form to the designated Safety Contact within 24 hours 
of becoming aware of the information.  If the outcome of the pregnancy is reported as premature 
birth, or as elective termination due to a medical reason or as spontaneous or accidental 
miscarriage, the details of the outcome should be described in the narrative section of the 
outcome Pregnancy Report Form.  The pregnancy outcome will generally be reported as a 
follow-up report.  Details of birth/delivery, including date of birth, weight, and sex of the 
fetus/newborn should also be described in the narrative field of the Pregnancy Report Form. 
 
Complete a new SAE Report Form if the delivery outcome meets the criteria for a SAE (e.g., 
congenital anomaly/birth defect, still birth, some other sickness, etc.).  The SAE Report Form 
should be completed with study patient’s details (e.g., patient number, initials, date of birth, 
investigational product information, etc.) and the details of the fetal SAE should be described in 
the narrative field of the SAE Report Form. 


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C. 
BRISTOL STOOL FORM SCALE 
 
 
 
 
 
 


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D. 
ELECTRONIC DAILY DIARY 
Note that the final text for the diary script will appear in the final Design Specifications for 
the electronic diary system and in the Study Procedure Manual. 
 
Daily Bowel Movement Diary 
• Enter the number of bowel movements you wish to report at this time. 
• Enter the time of the bowel movement in 12 hour format, entering 2 digits for the hours and 
2 digits for the minutes. 
• For AM press 1.  For PM press 2. 
• Did you feel like you completely emptied your bowels during this bowel movement?  If 
yes, press 1, if no press 0. 
Please refer to the Bristol Stool Scale diagram provided by your doctor's office.  Please rate the 
form/consistency of this stool.  For Type 1, press 1, For Type 2, press 2, For Type 3, press 3, 
For Type 4, press 4.  For Type 5, press 5.  For Type 6, press 6.  For Type 7, press 7. 
 
Rescue Medication usage 
• Have you taken any Dulcolax® today?  If yes, press 1, if no press 0. 
• How many times have you taken Dulcolax® today? 
• Enter the time you took Dulcolax® in 12 hour format, entering 2 digits for the hours and 
2 digits for the minutes. 
• For AM press 1.  For PM press 2. 
• Enter the number of tablets you took 
 
Daily Symptom Diary 
The patient will be asked to rate their symptoms on a scale of 0 to 10, where 0 is NO 
‘ABDOMINAL PAIN’ and 10 is ‘ABDOMINAL PAIN’ AS BAD AS YOU CAN IMAGINE. 
1. Abdominal Pain.  Rate your abdominal pain at its worst on a scale of 0 to 10, where 0 is 
NO PAIN and 10 is PAIN AS BAD AS YOU CAN IMAGINE. 
2. Abdominal Bloating.  Rate your abdominal bloating at its worst on a scale of 0 to 10, where 
0 is NO ABDOMINAL BLOATING and 10 is ABDOMINAL BLOATING AS BAD AS 
YOU CAN IMAGINE. 
3. Abdominal Discomfort.  Rate your abdominal discomfort at its worst on a scale of 0 to 10, 
where 0 is NO ABDOMINAL DISCOMFORT and 10 is ABDOMINAL PAIN AS BAD 
AS YOU CAN IMAGINE. 
4. If you had one or more bowel movement today, rate your straining with a bowel movement 
at its worst on a scale of 0 to 10, where 0 is NO STRAINING WITH A BOWEL 
MOVEMENT and 10 is STRAIN WITH A BOWEL MOVEMENT AS BAD AS YOU 
CAN IMAGINE. 
5. If you had one or more bowel movement today, rate your pain with defecation at its worst 
on a scale of 0 to 10, where 0 is NO PAIN WITH DEFECATION / WITH A BOWEL 
MOVEMENT and 10 is PAIN WITH DEFECATION / WITH A BOWEL MOVEMENT 
AS BAD AS YOU CAN IMAGINE 


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E. 
PATIENT QUESTIONNAIRES  
Patient Assessment of Constipation -Quality of Life (PAC-QOL), Patient Assessment of 
Constipation -Symptoms (PAC-SYM), Patient Global Assessment (PGA) Questionnaires 
PGA will be administered electronically via IWRS, while PAC-QOL and PAC-SYM are paper-based.  
 


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PAC-SYM© 
PATIENT ASSESSMENT OF CONSTIPATION© 
 
This questionnaire asks you about your constipation in the past 2 weeks.  Answer each question 
according to your symptoms, as accurately as possible.  There are no right or wrong answers. 
 
For each symptom below, please indicate how severe your symptoms have been during the past 2 
weeks.  If you have not had the symptoms during the past 2 weeks, check 0.  If the symptom 
seemed mild, check 1.  If the symptom seemed moderate, check 2.  If the symptom seemed severe, 
check 3.  If the symptom seemed very severe, check 4.  Please be sure to answer every question. 
 
English (USA) PAC-SYM Version 2.0-Sd (12-item, Standard version) PAC-SYM© 1999 Johnson & Johnson, All rights reserved. 


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Patient Global Assessment Questionnaire  
Directions to Patient:  For the question below, please choose the response that applies best to you and 
circle the number of your response. 
Constipation Severity 
How would you rate the severity of your constipation at its worst in the past 24 hours? 
1= none 
2 = mild 
3 = moderate 
4 = severe 
5 = very severe 
 
 
 


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F. 
REGULATIONS AND GOOD CLINICAL PRACTICE GUIDELINES 
 
Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
 
Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/LOB/media/MEDIA482.pdf