Clinical trial NCT02138136
Conditions: Constipation - Functional
Sponsor: Sucampo Pharma Americas, LLC
Start date: 2014-02-26; Completion date: 2017-05-01
Enrollment: 419 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is for children with constipation.

Children who completed 3 months of treatment in the earlier study (NCT02042183):

* were invited to participate
* will receive lubiprostone for 9 more months
* will see if lubiprostone safely relieves their constipation if taken for a whole year

Detailed description:

Arms: arm 1: Participants receive lubiprostone twice daily

Participants must have completed the entire 12-week treatment period during the preceding study. Those who received 12 mcg twice daily (BID) continued to receive 12 mcg, those who received 24 mcg BID continued with that dose.Those of the placebo arm in the previous study weighing less than 50 kg received 12 mcg BID and over 50 kg received 24 mcg BID during this study.
Interventions: intervention 1: Lubiprostone
Intervention descriptions: intervention 1: 12 or 24 mcg soft capsules for oral administration

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Multicentre, Long-term Safety, Efficacy, and Pharmacokinetics 
Study of Lubiprostone in Paediatric Subjects Aged ≥ 6 Years to < 18 
Years with Functional Constipation 
NCT Number: NCT02138136 
Document Date: Protocol Version 4: 23-Nov-2015 
 
 
 


Sucampo AG 
 
SAG/0211PFC-11S1-01 
 
 
CONFIDENTIAL 
 
16.1 
Study Information 
 


Sucampo AG 
 
SAG/0211PFC-11S1-01 
 
 
CONFIDENTIAL 
 
16.1.1 
Final Amended Protocol and Protocol Amendment Summaries 
16.1.1.1 
Final Amended Protocol 


 
Sucampo AG 
 
SAG/0211PFC-11S1 
 
 
CONFIDENTIAL 
 
 
 
 
 
A Multicentre, Long-term Safety, Efficacy, and Pharmacokinetics Study of 
Lubiprostone in Paediatric Subjects Aged ≥ 6 Years to < 18 Years with 
Functional Constipation 
PROTOCOL NUMBER 
SAG/0211PFC-11S1 
DRUG: 
Lubiprostone 
SPONSOR: 
Sucampo AG 
Baarerstrasse 22, CH-6300, Zug, Switzerland 
Original Protocol Version and Date: 
Version 1.0; 15 October 2013 
Protocol Version and Date: 
Version 2.0; 26 November 2013 
Version 3.0; 10 December 2013 
Version 4.0; 19 November 2015 
Protocol Amendments: 
Amendment 1; 26 November 2013 
Amendment 2; 10 December 2013 
Amendment 3; 19 November 2015 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document may contain trade secrets or privileged information. This document is classified 
as confidential and may not be disclosed, unless such disclosure is expressly permitted by Sucampo 
Pharmaceuticals, Inc. or one of its subsidiaries (Sucampo AG, Sucampo Pharma Americas, LLC, Sucampo 
Pharma, Ltd., or Sucampo Pharma Europe, Ltd.) or unless disclosure is required by applicable laws and regulations. 
In any event, persons to whom you disclose the information must be informed by you that this information is 
confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future 
related information supplied to you, which is hereby indicated to be confidential.




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CONTACT INFORMATION 
 
US 
: 
 
Name 
Dr. 
 
Title 
 
Office/Mobile Telephone Number 
 
Office Fax Number 
 
After Hours Contact Number 
 
E-mail Address 
 
 
 
EU 
: 
 
Name 
 MD, PhD, BBA  
Title 
 
Office  Telephone Number 
 
Office Fax Number 
 
After Hours Contact Number 
 
E-mail Address 
 
 
 
Sponsor Personnel: 
 
Name 
 
Title 
 
Office/Mobile Telephone Number 
 
Office Fax Number 
 
E-mail Address 
  
 
 
Name 
 
Title 
 
Office/Mobile Telephone Number 
 
Office Fax Number 
 
E-mail Address 
  
 
 
Name 
 
Title 
 
Office/Mobile Telephone Number 
 
Office Fax Number 
 
E-mail Address 
  
 
 
 
 
24-hr IRE Reporting (Fax) 
 
 
 
 
If any contact information changes during the course of the study, written notification will be 
provided to the Investigator and IRB/IEC, per requirements. A protocol amendment will not be 
required in this case. 


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INVESTIGATOR AGREEMENT 
I have read this protocol and discussed it with the Sponsor’s representative. I agree to conduct 
this study in accordance with the protocol, International Conference on Harmonization (ICH) 
Guideline on Good Clinical Practices and all applicable regulations. 
I will use only the informed consent documentation (ICD) approved by the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) and Sponsor or its representative and will fulfil 
all responsibilities for submitting pertinent information to the IRB/IEC responsible for this study. 
I will provide copies of the protocol and all pertinent information to all individuals responsible 
to me who assist in the conduct of this study. I will discuss this material with them to ensure 
they are fully informed regarding the drug and the conduct of the study. 
I agree that the Sponsor or its representatives shall have access to all original source 
documents, regardless of media, from which case report form (CRF) information may have 
been generated. 
I agree that all information regarding this protocol and lubiprostone will be treated as strictly 
confidential. I further agree not to use the name of Sucampo AG. (SAG), the name of any of 
its employees, the name of the drug or compound, or information relating to this protocol or 
any amendment hereto, in any publicity, news release, or other public announcement, written 
or oral, without the prior written consent of SAG. 
 
 
 
____________________________________________________ 
Principal Investigator Signature 
 
 
Date 
 
 
____________________________________________________ 
Name of Principal Investigator (Printed) 
 
 
 
 
 
 
____________________________________________________ 
Institution 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .............................. ERROR! BOOKMARK NOT DEFINED. 
CONTACT INFORMATION .................................................................................................... 3 
INVESTIGATOR AGREEMENT ............................................................................................. 4 
LIST OF APPENDICES ......................................................................................................... 8 
ABBREVIATIONS AND DEFINITIONS .................................................................................. 9 
PROTOCOL SYNOPSIS ...................................................................................................... 11 
SCHEDULE OF EVALUATIONS .......................................................................................... 15 
1. 
INTRODUCTION ...................................................................................................... 17 
1.1 
Disease Overview .................................................................................................... 17 
1.2 
Product Background ................................................................................................. 18 
1.2.1 
Preclinical information ........................................................................................ 18 
1.2.2 
Clinical information............................................................................................. 18 
1.3 
Rationale for Study ................................................................................................... 18 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 20 
2.1 
Objectives ................................................................................................................ 20 
2.2 
Endpoints ................................................................................................................. 20 
2.2.1 
Safety ................................................................................................................ 20 
2.2.2 
Efficacy .............................................................................................................. 20 
2.2.3 
Pharmacokinetics .............................................................................................. 21 
3. 
STUDY DESIGN ...................................................................................................... 22 
3.1 
Study Procedure Overview ....................................................................................... 23 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................. 24 
4.1 
Inclusion Criteria ...................................................................................................... 24 
4.2 
Exclusion Criteria ..................................................................................................... 24 
4.3 
Reproductive Potential ............................................................................................. 25 
4.4 
Contraception Specifications .................................................................................... 25 
4.5 
Withdrawal of Subjects ............................................................................................. 25 
4.6 
Emergency Unblinding ............................................................................................. 26 
5. 
STUDY AND CONCOMITANT TREATMENTS ........................................................ 27 


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5.1 
Study Medication Formulation .................................................................................. 27 
5.2 
Packaging ................................................................................................................ 27 
5.3 
Labeling ................................................................................................................... 27 
5.4 
Storage and Handling............................................................................................... 27 
5.5 
Supply and Dosing ................................................................................................... 28 
5.5.1 
Reduction in Study Medication Dosing ............................................................... 29 
5.5.2 
Randomisation and Blinding .............................................................................. 29 
5.5.3 
Allocation of Study Medication ........................................................................... 30 
5.6 
Compliance and Drug Accountability ........................................................................ 30 
5.7 
Concomitant Medications ......................................................................................... 30 
5.7.1 
Excluded Medication .......................................................................................... 30 
5.7.2 
Daily Fibre Therapy............................................................................................ 31 
5.7.3 
Rescue Medication ............................................................................................ 31 
6. 
STUDY PROCEDURES ........................................................................................... 32 
6.1 
Study Procedures by Visit ........................................................................................ 32 
6.1.1 
Completion of Study Procedures........................................................................ 32 
6.1.2 
Enrolment Period – Visit 9 (Study Day 1) ........................................................... 34 
6.1.3 
Treatment Period ............................................................................................... 35 
6.1.4 
Follow-up Period ................................................................................................ 37 
6.1.5 
Unscheduled Visit(s) .......................................................................................... 38 
6.2 
Efficacy Evaluations ................................................................................................. 38 
6.2.1 
Electronic Diary .................................................................................................. 38 
6.2.2 
Efficacy Endpoints ............................................................................................. 38 
6.3 
Safety Evaluations ................................................................................................... 39 
6.3.1 
Pharmacokinetic Evaluation ............................................................................... 40 
7. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................... 41 
7.1 
Definitions and Descriptions ..................................................................................... 41 
7.1.1 
Serious Adverse Event ...................................................................................... 41 
7.1.2 
Non-serious Adverse Event ............................................................................... 42 
7.1.3 
Severity .............................................................................................................. 42 
7.1.4 
Relationship to Study Medication ....................................................................... 42 
7.1.5 
Onset and Duration ............................................................................................ 42 
7.2 
Recording and Reporting of Adverse Events ............................................................ 43 
7.2.1 
Reporting of Immediately Reportable Events ..................................................... 43 
7.2.2 
Outcome ............................................................................................................ 44 
7.2.3 
Symptoms of the disease under study ............................................................... 44 
7.2.4 
Clinical laboratory evaluations ........................................................................... 44 
7.2.5 
Vital Signs .......................................................................................................... 45 


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7.2.6 
Overdose ........................................................................................................... 45 
7.3 
Contacting Sponsor Regarding Safety ..................................................................... 45 
7.4 
Coding of Adverse Events ........................................................................................ 45 
7.5 
Monitoring of Safety Data ......................................................................................... 45 
8. 
STATISTICAL METHODS AND DATA MANAGEMENT ........................................... 46 
8.1 
Determination of Sample Size .................................................................................. 46 
8.2 
Datasets Analysed ................................................................................................... 46 
8.3 
Analysis of Subject Characteristics and Completion Status ...................................... 46 
8.4 
Analysis of Exposure to Study Medication, Rescue Medication, and 
Concomitant Medication ........................................................................................... 46 
8.5 
Analysis of Safety ..................................................................................................... 47 
8.5.1 
Deaths, Serious Adverse Events, and Adverse Terminations ............................ 47 
8.5.2 
Adverse Events .................................................................................................. 47 
8.5.3 
Clinical Laboratory Tests ................................................................................... 47 
8.5.4 
Physical Examinations ....................................................................................... 48 
8.5.5 
Bone Growth Assessments ................................................................................ 48 
8.5.6 
Vital Signs .......................................................................................................... 48 
8.5.7 
Pharmacokinetic Evaluations ............................................................................. 48 
8.5.8 
Subgroup and Exploratory Analyses .................................................................. 48 
8.6 
Analysis of Efficacy .................................................................................................. 48 
8.6.1 
General Inferential Principles ............................................................................. 48 
8.6.2 
Efficacy Endpoints ............................................................................................. 49 
8.7 
Data Quality Assurance ............................................................................................ 51 
8.8 
Data Collection ......................................................................................................... 52 
9. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .................................... 53 
9.1 
Sponsor’s Responsibilities ....................................................................................... 53 
9.1.1 
GCP Compliance ............................................................................................... 53 
9.1.2 
Regulatory Approval .......................................................................................... 53 
9.1.3 
Indemnity/liability and Insurance ........................................................................ 53 
9.1.4 
Protocol Management ........................................................................................ 53 
9.1.5 
End of Trial Notification ...................................................................................... 53 
9.1.6 
Submission of Summary of Clinical Study Report to Competent Authorities 
of Concerned Member States and IECs ............................................................. 54 
9.2 
Investigator’s Responsibilities .................................................................................. 54 
9.2.1 
GCP Compliance ............................................................................................... 54 
9.2.2 
Protocol Adherence and Investigator Agreement ............................................... 55 
9.2.3 
Documentation and Retention of Records .......................................................... 55 
9.3 
Ethical Considerations .............................................................................................. 57 
9.3.1 
Informed Consent .............................................................................................. 57 


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9.3.2 
Institutional Review Board or Independent Ethics Committee approval .............. 58 
9.3.3 
Measures for Reduction of Stress and Pain in Paediatric Subjects .................... 58 
9.4 
Confidentiality .......................................................................................................... 59 
9.5 
Publication Policy ..................................................................................................... 59 
10. 
APPENDICES .......................................................................................................... 60 
11. 
REFERENCES......................................................................................................... 70 
 
LIST OF FIGURES 
Figure 1: 
Study Design Flow Chart ................................................................................... 22 
 
LIST OF APPENDICES 
Appendix 1 
DIARY QUESTIONS (Children ≥6 to  18 Years of age) .......................... 61 
Appendix 2 
PEDIATRIC BLOOD PRESSURE LEVELS ............................................. 65 
Appendix 3 
PEDIATRIC HEART RATE RANGES ...................................................... 69 
 


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ABBREVIATIONS AND DEFINITIONS 
ABPI 
Association of British Pharmaceutical Industry 
AE 
Adverse Event 
ALT 
Alanine Transaminase (SGPT) 
AST 
Aspartate Transaminase (SGOT) 
BID 
Twice Daily 
BM 
Bowel Movement 
BMC 
Bone Mineral Content 
BMD 
Bone Mineral Density 
BUN 
Blood Urea Nitrogen 
bpm 
Beats Per Minute 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
CS 
Clinically Significant 
DSMB 
Data Safety Monitoring Board 
DXA 
Dual-energy X-ray absorptiometry 
EDC 
Electronic Data Capture 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
HIPAA 
Health Insurance Portability and Accountability Act 
IBS 
Irritable Bowel Syndrome 
ICD 
Informed Consent Documentation 
ICH 
International Conference on Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRE 
Immediately Reportable Event 
IXRS 
Interactive Voice/Web Response System 
LAR 
Legally Authorised Representative 
LDH 
Lactose Dehydrogenase 
MAO 
Monoamine Oxidase 


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MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MCT 
Medium Chain Fatty Acid Triglycerides 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency (UK) 
mITT 
Modified Intent-to-Treat 
NCS 
Non-clinically Significant 
OTC 
Over-the-Counter 
QD 
Once Daily 
PK 
Pharmacokinetics 
QoL 
Quality of Life 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBM 
Spontaneous Bowel Movement 
SNRI 
Serotonin –Norepinephrine Reuptake Inhibitor 
SOC 
System Organ Class 
SSRI 
Serotonin-Specific Reuptake Inhibitor 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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PROTOCOL SYNOPSIS 
 
A Multicentre, Long-term Safety,  Efficacy and Pharmacokinetics Study of Lubiprostone in Paediatric 
Subjects Aged ≥6 to <18 years with Functional Constipation 
Study Phase 
Phase 3 
Short Title 
Long-term safety extension study of lubiprostone for the treatment of paediatric 
functional constipation in subjects aged ≥6 to <18 years  
Objectives, Study 
Medication and Dose 
Regimen: 
To assess the long-term safety, efficacy, and pharmacokinetics of oral 
lubiprostone 12 or 24 mcg capsules dosed twice daily (BID) when administered 
orally for 36 weeks in paediatric subjects with functional constipation. 
Evaluation of lubiprostone safety is the primary objective in this study. 
 
Dose assignment will be based on the dose they were receiving at the time of 
rolling over from the preceding, double-blind study (SAG/0211PFC-1131) into 
this safety extension study for those subjects who were randomised to receive 
lubiprostone during the preceding study. For subjects who received placebo 
during the preceding study, assignment of dose will be assigned based on 
subject body weight at the time of rollover to this extension study. All dose 
assignment will be handled by an Interactive Voice/Web Response system 
(IXRS) and will continue to maintain blinding with respect to the treatment 
assignment in the preceding trial. 
Assumed No. of Sites: 
Est. No. Enrolled 
Subjects: 
 
Est. No. Screened 
Subjects: 
Approximately 130 (Northern America and Europe)  
415 subjects who completed Study SAG/0211PFC-1131 
 
 
NA 
Duration of Participation: 
Duration of Treatment: 
Up to 42 weeks (including follow-up)  
36 weeks  
Study Schedule: 
Visit 9: 
Enrolment (Clinic Visit) 
Day 1 (coincides with 
SAG/0211PFC-1131 study 
Visit 7) 
Visit 10: 
Interim Treatment Visit (Clinic 
Visit) 
Week 1 Visit (±2 days) 
Visit 11: 
Telephone Assessment 
Week 4 Visit (±3 days); 
Month 1 
Visit 12: 
Interim Treatment Visit (Clinic 
Visit) 
Week 12 Visit (±3 days); 
Month 3 
 
Visit 13: 
Telephone Assessment 
Week 16 Visit (±3 days); 
Month 4 
Visit 14: 
Interim Treatment Visit (Clinic 
Visit) 
Week 24 Visit (±3 days); 
Month 6 
Visit 15: 
Telephone Assessment 
Week 28 Visit (±3 days); 
Month 7 
Visit 16: 
End-of-Treatment (Clinic Visit) 
Week 36 Visit (+3 days); 
Month 9 
Visit 17: 
Follow-Up (Clinic Visit) 
Week 40 Visit (+3 days); 
Month 10 


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Inclusion Criteria: 
 
 
1. Written informed consent obtained from subject and/or parent/legal 
guardian (and assent from subject where applicable). 
2. Subject must have completed the entire 12-week treatment period from the 
preceding study (SAG/0211PFC-1131) prior to enrolment.  
3. 
Subject must continue to abstain from taking concomitant medication 
(prescribed or over-the-counter) that affects gastrointestinal motility; these 
medications include: 
a. Cholinesterase 
inhibitors; 
anti-spasmodic, 
anti-diarrheal, 
anti-
constipation, or prokinetic agents; laxative agents (e.g., PEG 3350), 
including homeopathic remedies;  
b. Tricyclic antidepressants; or  
c. Any medication, at the discretion of the Investigator, known to relieve 
or cause constipation or constipation-related symptoms, and which the 
Investigator, based on the medical history of the subject, suspects to 
be a contributing factor to the patient’s chronic constipation, or may 
otherwise confound the evaluation of treatment response. 
Exceptions: Treatment with anticholinergic agents, SSRIs, SNRIs, or 
MAO inhibitors is allowed if a stable dose has been used for at least 30 
days prior to the Baseline Visit (of the preceding study SAG/0211PFC-
1131) and not likely to change during the study. 
4. 
Subject (and if necessary, parent/legal guardian) must be willing and able 
to use or administer recommended (rectal and/or oral) rescue medications 
if needed. 
5. If subject is taking a fibre supplement (e.g., Metamucil®, PerDiem®, 
Fybogel), usage must have been at a stable dose not likely to change 
during the study. 
6. Subject and his/her parent/legal guardian must be willing and able to fill out 
his/her own diary. 
 
Exclusion Criteria: 
 
 
 
1. Subject has current evidence of untreated faecal impaction. 
2. Subject has experienced an adverse event during the SAG/0211PFC-1131 
study which the Investigator considers to be clinically significant and would 
limit the subject’s ability to participate in the trial. 
3. Subject has had a significant change in their medical status, newly 
diagnosed and uncontrolled cardiovascular, liver or lung disease, 
neurologic or psychiatric disorder, or other systemic disease, which the 
Investigator considers to be clinically significant and would limit the 
subject’s ability to participate in the trial. 
4. Subject has developed abnormal laboratory test (haematology, urinalysis, 
or blood chemistry), which in the Investigator’s opinion is clinically 
significant, unexplained, and would limit the subject’s ability to participate 
in the trial. 
5. Subject (female of childbearing potential) has a positive pregnancy test, 
refuses/unwilling to undergo pregnancy testing, and/or does not agree to 
use protocol-specified contraceptive measures for the duration of the study. 
6. Subject demonstrated non-compliance with study protocol (i.e., dosing 
schedule, visit schedule, diary completion, or study procedures) during the 
SAG/0211PFC-1131 study. 
 
Rescue Treatment 
In the event that no bowel movement (BM) has occurred within a 3-day period, 
the use of recommended rescue medications may be allowed per Investigator’s 
instructions. Recommended rescue medications include bisacodyl, senna, 
sodium picosulfate, and saline enemas. 


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Safety Endpoints: 
The safety endpoints are as follows: 
 
Incidence of adverse events (AEs) grouped by MedDRA System Organ 
Class (SOC) and Preferred Term 
 
Changes from baseline in clinical laboratory parameters (haematology, 
serum chemistry, urinalysis)  
 
Changes from baseline in physical examination  
 
Changes from baseline in vital sign measurements, including height and 
weight 
o 
Height will be measured using a wall-mounted stadiometer, if 
available   
 
For those subjects who were aged 6 to 9 or 14 to 17 at the time of enrolment 
into the SAG/0211PFC-1131 study, and who were qualified to participate 
and enrolled in the dual-energy X-ray absorptiometry (DXA) substudy: 
o 
Percent changes from baseline in bone mineral density (BMD) and 
bone mineral content (BMC) 
o 
Changes from baseline in BMD Z-scores and in height-adjusted Z-
scores, as assessed by DXA for DXA Subgroup 
o 
Changes from baseline in height and weight Z-scores for DXA 
Subgroup 
o 
Incidence of clinical fractures  
 
A Data Safety Monitoring Board (DSMB) will monitor safety data on a regular 
basis throughout the study. Specifics, including meeting frequency and 
stoppage criteria, are provided in the DSMB Charter. 
Efficacy Endpoints: 
The efficacy endpoints are as follows: 
 
Overall and monthly changes from baseline in BM and SBM frequency 
rate 
 
Overall and monthly assessments of the average degree of, and changes 
from baseline in: 
o 
Stool consistency of SBMs 
o 
Straining associated with SBMs 
o 
Abdominal pain associated with SBMs 
o 
Constipation severity 
 
Monthly SBM Response 
o A monthly responder is defined as a subject who is a weekly responder 
for 3 of 4 weeks per month. 
o A weekly responder is defined as a subject who has a frequency rate 
of ≥ 3 SBMs/week and an increase from baseline of ≥ 1 SBM/week for 
that week. 
 
Overall and monthly assessment of average treatment effectiveness 
rating 
 
Overall Health-related quality of life (PedsQL™) 
 
Overall and monthly change from baseline in incontinence episodes 
frequency (analysis performed for subset of subjects presenting with 
incontinence at baseline) 
 
Overall and monthly change from baseline in the production of large 
diameter stool (a stool that clogs the toilet) frequency  
 
Overall and monthly change from baseline in frequency of faecal 
impaction  
 
Overall and monthly change from baseline in proportion of BMs and SBMs 
in toilet overall 
 
Overall and monthly change from baseline in frequency of retentive 
posturing or excessive volitional stool retention 


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Pharmacokinetic 
Evaluation: 
Plasma samples will be collected for population pharmacokinetic (PK) modeling 
at Visit 9 as follows: 
 
Pre-dose and 1 sample between 30 and 90 minutes after dose 
administration (2 samples total) 
A population PK analysis will be performed using the concentration-time data 
from the sparse PK samples in this study. The analysis may include data from 
other studies with lubiprostone in adults, paediatric subjects, or healthy 
volunteers. A separate analysis plan for the population PK analysis will be 
prepared prior to database lock. 
Sample Size Estimate 
Calculation 
For purposes of establishing the safety profile with lubiprostone long-term 
exposure in paediatric functional constipation, safety data from subjects 
enrolled in this study will be considered together with the 100 subjects enrolled 
in Sucampo study SAG/0211PFC-11S2 (subjects in this study will be below 6 
years old). 
 
The sample size is based on the expected attrition that would occur and the 
remaining number of safety evaluable subjects at each timeframe during the 
study. 
Statistical Methodology 
Efficacy analysis will be based on modified intent-to-treat (mITT) population 
which includes all enrolled subjects who take at least one dose of study 
medication and have at least one treatment period diary entry. Categorical and 
discrete variables will be summarized by counts and percentage, and 
continuous variables will be summarized by descriptive statistics. Detailed 
statistical methodology will be documented in the Statistical Analysis Plan 
(SAP). 
 
Adverse events will be summarized in terms of incidence by treatment group 
and overall. Changes from baseline or clinical abnormalities in clinical 
laboratory data, physical examinations, and vital signs will be summarized by 
treatment group and overall. 
 
The PK profile for lubiprostone will be determined from the concentration-time 
data for all evaluable subjects based on the plasma concentrations lubiprostone 
(if measurable) and of lubiprostone’s metabolite, M3. Actual post-dose sampling 
times relative to time of study medication administration, rather than scheduled 
sampling times, will be used in all PK profile computations involving sampling 
times. 
 
 




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4 PK samples will be collected predose and 1 sample between 30 and 90 minutes after dose administration (2 samples total). PK samples will be taken under non-fasting conditions. The 
samples will be collected via direct venipuncture. Approximately 8 mL of blood will be taken for each sample such that the total of all PK samples does not exceed 50 mL or 5 mL/kg of body 
weight; 
5 Urine pregnancy tests will be performed at all study visits on subjects of childbearing potential. 
6 All subjects who withdraw from the study after Visit 12 (Month 3) should complete the final visit of the treatment period (Visit 16) and therefore have a final DXA assessment performed. This 
will only be required for subjects that were originally part of the DXA subgroup. Any subject demonstrating a decline in 4% in BMD at any skeletal site from Screening to End of Treatment 
should additionally undergo a follow-up DXA assessment 6 to 12 months later;  
7 Observe the subject or parent/legal guardian as he/she administers the first dose of study medication while in the clinic at Visit 9. Over the next 1 hour, monitor subject for any adverse 
reactions. One bottle of study medication will be provided at Visit 9 and then 3 bottles each at Visits 10, 12 and 14. Subjects should return the used bottle of study medication at each clinic 
visit for collection by site for drug accountability. If the study medication is not returned, the bottle of all unused study medication should be returned to the site at the subsequent office visit.  
The subject will be instructed to take the study medication only from the newly dispensed bottle; 
8 Change eDiary mode to new treatment mode (associated with current study - SAG/0211PFC-11S1) at Visit 9.  
 


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1. 
INTRODUCTION 
1.1 
Disease Overview 
Constipation in children has similar characteristics to that of constipation in adults in that 
symptoms include infrequent bowel movements (BMs), hard stools, and painful passage of 
stools. Children may also experience faecal retention due to withholding.1,2 There is a tendency 
to avoid defecation and withhold BMs due to pain experienced from the passage of large 
stools. This withholding of BMs can result in episodes of faecal incontinence. Functional 
constipation occurs in all paediatric age groups, from newborns to young adults and its severity 
may vary from mild and short-lived to severe and chronic with faecal impaction. It is responsible 
for 3–5% of paediatric outpatient visits and 25% of paediatric gastroenterology 
consultations.1,2,3 Standardized diagnostic criteria for paediatric functional constipation have 
been defined by the Rome Committee for Functional Gastrointestinal Disorders.3 Under Rome 
III, the diagnostic criteria for childhood functional constipation require that children of a 
developmental age of at least 4 years with insufficient criteria for diagnosis of irritable bowel 
syndrome (IBS) present with two or more of the following at least once per week for 2 months 
prior to diagnosis: 
• Two or fewer defecations in the toilet per week 
• At least one episode of faecal incontinence per week 
• History of retentive posturing or excessive volitional stool retention 
• History of painful or hard bowel movements 
• Presence of a large faecal mass in the rectum 
• History of large diameter stools which may obstruct the toilet 
One systematic review showed a worldwide prevalence of childhood constipation in the 
general population ranging from 0.7% to 29.6%.4 Similar prevalence rates were reported for 
boys and girls. Childhood constipation continues beyond puberty in up to one third of the 
children followed up.5  Children aged 2 to 4 years seem to have a higher recurrence rate and 
a need for prolonged medication and support than younger infants.6 One follow-up study has 
noted increased risk of persistent constipation in children who developed constipation early in 
infancy and who have a family history of constipation.7  Another follow-up study assessing the 
clinical course of severe functional constipation in early childhood found that after initial 
success of treatment, a relapse occurred in 15% of the children within 3 years. Symptom 
duration of 3 months or less before referral was significantly correlated with better outcome.8 
Medical treatment is aimed at disimpaction of the impacted faeces and restoration of regular 
bowel habits, which consist of passage of soft, normal stools without discomfort. The 
administration of laxatives is also used to achieve a normal bowel habit of passing a soft stool 
without pain. Even though the traditional treatment is well established and safe, for many 
patients it does not provide a satisfactory improvement, prompting interest in other therapeutic 
strategies.9 


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1.2 
Product Background 
Lubiprostone (24-mcg capsules administered twice daily [BID]) is currently approved in the US 
under the trade name Amitiza® for the treatment of adults with chronic idiopathic constipation 
and opioid-induced constipation in adults with chronic, non-cancer pain, and for women with 
irritable bowel syndrome with constipation (8 mcg BID). Lubiprostone 24-mcg BID is also 
approved for treatment of adult chronic idiopathic constipation in the United Kingdom and 
Switzerland. Lubiprostone was approved for marketing in Japan on 29 June 2012 for the 
treatment of chronic constipation (excluding constipation caused by organic diseases) in the 
adult population. In several well-controlled clinical studies in subjects with chronic idiopathic 
constipation, opioid-induced constipation or irritable bowel syndrome with constipation, 
lubiprostone has been shown to increase the frequency of spontaneous bowel movements 
(SBMs) in adults, to improve stool consistency, and to reduce straining, abdominal bloating, 
and abdominal discomfort.10 An open-label safety and efficacy study of 4 weeks’ duration has 
also been conducted in paediatric functional constipation subjects aged 3-17 years who were 
treated with lubiprostone 12 mcg once daily (QD), 12 mcg BID, or 24 mcg BID and 
improvement in SBM frequencies were reported in all dose groups.11 
1.2.1 
Preclinical information 
A full summary of the findings from all non-clinical studies can be found in the current 
Investigator Brochure. 
1.2.2 
Clinical information 
A full summary of previous clinical studies with lubiprostone, known and potential side effects 
can be found in the current Investigator Brochure.  
1.3 
Rationale for Study 
Even though traditional treatment of functional constipation in children is available and safe, 
for many patients it does not provide a satisfactory improvement, prompting interest in other 
therapeutic strategies. Since lubiprostone has been shown to increase the frequency of SBMs 
in both adults and children, further evaluation in well controlled studies in children is needed 
to demonstrate use in a paediatric population. The doses selected for this study are based on 
the results obtained during the previous open-labeled study in children.12 Highly statistically 
significant (p<0.0001) changes from baseline SBM frequency at Week 1 were observed overall 
for children treated with lubiprostone, with children treated with either lubiprostone 12 mcg BID 
or 24 mcg BID achieving a mean SBM frequency of > 3 SBMs following one week of treatment 
with lubiprostone. The greatest Week 1 improvement was observed for the lubiprostone 24 
mcg BID group. Results from this study also suggested that allowance for dose escalation in 
some subjects initially dosed with 12 mcg BID may have provided some additional treatment 
benefits. 
Subjects who completed the entire 12-week treatment in the preceding double-blind study 
(SAG/0211PFC-1131) will be eligible to enrol into this long-term safety study. Dose assignment 
will be based on the dose they were receiving at the time of rolling over from the previous study 
into this safety extension study for those subjects who were randomised to receive lubiprostone 
during the preceding study. For subjects who received placebo during the preceding study, 


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assignment of dose will be assigned based on subject body weight at the time of rollover to 
this extension study. All dose assignment will be handled by an Interactive Voice/Web 
Response system (IXRS) and will continue to maintain blinding with respect to the treatment 
assignment in the preceding trial. 
Lubiprostone has a well-documented safety record in clinical studies involving over 3,500 
subjects. The safety record, along with previously observed improvement in constipation signs 
and symptoms in both children and adults, provides a potential treatment option in a paediatric 
population. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
To assess the long-term safety, efficacy, and pharmacokinetics of oral lubiprostone 12 or 24 
mcg capsules dosed twice daily (BID) when administered orally for 36 weeks in paediatric 
subjects with functional constipation. Evaluation of lubiprostone safety is the primary objective 
in this study. 
2.2 
Endpoints 
2.2.1 
Safety 
The safety endpoints are as follows: 
 
Incidence of adverse events grouped by MedDRA System Organ Class (SOC) and 
Preferred Term  
 
Changes from baseline in clinical laboratory parameters (haematology, serum chemistry, 
urinalysis)  
 
Changes from baseline in physical examination  
 
Changes from baseline in vital sign measurement, including height, and weight  
o 
Height will be measured using a wall-mounted stadiometer, if available  
 
For those subjects who were aged 6 to 9 or 14 to 17 at the time of enrolment into the 
SAG/0211PFC-1131 study, and who were qualified to participate and enrolled in the DXA 
substudy: 
o 
Percent changes from baseline in BMD and BMC 
o 
Changes from baseline in BMD Z-scores and in height-adjusted Z-scores, as 
assessed by DXA for DXA Subgroup 
o 
Changes from baseline in height and weight Z-scores 
o 
Incidence of clinical fractures  
 
A DSMB will monitor safety data on a regular basis throughout the study. Specifics, including 
meeting frequency and stoppage criteria, are provided in the DSMB Charter. 
2.2.2 
Efficacy 
The efficacy endpoints are as follows: 
 
Overall and monthly changes from baseline in BM and SBM frequency rate 
 
Overall and monthly assessments of the average degree of, and changes from baseline 
in: 
o 
Stool consistency of SBMs 
o 
Straining associated with SBMs 
o 
Abdominal pain associated with SBMs 
o 
Constipation severity 
 
Monthly SBM Response 
o 
A monthly responder is defined as a subject who is a weekly responder for 3 of 4 
weeks per month. 


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o 
A weekly responder is defined as a subject who has a frequency rate of ≥ 3 
SBMs/week and an increase from baseline of ≥ 1 SBM/week for that week. 
 
Overall and monthly assessment of average treatment effectiveness rating 
 
Overall Health-related quality of life (PedsQL™) 
 
Overall and monthly change from baseline in incontinence episodes frequency  (analysis 
performed for subset of subjects presenting with incontinence at baseline) 
 
Overall and monthly change from baseline in the production of large diameter stool (a 
stool that clogs the toilet) frequency  
 
Overall and monthly change from baseline in frequency of faecal impaction  
 
Overall and monthly change from baseline in proportion of BMs and SBMs in toilet overall 
 
Overall and monthly change from baseline in frequency of retentive posturing or 
excessive volitional stool retention  
2.2.2.1 Patient Reported Outcomes 
Hand-held electronic diaries will be utilized to collect daily responses to questions involving 
bowel habit symptoms, study drug administration, and rescue medication administration (see 
Appendix 1). 
 
The PedsQL™ Generic Core Scales13 will be completed by the subject or parent/legal guardian 
via paper questionnaires at Visit 9, Visit 12, Visit 14 and Visit 16. 
2.2.3 
Pharmacokinetics 
Plasma samples will be collected for population PK modeling at Visit 9 as follows: 
 
Pre-dose and 1 sample between 30 and 90 minutes after dose administration (2 samples 
total) 
A population PK analysis will be performed using the concentration-time data from the sparse 
PK samples in this study. The analysis may include data from other studies with lubiprostone 
in adults, paediatric subjects, or healthy volunteers. A separate analysis plan for the population 
pharmacokinetic analysis will be prepared prior to database lock. 




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3.1 
Study Procedure Overview 
A detailed description of the procedures to be performed is outlined in Section 6, study 
procedures. The schedule of events is outlined in tabular format in the Protocol Synopsis 
section. 
 
There will be four distinct visits or periods during the study: 
 
 
Enrolment Visit (Visit 9; Day 1): This visit is considered study Day 1 and the visit takes 
place on the first day of study medication administration and will coincide with Visit 7 of 
the preceding study SAG/0211PFC-1131.   
 
 
Interim Treatment Clinic Examinations (Visits 10, 12, 14; Weeks 1, 12, 24) and End-
of-Treatment Visit (Week 36): A clinic visit will occur on Study Days 8 (±2 days), 85 (±3 
days), 169 (±3 days) and 253 (±3 days). Clinical assessments will be performed to 
evaluate the safety of study treatment.  
 
Interim Telephone Assessments (Visits 11, 13, and 15; Weeks 4, 16, and 28): A 
telephone assessment will be performed by site personnel at Study Days 29 (±3 days), 
113 (±3 days), and 197 (±3 days). This assessment will be performed to evaluate the 
compliance of the subject with the study medication and electronic diary and to identify 
any adverse events (AEs) or changes in concomitant medications. 
 
 
Follow-up Visit (Visit 17; Week 40 [Day 281 + 3 days]): A follow-up clinic visit will occur 
to review any ongoing or new onset of AEs, record any changes in concomitant 
medications. The subject’s overall condition will be assessed; and blood and urine will 
be collected for laboratory analyses. This will conclude the subject’s involvement in the 
study. 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects must satisfy the following criteria before entering the study: 
 
1. 
Written informed consent obtained from subject or parent/legal guardian (and assent 
from subject where applicable). 
2. 
Subject must have completed the entire 12-week treatment period during the preceding 
study (SAG/0211PFC-1131).  
3. 
Subject must continue to abstain from taking concomitant medication (prescribed or 
over-the-counter) that affects gastrointestinal motility; these medications include: 
a. Cholinesterase inhibitors; anti-spasmodic, anti-diarrheal, anti-constipation, or 
prokinetic agents; laxative agents (e.g., PEG 3350), including homeopathic 
remedies;  
b. Tricyclic antidepressants; or  
c. Any medication, at the discretion of the Investigator, known to relieve or cause 
constipation or constipation-related symptoms, and which the Investigator, based 
on the medical history of the subject, suspects to be a contributing factor to the 
patient’s chronic constipation, or may otherwise confound the evaluation of 
treatment response. 
Exceptions: Treatment with anticholinergic agents, SSRIs, SNRIs, or MAO inhibitors 
is allowed if a stable dose has been used for at least 30 days prior to the Baseline Visit 
(of the preceding study SAG/0211PFC-1131) and not likely to change during the study. 
4. 
Subject (and if necessary, parent/legal guardian) must be willing and able to use or 
administer recommended (rectal and/or oral) rescue medications if needed. 
5. 
If subject is taking a fibre supplement (e.g., Metamucil®, PerDiem®, Fybogel), usage 
must have been at a stable dose not likely to change during the study. 
6. 
Subject and his/her parent/legal guardian must be willing and able to fill out his/her own 
diary. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in the 
study: 
 
1. 
Subject has current evidence of untreated faecal impaction. 
2. 
Subject has experienced an adverse event during the SAG/0211PFC-1131 study which the 
Investigator considers to be clinically significant and would limit the subject’s ability to 
participate in the trial. 
3. 
Subject has had a significant change in their medical status, newly diagnosed and 
uncontrolled cardiovascular, liver or lung disease, neurologic or psychiatric disorder, or 
other systemic disease, which the Investigator considers to be clinically significant and 
would limit the subject’s ability to participate in the trial. 


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4. 
Subject has developed an abnormal laboratory test (haematology, urinalysis, or blood 
chemistry), which in the Investigator’s opinion is clinically significant and would limit the 
subject’s ability to participate in the trial. 
5. 
Subject (female of childbearing potential) has a positive pregnancy test, refuses/is 
unwilling to undergo pregnancy testing, and/or does not agree to use protocol-specified 
contraceptive measures for the duration of the study. 
6. 
Subject demonstrated non-compliance with study protocol (i.e., dosing schedule, visit 
schedule, diary completion, or study procedures) during the SAG/0211PFC-1131 study. 
4.3 
Reproductive Potential 
All female subjects of childbearing potential will have urine pregnancy tests performed at all 
site visits. Childbearing potential will be defined as any female subject who has reported first 
menses. 
4.4 
Contraception Specifications 
Female subjects of child-bearing potential must agree to remain abstinent or to use adequate 
contraception during study participation. The type of contraception being used by the subject 
shall be recorded in the source document. Adequate contraception is defined as use of any of 
the following: 
 
Oral Contraceptive– must have been used for at least 3 months prior to the Screening 
Visit (Visit 1); 
 
Intrauterine Device (IUD); or 
 
Double barrier method. 
4.5 
Withdrawal of Subjects 
A subject is free to withdraw from the study at any time for any reason without prejudice to 
their future medical care by the physician or at the institution. The Investigator or Sponsor may 
also withdraw the subject at any time in the interest of subject safety. The primary reason for 
withdrawal must be recorded in the subject’s medical record and on the withdrawal form in the 
electronic Case Report Form (eCRF). 
Subject participation may be terminated prior to completion of the clinical study for any of the 
following reasons: 
 
 
AE;  
 
Lack of efficacy;  
 
Subject choice;  
 
Lost to follow-up;  
 
Non-compliance;  
 
Investigator decision;  
 
Sponsor request; or 
 
Any other reason upon agreement between the Investigator and the Sponsor. 
 


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Subjects who withdraw from the study early or who are terminated from the study should 
complete the final visit of the treatment period (Visit 16) as outlined in Section 6.1.3.4 and the 
Follow-up Visit (Visit 17) as outlined in Section 6.1.4.1. All subjects who withdraw from the 
study after Visit 12 (Month 3) should have a final DXA assessment performed. This will only 
be required for subjects that were originally part of the DXA subgroup. 
 
When a subject withdraws prior to completing the study, the reason for withdrawal shall be 
documented in the source documents and on the appropriate eCRF page. In any case where 
the action taken with study medication is listed as permanently withdrawn due to an adverse 
event, the reason selected for withdrawal in the eCRF must be “AE” (i.e., Investigator decision 
or other category should not be selected in such cases). 
Attempts should be made to locate subjects who are lost to follow-up so that as much study 
information as possible may be obtained. Every effort should be made to retrieve dispensed 
study medication, electronic diaries, and obtain the general overall status of the subject at the 
time of withdrawal from the study. The subject’s source documents should verify that at least 
two attempts have been made by telephone to locate the subject and that a final attempt to 
locate the subject has been made by certified or traceable mail. 
4.6 
Emergency Unblinding 
Dose assignment will only be known in subjects who were at least 50 kg in weight at the time 
of randomisation in the preceding study (SAG/0211PFC-1131). In the event emergency 
unblinding of study dose is necessary, the Investigator shall utilize the RTSM system to obtain 
subject dose details. The individual subject dose details should be revealed only in case of an 
emergency where the further treatment of the subject is dependent on knowing the actual dose 
he or she has received. 
 
It is strongly encouraged that unblinding only be completed after consultation with the study 
medical monitor and/or Sponsor, provided this does not compromise subject safety. If 
unblinding should occur (either by accident or for a medical emergency), the Investigator must 
promptly and immediately notify the Sponsor, study medical monitor, and IRB/IEC, and 
document the circumstances surrounding this action in a memorandum to the study file.   
 
 


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5. 
STUDY AND CONCOMITANT TREATMENTS 
5.1 
Study Medication Formulation 
Lubiprostone drug substance is white, odourless crystals or crystalline powder and is very 
soluble in ether and ethanol, and practically insoluble in hexane and water. Lubiprostone is 
available for oral administration in a soft gelatin capsule formulation. Each soft gelatin capsule 
is filled with lubiprostone dissolved in medium chain fatty acid triglycerides (MCT) solution. 
Lubiprostone is the sole active ingredient. Each capsule contains 12 or 24 mcg lubiprostone.  
5.2 
Packaging 
An independent packaging company, not involved in the conduct or monitoring of the study, 
will label, package, and distribute study medication. Study medication labeling will be provided 
in accordance with current Good Manufacturing Practice (cGMP) requirements and local 
regulatory specifications and requirements. The study medication will be packaged in bottles 
with a child-resistant cap. Each bottle will contain a 4-week supply plus a 4-day overage (64 
capsules) of study medication (lubiprostone 12- or 24-mcg capsules). 
5.3 
Labeling 
All study medication product will be labeled with a minimum of the following information: 
 
Protocol Number;  
 
Bottle Number (if applicable);  
 
Dosage form (including product name); 
 
Manufacturing and storage information;  
 
Directions for use, storage conditions, expiry date (if applicable), batch number;  
 
The statements ‘For clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by 
Federal (United States) Law to Investigational Use’, or the equivalent texts outside USA, 
as applicable;  
 
The Sponsor's name and address;  
 
Any additional labeling requirements for participating countries and/or controlled 
substances will also be included on the label;  
 
Subject Number (To be written by the site); 
 
Subject Initials (To be written by the site, where applicable); 
 
Dispense Date (To be written by the site). 
5.4 
Storage and Handling 
The Investigator has overall responsibility for ensuring that study medication is stored in a safe, 
limited-access location under the specified appropriate storage conditions until it is assigned 
and handed over to the study subject. The medication will be stored at room temperature, 
defined as thermostatically-controlled to normal working environment of 20°C (68°F) to 25°C 
(77°F); excursions between 15ºC and 30ºC (59ºC to 86ºF) are allowed. Limited responsibility 


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may be delegated to the pharmacy or member of the study team, but this delegation must be 
documented. Study medication will be distributed by the pharmacy or nominated member of 
the study team. Temperature monitoring is required at the storage location to ensure that the 
investigational product is maintained within an established temperature range. The Investigator 
is responsible for ensuring that the temperature is monitored throughout the total duration of 
the trial and that records are maintained. The study subjects have to be advised that they store 
the study medication at room temperature, and that no temperature-control is needed. 
No study medication stock or returned inventory may be removed from the investigational site 
without prior consent by the Sponsor. All returned and unused study medication shall be 
returned or destroyed as instructed by the Sponsor.  
The Sponsor will be permitted upon request to inspect the supplies storage and distribution 
procedures and records provided that the blind of the study is not compromised. Due to the 
titration aspect of the preceding double-blinded study (SAG/0211PFC-1131), bottles will not 
specifically identify whether they contain lubiprostone 12 or 24 mcg so as to maintain the prior 
blind. 
5.5 
Supply and Dosing 
Each bottle of study medication will contain 64 capsules, sufficient for 28 days plus a 4-day 
overage in the event that any capsules are lost, accidentally destroyed, or there is a delay in 
the completion of the scheduled clinic visit. Each treatment day should consist of two (2) doses 
of study medication, one (1) capsule per dose in the morning and in the evening. If a dose is 
missed, the subject should take the missing dose as soon as possible, but should not “double 
up” doses, i.e., take 2 doses at one meal.  
 
The subject and his/her parent/legal guardian will be instructed to administer study medication 
with meals and at least 8 ounces (240 mL) of fluid. All doses should be taken at least 5 hours 
apart. The parent/legal guardian should record the actual time the dose was taken in the 
electronic diary. If the dose was missed entirely, the parent/legal guardian should indicate the 
omission in the electronic diary as instructed. The study medication will be handled by 
authorized personnel and dispensed under the supervision of the Investigator or designated 
site personnel. 
Each subject will receive one 64-capsule bottle of study medication at the Enrolment Visit (Day 
1), and three bottles each at Visits 10, 12, and 14. The first dose of study medication will be 
administered in the clinic at the Enrolment Visit and the Study Coordinator will record this first 
dose. 
 
Subjects should return the used bottle of study medication at each clinic visit for collection by 
site for drug accountability. If the study medication is not returned, the bottle of all unused study 
medication should be returned to the site at the subsequent office visit. The subject will be 
instructed to take the study medication only from the newly dispensed bottle. The last dose of 
study medication in this study will be taken on the day of End of Treatment (Visit 16). 
 


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5.5.1 
Reduction in Study Medication Dosing 
A dose reduction may be initiated by the Investigator, if one of the following conditions is 
reported by the subject to the site and has been ongoing for three or more days: 
 
 
Nausea – In cases where the subject is experiencing severe nausea, the Investigator 
may reduce the study medication to once daily (QD) dosing at their discretion and in 
consultation with the subject. 
 
Diarrhea – In cases where the subject is experiencing severe diarrhea, the Investigator 
may reduce the study medication to QD dosing at their discretion and in consultation 
with the subject. 
 
Other – In cases where the subject is experiencing some other type of AE, the 
Investigator may reduce the study medication to QD dosing upon consultation with and 
approval of the medical monitor. 
 
Once the adverse event is reported by the subject, site personnel should follow the subject for 
any change in the nature of the event. If the event has not resolved after 3 days, a reduction 
to QD dosing may be initiated by the elimination of the morning dose of the study medication 
such that only the evening dose is taken once a day. Once a dose reduction occurs, the subject 
may resume administration of the BID dose regimen per Investigator discretion.  
Note: Investigators should assess the need for reduction of the study medication at 
each visit. 
5.5.2 
Randomisation and Blinding 
This study will not involve randomisation. Due to the titration aspect of the preceding double-
blinded study (SAG/0211PFC-1131), bottles will not specifically identify whether they contain 
lubiprostone 12 or 24 mcg so as to maintain the prior blind. Dose assignment will be based on 
the dose they were receiving at the time of rolling over from the preceding, double-blind study 
(SAG/0211PFC-1131) into this safety extension study for those subjects who were randomised 
to receive lubiprostone during the preceding study. For subjects who received placebo during 
the preceding study (as identified via IXRS), assignment of dose by the IXRS will be based on 
subject body weight at the time of rollover to this extension study. Dose assignment will only 
be known in subjects who were at least 50 kg in weight at the time of randomisation in the 
preceding study (SAG/0211PFC-1131). All dose assignments will be handled by the IXRS and 
will continue to maintain blinding with respect to the treatment assignment in the preceding 
trial. 
Most study personnel will remain blinded to doses assigned to subjects weighing less than 50 
kg until the clinical database has been locked. To allow for the execution of clinical trial–related 
services, the following individuals will be unblinded during the study: 
 
External RTSM vendor 
 
Sponsor Quality Assurance representative 
 
Sponsor Pharmacovigilance representative 
 
External clinical supply distribution vendor 


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 
External third party unblinded biostatistician (e.g., DSMB statistician) 
 
DSMB members 
 
Bioanalytical laboratory and third-party pharmacokinetic analyst 
 
Sponsor Drug Supply Management representative 
Emergency unblinding by the Investigator of a subject’s assigned treatment is addressed in 
Section 4.6 of this protocol. 
5.5.3 
Allocation of Study Medication 
Subjects will keep the unique 7-digit subject identifier (“xxxx-yyy”) that was assigned in the 
preceding double-blind study (SAG/0211PFC-1131). This subject ID number will also be used 
as a unique identifier for the subject throughout the study for lab reports, diary, study 
medication labels, eCRFs, etc. 
5.6 
Compliance and Drug Accountability 
It is the responsibility of the Investigator to ensure that all study medication received at the site 
will be inventoried and accounted for throughout the study and the result recorded in the Drug 
Accountability Form and in subject’s eCRF. See Section 5.5 for instructions about return of 
study medication. Study medication returned by the subjects will be stored and disposed of 
according to the Sponsor’s instructions. Contents of the study medication bottles must not be 
combined.  
Designated study personnel will maintain a log of all study medications dispensed and 
returned. The Sponsor or designee will verify the drug accountability log during on-site 
monitoring visits. Study medication supplies for each subject will be inventoried and accounted 
for throughout the study. Study medication administration will be documented in the source 
documentation, including dispensation information and capsule counts, and entered in the 
appropriate eCRF page. Study medication dosing will also be recorded by the subject or 
parent/legal guardian in the electronic diaries. 
5.7 
Concomitant Medications 
5.7.1 
Excluded Medication 
The following medications are to be excluded during the course of the study and must be 
discontinued from the Enrolment Visit through the end of the first week following the End-of-
Treatment Visit: 
 
Anti-spasmodics;  
 
Cholinesterase inhibitors; 
 
Anti-diarrheal medications;  
 
Anti-constipation medications (e.g., Linzess™/ Constella™, Relistor®, or Resolor®);  
 
Prokinetic agents;  
 
Laxative agents (e.g., PEG 3350), including homeopathic remedies; 


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 
Tricyclic antidepressants; 
 
Any medications at the discretion of the Investigator known to relieve or cause 
constipation or constipation symptoms, and which the Investigator, based on the medical 
history of the subject, suspects to be a contributing factor to the patient’s chronic 
constipation, or may otherwise confound the evaluation of treatment response. 
 
Exceptions: Treatment with anticholinergic agents, SSRIs, SNRIs, or MAO inhibitors is 
allowed if a stable dose has been used for at least 30 days prior to the Baseline Visit (of the 
preceding study SAG/0211PFC-1131) and not likely to change during the study. 
 
These medications should be documented as concomitant medications. The Sponsor (medical 
monitor) must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are taken. Continued participation of the subject will be at the 
discretion of the Sponsor. 
5.7.2 
Daily Fibre Therapy 
The use of a daily fibre supplement shall be permitted as long as the usage schedule and dose 
has been stable for at least 30 days prior to the Baseline Visit (of the preceding study 
SAG/0211PFC-1131). The schedule of usage and dose of the daily fibre supplement should 
not change during the course of the study. Any fibre supplement used should be documented 
as a concomitant medication. 
5.7.3 
Rescue Medication 
If necessary, rescue medication may be used to help induce a BM. The use of approved rescue 
medications is outlined below. Each parent/legal guardian should be educated on the protocol-
specified use of rescue medications at the Enrolment Visit (Visit 9) and throughout the study. 
In the event that no BM has occurred within a 3-day period, the use of rescue medications is 
permitted per the Investigator’s instructions as described below.  
 
a. 
Rescue medication 1: The subject or parent/legal guardian administer the clinically 
recommended dose of bisacodyl, senna, or sodium picosulfate. 
b. 
Rescue medication 2: If the first rescue medication fails to induce a bowel 
movement, the subject or parent/legal guardian may administer a repeat dose of 
bisacodyl, senna, sodium picosulphate, or administer a saline enema.  
c. 
If both rescue medications fail, the subject or parent/legal guardian may contact the 
Investigator who may prescribe another medication at their discretion for immediate 
short-term use. The recommendation may include a medication from the excluded 
medication list other than any form of polyethylene glycol (PEG), Linzess™/ 
Constella™, Relistor®, or Resolor® (Section 5.7.1), all of which are considered 
prohibited rescue medications.  
 
Should the use of rescue therapy be necessary, it will be recorded in the electronic diary by 
the subject or parent/legal guardian, and recorded on the Rescue Medication eCRF page. 


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6. 
STUDY PROCEDURES 
6.1 
Study Procedures by Visit 
6.1.1 
Completion of Study Procedures 
The Schedule of Evaluations included in the protocol synopsis summarises the frequency and 
timing of the entry, efficacy and safety measurements for this study. All study visits should be 
scheduled so that each visit occurs within the allotted timeframe. All visits should be based 
upon the date of the first dose of study medication. 
 
Subjects are expected to complete all study periods. Subjects who withdraw from the study 
early or who are terminated from the study should complete the final visit of the treatment 
period (Visit 16) and the follow-up visit (Visit 17). All subjects who withdraw from the study after 
Visit 12 (Month 3) should have a final DXA assessment performed. This will only be required 
for subjects that were originally part of the DXA subgroup. All visits are outlined in this section.  
 
The details of the procedures for the Enrolment Visit and subsequent visits as specified are 
below. 
 
Medical History – An updated medical history of the subject will be recorded. Particular 
attention should be made regarding the subject’s continued status of functional constipation 
and related symptoms.  
 
Inclusion/Exclusion – The subject will be assessed to determine their eligibility for the study 
based upon the inclusion (Section 4.1) and exclusion (Section 4.2) criteria.  
 
Height – The subject’s height will be recorded using a wall-mounted stadiometer, where 
available, in inches or centimeters. Alternate methods and further guidance will be provided in 
a study manual. 
 
Weight – The subject’s weight will be recorded in pounds or kilograms.  
 
Vital Signs – The subject’s blood pressure, heart rate, respiratory rate, and temperature will 
be recorded. The time of vital sign measurements should be recorded in the source 
documents. Vitals may be repeated, however all measurements taken should be recorded in 
the source documents.  Any repeat readings at a particular timepoint should be recorded as 
unscheduled data points. Subjects should be asked to remain seated for at least 5 minutes 
prior to all measurements of vital sign parameters. Vital sign assessments will be performed 
prior to PK sampling when these assessments are collected at the same visit. 
 
Age-appropriate equipment, e.g., blood pressure cuffs, should be used for all assessments. 
 
Physical Examination – A complete physical examination of the subject will be performed by 
appropriate site personnel. Physical examination findings should correlate with the subject’s 
medical history and current diagnosis. 
 
Abbreviated Physical Examination – An abbreviated physical examination of the subjects 
will be performed by appropriate site personnel. This examination reviews only those body 
systems where there has been a change in health or there is new finding to report. 


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Laboratory Tests – Urine and blood samples will be collected and sent to a central laboratory 
for analysis (see Section 6.3 for details). Age-appropriate normative clinical laboratory values, 
based on the clinical laboratory’s paediatric ranges, will be used to determine abnormal 
laboratory values for this study. 
 
Pregnancy Test – All female subjects of childbearing potential will have a urine pregnancy 
test performed at all clinic visits.  Childbearing potential will be defined as any female subject 
who has reported first menses. 
 
Pharmacokinetic Evaluations – Sample collections for the determination of lubiprostone and 
metabolite M3 concentrations will be performed in all subjects. 
 
Bone Growth Assessments – For those subjects who were aged 6 to 9 or 14 to 17 at the 
time of enrolment into the SAG/0211PFC-1131 study, and who were qualified to participate 
and enrolled in the DXA substudy, BMD and BMC measurement using DXA will be performed 
at Month 9 (Visit 16). All subjects who withdraw from the study after Visit 12 (Month 3) should 
complete the final visit of the treatment period (Visit 16) and therefore have a final DXA 
assessment performed. This will only be required for subjects that were originally part of the 
DXA subgroup. Analysis of scans will be performed by a central reader. 
Any subject demonstrating a decline in 4% in BMD at any skeletal site from Screening to End 
of Treatment should additionally undergo a follow-up DXA assessment 6 to 12 months later. 
Adverse Events – AEs will be reported by the subject from the time of informed consent 
through the end of the follow-up period. AEs will be followed by the Investigator as determined 
by Sponsor or designee. Further details on AE reporting are provided in Section 7. 
Concomitant Therapy – An updated concomitant therapy history of the subject will be 
recorded. The subject must be reminded that prescription and laxative medications are 
disallowed per Section 5.7.1 of the protocol and not to change their diet or lifestyle. A subject, 
who has been routinely administering a daily fiber supplement during the preceding double-
blind study (SAG/0211PFC-1131), may remain on the supplement throughout the study 
provided the regimen and dose does not change. Similarly, treatment with anticholinergic 
agents, SSRIs, SNRIs, or MAO inhibitors is allowed if a stable dose has been used for at least 
30 days prior to the Screening Visit and not likely to change during the study. 
Electronic Diary – The electronic diary dispensed to the subject or parent/legal guardian in 
the previous blinded study (SAG/0211PFC-1131) will continue to be used. If necessary the 
subject or parent/legal guardian will receive another demonstration and set of instructions for 
use. At enrolment (Visit 9), ensure that the electronic diary is set to capture treatment-related 
responses associated with this long-term safety study. The daily diary will record information 
throughout the study. Information from the electronic diary will be automatically transmitted 
from the device each night to a secure study database and will be available for review by the 
site as needed.  The parent/legal guardian and, for certain diary questions, the subject must 
complete the diary each evening per the instructions. Additionally, the occurrence of bowel 
movements and use of rescue medications can be recorded in real-time throughout the day, 
with the opportunity to review any episodic entries at the time of the evening report. A maximum 
recall period of 24 hours will be allowed for entry of study-related event data in the diary. 


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6.1.2 Enrolment Period – Visit 9 (Study Day 1) 
At this visit, a review of the inclusion and exclusion criteria will be conducted for all subjects to 
ensure the subject remains eligible for the study. Consent/assent must be obtained before any 
study procedures are performed. 
 
Note: This visit will coincide with Visit 7 from the preceding study (SAG/0211PFC-1131). The 
following procedures that are recorded as part of Visit 7 from SAG/0211PFC-1131 will also be 
recorded to this visit and therefore do not need to be repeated: 
 
 
Completion of PedsQL™ questionnaire by subject or parent/legal guardian prior to 
conducting other visit procedures; 
 
Measure predose vital signs, including height and weight; measure heart rate and blood 
pressure 1 hour after the first dose of study medication. Subjects should be asked to 
remain seated for at least 5 minutes prior to measurement of vital sign parameters. If 
blood pressure and/or heart rate are confirmed to be clinically significantly changed (as 
defined in Section 6.3) at the 1 hour postdose measurement relative to predose, 
additional measurements should be taken again at 2 hours and 3 hours postdose. Record 
the time of vital sign measurements in the source documents. A wall-mounted 
stadiometer, where available, should be used for measurement of height. Age-
appropriate equipment, e.g., blood pressure cuffs, should be used for all assessments; 
 
Collect blood and urine samples for clinical laboratory analysis. A total of about 5.5 mL 
of blood will be collected for clinical laboratory analysis; 
 
Perform a full physical examination; 
 
Measurement of BMD and BMC via DXA of lumbar spine and total body (less head), if 
available, for DXA Subgroup (Subjects 6 to 9 and 14 to 17 years of age). This will only 
be required for subjects that were originally part of the DXA subgroup; and 
 
Urine Pregnancy Test – All female subjects of childbearing potential will have a urine 
dipstick pregnancy test to determine their pregnancy status prior to the dispensing of 
study medication. 
 
As part of this visit, the following procedures will take place: 
 
 
Update medical history. Any new medical information should be added to the subject’s 
baseline history (AEs will be captured on the AE page); 
 
Collect PK samples – Pre-dose and 1 sample between 30 and 90 minutes after dose 
administration (2 samples total). PK samples will be taken under non-fasting conditions. 
The samples will be collected via direct venepuncture. Approximately 8 mL of blood will 
be taken for each sample (16 mL in total) such that the total of all PK samples does not 
exceed 50 mL or 5 mL/kg of body weight; 
 
Review and record any new AEs and follow-up on any ongoing AEs; 
 
Update Concomitant Therapy – Concomitant medications (prescribed and over-the-
counter [OTC]) used since the last visit will be reviewed. The subject or parent/legal 


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guardian should again be instructed not to use any prescription or OTC laxatives unless 
prescribed by the Investigator; 
 
Review and discuss rescue medication use and remind subject or parent/legal guardian 
to record rescue medication use in electronic diary; 
 
The electronic diary dispensed to the subject or parent/legal guardian in the previous 
blinded study (SAG/0211PFC-1131) will continue to be used. If necessary the subject or 
parent/legal guardian will receive another demonstration and set of instructions for use. 
Ensure that the electronic diary is set to capture treatment-related responses associated 
with this long-term safety study; 
 
Dispense first bottle of study medication, provide dosing instructions and remind the 
subject or parent/legal guardian to bring the bottle with any remaining study medication 
to every visit; 
 
Observe the subject or parent/legal guardian as he/she administers the first dose of study 
medication while in the clinic. Over the next 1 hour, monitor subject for any adverse 
reactions. Ensure blood pressure and heart rate are collected at 1 hour postdose as 
described above; 
 
Schedule the next clinic visit (Visit 10/Study Day 8). 
6.1.3 Treatment Period 
The treatment period will begin at the Enrolment Visit on the day the first dose of study 
medication is administered (Study Day 1) and will end upon administration of the last dose.  
 
Note: If at any time during the study, the subject discontinues from the study, the subject 
should be withdrawn from the study and complete the final visit of the treatment period (Visit 
16) and the Follow-up Visit (Visit 17). All subjects who withdraw from the study after Visit 12 
(Month 3) should have a final DXA assessment performed. The DXA assessment will only be 
required for subjects that were originally part of the DXA subgroup. 
 
6.1.3.1 Interim Clinic Assessment – Visit 10 (Week 1/Day 8 ± 2 days) 
During this visit, the following procedures will be performed: 
 
 
Measure vital signs, including height and weight. Subjects should be asked to remain 
seated for at least 5 minutes prior to measurement of vital sign parameters. Record the 
time of vital sign measurements in the source documents. A wall-mounted stadiometer, 
where available, should be used for measurement of height. Age-appropriate equipment, 
e.g., blood pressure cuffs, should be used for all assessments; 
 
Perform an abbreviated physical examination; 
 
Collect blood and urine samples for laboratory analysis (including a pregnancy test, if 
applicable). A total of about 5.5 mL of blood will be collected for clinical laboratory 
analysis; 
 
Review and update concomitant therapy; 
 
Review and record any new AEs and follow-up on any ongoing AEs; 


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 
Review and discuss rescue medication use and remind subject or parent/legal guardian 
to record rescue medication use in electronic diary; 
 
Review compliance associated with completion of the electronic diary; 
 
Collect the previously dispensed bottle of study medication and perform drug 
accountability. Review study medication compliance with the subject and/or parent/legal 
guardian.  If the study medication is not returned, the bottle of all unused study medication 
should be returned to the site at the subsequent office visit; 
 
Dispense new supply of study medication (3 bottles). The subject and/or legal guardian 
will be instructed to take the study medication only from the newly dispensed bottles; 
 
Confirm the next telephone contact (i.e., at Study Day 29). 
 
6.1.3.2 Interim Telephone Assessments – Visits 11, 13 and 15 (Week 4/Day 29 ±3 days, 
Week16/Day 113 ±3 days, and Week 28/Day 197 ±3 days)  
During these telephone assessments, the following procedures will be performed: 
 
 
Review and update concomitant therapy; 
 
Review and record any new AEs and follow-up on any ongoing AEs; 
 
Review compliance associated with study medication; 
 
Review and discuss rescue medication use and remind subject or parent/legal guardian 
to record rescue medication use in electronic diary; 
 
Review compliance associated with completion of the electronic diary; 
 
Confirm the next scheduled clinic visit. 
6.1.3.3 Interim Clinic Assessment – Visits 12 and 14 (Week 12/Day 85 ±3 days and Week 
24/Day 169 ±3 days) 
During these visits, the following procedures will be performed: 
 
 
Completion of PedsQL™ questionnaire by subject or parent/legal guardian prior to 
conducting other visit procedures; 
 
Measure vital signs, including height and weight. Subjects should be asked to remain 
seated for at least 5 minutes prior to measurement of vital sign parameters. Record the 
time of vital sign measurements in the source documents. A wall-mounted stadiometer, 
where available, should be used for measurement of height. Age-appropriate equipment, 
e.g., blood pressure cuffs, should be used for all assessments; 
 
Perform an abbreviated physical examination; 
 
Collect blood and urine samples for clinical laboratory analysis (including a urine 
pregnancy test if applicable). A total of about 5.5 mL of blood will be collected for clinical 
laboratory analysis; 
 
Review and update concomitant therapy; 
 
Review and discuss rescue medication use and remind subject or parent/legal guardian 
to record rescue medication use in electronic diary; 


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 
Review and record any new AEs and follow-up on any ongoing AEs; 
 
Review compliance associated with completion of the electronic diary; 
 
Collect the previously dispensed bottle of study medication and perform drug 
accountability. Review study medication compliance with the subject or parent/legal 
guardian.  If the study medication is not returned, the bottle of all unused study medication 
should be returned to the site at the subsequent office visit; 
 
Dispense new supply of study medication (3 bottles). The subject will be instructed to 
take the study medication from the newly dispensed bottles; 
 
Schedule the next telephone contact. 
6.1.3.4 End-of-Treatment Visit – Visit 16 (Week 36/Day 253 +3 days)  
During this visit, the following procedures will be performed: 
 
 
Completion of PedsQL™ questionnaire by subject or parent/legal guardian prior to 
conducting other visit procedures; 
 
Measure vital signs, including height and weight. Subjects should be asked to remain 
seated for at least 5 minutes prior to measurement of vital sign parameters. Record the 
time of vital sign measurements in the source documents. A wall-mounted stadiometer, 
where available, should be used for measurement of height. Age-appropriate equipment, 
e.g., blood pressure cuffs, should be used for all assessments; 
 
Perform a full physical examination; 
 
Collect blood and urine samples for clinical laboratory analysis (including a urine 
pregnancy test if applicable). A total of about 5.5 mL of blood will be collected for clinical 
laboratory analysis; 
 
Measurement of BMD and BMC via DXA of lumbar spine and total body (less head), if 
available for those subjects enrolled in DXA subgroup only; 
 
Review and update concomitant therapy; 
 
Review and record any new AEs and follow-up on any ongoing AEs; 
 
Review compliance associated with completion of the electronic diary; 
 
Collect the previously dispensed bottle of study medication and perform drug 
accountability. Review study medication compliance with the subject and/or parent/legal 
guardian.  If the study medication is not returned, the bottle of all unused study 
medication must be returned to the site at the subsequent office visit. 
6.1.4 Follow-up Period  
The follow-up period lasts for 4 weeks following the final dose of study medication. AEs should 
be followed to assess their status and resolution during this timeframe. Any new concomitant 
medications should also be recorded.  
6.1.4.1 Follow-up (Clinical Assessment) – Visit 17 (Week 40/Day 281 +3 days)  
The follow-up visit is scheduled to assess all AEs since the end of treatment to determine if 
resolution has occurred or update the ongoing status of these events. Also, any new events 
should be recorded. A review of the subject’s concomitant therapy should be made to 
determine if any changes have been made.  
 


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At this visit, the following procedures will be performed:  
 
Review and update concomitant therapy; 
 
Review and record any new AEs and follow-up on any ongoing AEs; 
 
Vital signs including height and weight; 
 
Abbreviated physical examination;  
 
Collect blood and urine samples for clinical laboratory analysis (including a urine 
pregnancy test if applicable). A total of about 5.5 mL of blood will be collected for 
clinical laboratory analysis; and 
 
Collect electronic diary. 
 
6.1.5 Unscheduled Visit(s) 
Additional visits may be scheduled, at the discretion of the Investigator, to ensure the safety 
and well-being of subjects who experience AEs during the course of the study warranting 
further evaluation. Any additional visits should be fully documented in the subject’s eCRF on 
the Unscheduled Visit Screen(s). 
 
6.2 
Efficacy Evaluations 
The parent/legal guardian and, in some cases, the subject him/herself will answer questions 
about the subject’s constipation, including recordation of bowel movements (BMs), associated 
stool consistency and bowel straining ratings, as well as evaluations of abdominal pain, 
constipation severity, and treatment effectiveness. This information will be assessed as part of 
the daily and weekly evaluations recorded in the electronic diary. Additionally, subjects will 
complete the PedsQL™ questionnaire at all clinic visits (except Visits 10 and 17), with 
responses recorded on paper at specified clinic visits.  
 
6.2.1 Electronic Diary 
The electronic diary is a hand-held device with a visual display. It is designed to query the 
parent/legal guardian daily about the status of their child’s constipation (see Appendix 1). The 
diary will prompt the parent/legal guardian and, in some cases, the subject to provide 
information each evening prior to bedtime about the constipation-related events during the 
preceding day or week. Additionally, the occurrence of bowel movements and use of rescue 
medications can be recorded in real-time throughout the day, with the opportunity to review 
any episodic entries at the time of the evening report. A maximum recall period of 24 hours will 
be allowed for entry of study-related event data in the diary. 
 
Information from the subject diary is automatically transmitted each night to a secure study 
database and available for review by the site as needed. Since the diary information is being 
gathered for efficacy, it is important that the diary is completed each day. Additional information 
about the electronic diary and its usage will be provided to the sites in a reference manual 
prepared by the diary vendor.   
 
6.2.2 Efficacy Endpoints 
The efficacy endpoints are provided in Section 2.2.1.  
 


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6.3 
Safety Evaluations 
The following safety evaluations will be performed during the study to measure the safety of 
the study medication: 
 
Adverse Events: AEs will be reported by the subject from the time of informed consent 
through the end of the follow-up period. AEs will be followed by the Investigator as determined 
by Sponsor or designee. Further details on AE reporting are provided in Section 7. Any study 
medication related AEs persisting at the end of the study will be followed until resolution, or 
until a clinically stable endpoint has been reached. 
 
In this study, faecal impaction and bone fractures will be captured as AEs. The events of faecal 
impaction will be used for the analysis of the fecal impaction frequency during the study (see 
Section 8.6.2.5). 
 
Clinical Laboratory Tests: The following laboratory tests will be conducted and the 
appropriate Investigator shall determine the clinical significance of any out-of-range values. 
 
 
Hematology Panel: Hemoglobin, hematocrit, MCV, MCH, MCHC, RBC, WBC, white 
blood cell with absolute counts and percent differentials (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), platelet count. 
 
 
Chemistry Panel: Total cholesterol, triglycerides, glucose, total protein, albumin, 
alkaline phosphatase, AST, ALT, GGT, iron, LDH, total bilirubin, direct bilirubin, BUN, 
uric acid, creatinine, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, 
magnesium.  
 
 
Urinalysis: Protein, glucose, ketones, occult blood, pH, specific gravity, color, 
appearance, leukocyte esterase, nitrite, bilirubin, and macroscopic examination.  
Microscopic examination will be done if abnormalities are present. Urine samples will be 
collected, when possible. 
 
Physical Examination: Physical examinations will be conducted at various timepoints during 
the study. Any new post treatment findings or changes, as noted by the Investigator, will be 
reported as an AE. 
 
Vital Signs:  
Vital signs (including height and weight at designated visits) will be recorded during the study. 
Any post treatment clinically significant changes in vital signs (including weight) shall be noted 
by the Investigator and reported as an AE. Additional guidance regarding assessment of 
changes in blood pressure and heart rate are provided below. 
 
Normal blood pressure ranges will be based on the National Institutes of Health National Heart, 
Lung, and Blood Institute chart (Appendix 2). If, at 1 hour postdose, a change in blood pressure 
of greater than 15 mmHg from the predose assessment is observed, and this change is 
confirmed by a repeat measure, additional measurements must be taken at 2 and 3 hours 
postdose. If the observed change is sustained through the three post-dose measurements, it 
should be considered a clinically significant change, which must be reported as an adverse 
event.  


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Normal heart rate ranges will be based on the Silverman pediatric ranges (Appendix 3). If, at 
1 hour postdose, a change in heart rate of greater than 20 beats per minute (bpm) from the 
predose assessment is observed, and this change is confirmed by a repeat measurement, 
additional measurements must be taken at 2 and 3 hours postdose. If the observed change is 
sustained through the three post-dose measurements, it should be considered a clinically 
significant change, which must be reported as an adverse event. 
 
Rescue Medication Usage: All medications used emergently by the subject to relieve 
constipation, will be captured during their participation in the study. 
 
Bone Growth Assessments: BMD and BMC assessments will be performed during the study 
for those subjects enrolled in DXA Subgroup only. 
 
Any subject demonstrating a decline in 4% in BMD at any skeletal site from Screening to End 
of Treatment should additionally undergo a follow-up DXA assessment 6 to 12 months later.  
 
6.3.1 
Pharmacokinetic Evaluation  
Plasma samples will be collected from all subjects and analysed to determine levels of 
lubiprostone (if measurable) and metabolite M3. These concentration-time data will be used in 
a population PK analysis. PK samples will be taken under non-fasting conditions. The samples 
will be collected via direct venepuncture. Approximately 8 mL of blood will be taken for each 
sample such that the total of all PK samples does not exceed 50 mL or 5 mL/kg of body weight. 


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7. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
As defined in ICH GCP Guideline E6,14 an AE is any untoward medical occurrence in a clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, disease or exacerbation 
of a pre-existing condition temporally associated with the use of a medicinal (investigation) 
product, whether or not related to the medicinal product. For this study, all safety information 
will be collected from the time of informed consent and any untoward medical occurrence after 
enrolment will be defined as an AE. Adverse events that are reported after initiation of study 
medication will be defined as treatment-emergent AEs. 
 
In this study, faecal impaction and bone fractures will be captured as AEs. The events of faecal 
impaction will be used for the analysis of the faecal impaction frequency during the study (see 
Section 8.6.2.5). 
 
Each AE requires a complete and thorough description including date of onset, duration, 
intensity/severity, its relationship to the study drug and any corrective actions taken. Each AE 
should also be categorized as “serious” or “non-serious”. 
 
Timely, accurate, and complete reporting and analysis of safety information from the clinical 
study are crucial for the protection of subjects and are mandated by regulatory agencies 
worldwide. 
 
7.1 
Definitions and Descriptions 
7.1.1 Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: 
 
Results in death; 
 
Is life-threatening (the subject was at risk of death at the time of the event. It does not 
refer to an event which hypothetically might have caused death if it were more severe); 
 
Requires hospitalization or prolongation of existing hospitalization; 
o 
This criterion applies if the event requires inpatient hospitalization and results in an 
overnight stay in hospital or, if in the opinion of the investigator, prolongs an existing 
hospitalization.   
o 
Hospitalizations for less than 24 hours with no admission are not considered 
“hospitalization”.  
o 
A hospitalization (including hospitalization for an elective procedure or routinely 
scheduled treatment or pre-planned procedures) for a pre-existing condition which 
has not worsened does not constitute an SAE. 
 
Results in persistent or significant disability/incapacity; 
 
Is a congenital anomaly/birth defect; and/or 
 
Is an important medical event (an event that may not fit the other criteria for a SAE as 
listed above, but based upon appropriate medical judgment, may jeopardize the subject 
or may require intervention to prevent one of the outcomes listed above). Examples of 
such events (per 21 CFR 312.3215) are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization or development of drug dependency or drug abuse. 


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7.1.2 Non-serious Adverse Event 
A non-serious AE is any event that does not meet the above-mentioned SAE definition. 
7.1.3 Severity 
The severity of each AE will be determined based upon the following criteria: 
 
Mild: 
Transient symptoms, no interference with subject’s daily activities. Less 
than 48 hours, no medical intervention/therapy required. 
Moderate: 
Marked symptoms, moderate interference with the subject’s daily 
activities. No or minimal medical intervention/therapy required. 
Severe:  
Considerable interference with the subject’s daily activities. Medical 
intervention/therapy required; hospitalization possible. 
7.1.4 Relationship to Study Medication 
The relationship to study medication will be determined and recorded on eCRF by an 
Investigator using the following criteria based on the World Health Organization (WHO) 
classification: 
 
Causality 
Definition 
Unrelated 
 
Concurrent illness, concurrent medication, or other known cause is clearly responsible 
for the adverse event OR based upon available information regarding subject history, 
disease process, relationship of adverse event to dosing, and drug pharmacology, a 
relationship between the drug and adverse event is unlikely. 
Possible 
The adverse event follows a reasonable sequence from the time of drug administration, 
but could also have been produced by the subject’s clinical state or by other drugs 
administered to the subject.  
Event with a time to drug intake that makes a relationship improbable (but not 
impossible). Disease or other drugs provide plausible explanations 
Probably 
The adverse event follows a reasonable sequence from the time of drug administration, 
follows a known response pattern of the study treatment class, is confirmed by 
improvement on stopping the study treatment is the most likely of all causes. 
Event with reasonable time relationship to drug intake: 
• Unlikely to be attributed to disease or other drugs 
• Response to withdrawal clinically reasonable 
• Rechallenge not required 
Definite 
The adverse event follows a reasonable sequence from the time of drug administration, 
follows a known response pattern of the study treatment class, is confirmed by 
improvement on stopping the study treatment, and there is no other reasonable cause 
exists. 
 
7.1.5 Onset and Duration 
The date and time the event was reported to investigator will be recorded, as well as the start 
date and time and resolution date and time of the event. 


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7.2 
Recording and Reporting of Adverse Events 
All AEs will be recorded in the source document and applicable eCRF(s) from the time the 
informed consent is signed until the end of study. AEs occurring prior to the first dose of study 
drug will be considered non-treatment emergent. Any ongoing AEs will be followed until they 
are resolved, stabilized, or until 30 days after the end of treatment exposure. The Investigator 
shall notify the Sponsor at any time when an SAE is believed to be related to the administration 
of study medication, even after the end of the study. At any time during the study, those events 
meeting the definition of an Immediately Reportable Event (IRE) must be recorded on source 
document, IRE Reporting Form, and applicable eCRF(s), and then reported to Sponsor or 
designee using the IRE Reporting Form as specified in Section 7.2.1. 
  
All AEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject’s participation in the study, must be followed until either: 
 
the event resolves; 
 
the event stabilizes; 
 
the event returns to baseline, if a baseline value is available;  
 
the event can be attributed to other than the study medication, or to other than study 
conduct; 
 
the Investigator does not anticipate any further improvement or worsening of the event. 
All AEs, regardless of seriousness, severity or presumed relationship to study medication, 
must be recorded using medical terminology in the source document and in the eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should 
be reported as “upper respiratory infection”). Investigators must record on the source 
document and eCRF their opinion concerning the relationship of the AE to study therapy and 
the severity of the event. All measures required for AE management must be recorded in the 
source document and reported according to Sponsor instructions. 
7.2.1 Reporting of Immediately Reportable Events 
The following events, regardless of severity or seriousness, are considered immediately 
reportable IREs and are to be reported via the IRE Form within 24 hours to the Sponsor or 
designee: 
 
All Serious Adverse events; 
 
All pregnancies; and 
 
Events of Special Interest (list all events of special interest). 
o 
Chest pain/chest discomfort 
o 
Dyspnea/shortness of breath/difficulty breathing 
o 
Hepatotoxicity/liver enzyme increased 
o 
Anaphylaxis, including anaphylactoid reaction and anaphylactic shock 
 
Immediately Reportable Events, such as SAEs, should be recorded on the Adverse Event 
source document and eCRF. In addition, any IRE occurring during the clinical study must be 
reported within 24 hours to the Sponsor or designee using the IRE form. The initial report of 
an IRE must be documented on the study IRE form, signed by the Investigator and submitted 
by facsimile. The Investigator must provide the following information: protocol number, 


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subject’s initials and study number AE term and associated dates, causal relationship between 
the event and study medication, relevant history, study medication dosing details, full 
description of the event, and other required data within the IRE form. All oral reports of an IRE 
must be followed immediately by a facsimile of the IRE form signed by the Investigator. 
Investigators should not leave oral reports of IREs on any voicemail aside from the Sponsor’s 
Medical Monitor or designee. The details of the adverse event reporting requirement are also 
outlined in a safety reporting plan. 
 
The Sponsor assumes responsibility for reporting of expedited and periodic safety reports to 
the appropriate regulatory authorities. The Sponsor will report to the Investigator any new 
safety events occurring in other studies. The Investigator may need to report SAEs to the 
appropriate IRB/IEC in accordance with local regulations. 
7.2.1.1 Reporting of Pregnancies 
Any pregnancy occurring in a female subject after the first intake of study medication, while 
not an AE, is considered an IRE. It must be reported within 24 hours of the Investigator learning 
of the event using an IRE Pregnancy Report Form. Any subject, who becomes pregnant, shall 
be removed from the clinical study and followed for the duration of the pregnancy. Follow-up 
information regarding the outcome of the pregnancy and any postnatal sequelae in the infant 
up to one year of age will be required. 
 
7.2.2 
Outcome  
The investigator should follow all IREs until resolution (return to baseline status) or loss to 
follow-up or until no further improvement or worsening of the participant’s condition is 
expected. Loss to follow-up implies that the Investigator site is no longer aware of the 
participant’s whereabouts, and is unable to obtain current contact information. All attempts to 
contact the participant must be captured in the appropriate trial source document. 
7.2.3 
Symptoms of the disease under study 
Symptoms of the disease under study should not be classed as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease. However, significant 
worsening of the symptoms should be recorded as an AE.  
7.2.4 
Clinical laboratory evaluations 
A change in the value of a safety laboratory investigation can represent an AE if the change is 
clinically relevant or if, during treatment with the investigational product, a shift of a parameter 
is observed from a normal value to a pathological value, or a further worsening of an already 
pathological value. When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing treatment or after 
the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration. 
If, at the end of the treatment phase, there are pathological laboratory values which were not 
present at baseline, per investigator discretion further clinical or laboratory investigations 
should be performed until the values return to within reference range or until a plausible 
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The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. 
7.2.5 
Vital Signs 
A change in the value of a vital sign measurement can represent an AE, as discussed in 
Section 6.3 for blood pressure and heart rate. The Investigator should decide, based on the 
criteria in Section 6.3, or per their discretion (for other vital sign measurements), and the clinical 
condition of a subject, whether a change in vital signs is clinically significant and therefore 
represents an AE. 
7.2.6 
Overdose 
There are no specific treatments or monitoring guidelines prescribed for subjects with 
lubiprostone overdose. It will be left to the discretion of the Investigator’s clinical judgment on 
how to provide appropriate symptomatic treatment.   
 
Any incidences of overdose with the investigational product will follow the same reporting 
procedures as an AE (see Section7.2 ), and only where applicable, as an IRE (see Section 
7.2.1).  
7.3 
Contacting Sponsor Regarding Safety 
Any medical safety related issue regarding the conduct of the trial needs to be addressed by 
the Medical Monitor. The names of the individuals (and corresponding telephone numbers) 
who should be contacted regarding safety issues are listed on the Sponsor Contact Information 
page in the front section of this protocol. 
7.4 
Coding of Adverse Events 
All AEs will be coded by the Sponsor’s designee using the current Medical Dictionary for 
Regulatory Activities (MedDRA)® terminology. 
 
7.5 
Monitoring of Safety Data 
A Data Safety Monitoring Board (DSMB) will monitor safety data on a regular basis throughout 
the study. Specific details, including meeting frequency and stoppage criteria, are provided in 
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8. 
STATISTICAL METHODS AND DATA MANAGEMENT 
The statistical analyses described in this section will be performed for the core study as further 
outlined in the SAP, which will be finalised prior to database lock and will be included in the 
Clinical Study Report for this protocol.  Due to the titration aspect of the preceding double-
blinded study (SAG/0211PFC-1131), bottles will not specifically identify whether they contain 
lubiprostone 12 or 24 mcg so as to maintain the prior blind. Dose assignment will only be 
known in subjects who were at least 50 kg in weight at the time of randomisation in the 
preceding study (SAG/0211PFC-1131). All dose assignments will be handled by the IXRS and 
will continue to maintain blinding with respect to the treatment assignment in the preceding 
trial. Investigators will be provided with subject treatment dose information associated with their 
study participants upon finalisation of the Clinical Study Report. 
8.1 
Determination of Sample Size 
The sample size goal is based on the expected attrition that would occur and the remaining 
number of safety evaluable subjects at each timeframe during the study.  
8.2 
Datasets Analysed 
Two analysis populations, Safety population and the modified Intent-to-Treat (mITT) population 
and these will be defined as follows: 
 
The Safety population will consist of all enrolled subjects who take at least one dose 
of study medication. 
 
The mITT population will include all enrolled subjects who take at least one dose of 
study medication and have at least one treatment period diary entry.  
8.3 
Analysis of Subject Characteristics and Completion Status 
Subject demographic data will be summarized by treatment group and overall with descriptive 
statistics. The summaries will include mean, median, standard deviation, minimum and 
maximum for continuous variables, and counts and percentages for each level of categorical 
variables.  
Baseline disease status will be assessed by constipation history, baseline period assessments 
of the subject’s evaluation of BM frequency rates, SBM frequency rates, stool consistency, 
bowel straining, abdominal pain, constipation severity, incontinence episodes, occurrence of 
large diameter stools, retentive posturing, and the health-related quality of life using the 
PedsQL™ questionnaires. These data will be summarized with descriptive statistics as 
outlined above. 
8.4 
Analysis of Exposure to Study Medication, Rescue Medication, and 
Concomitant Medication 
Assessments of actual exposure to study medication and rescue medication will be made 
based on the eCRF and diary data. Results will be summarized by descriptive statistics. 


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Concomitant medications will be classified by the World Health Organization (WHO) medical 
dictionary, and numbers and percentages of subjects receiving each classified medication will 
be calculated for all medications. 
8.5 
Analysis of Safety 
8.5.1 
Deaths, Serious Adverse Events, and Adverse Terminations 
Subjects with these critical events will be identified in separate listings, with the event, timing 
and outcome information and relevant demographic and baseline data. 
8.5.2 
Adverse Events 
The original terms used in the eCRF by Investigators to identify AEs will be coded to MedDRA® 
system organ class and preferred terms. Adverse events will be summarized in terms of 
incidence per dose group and overall. The incidence of an AE is defined as the number of 
subjects who experienced at least one episode during the study. Adverse event incidence rates 
will be summarized by system organ class (SOC) and preferred term (as determined by the 
coding). 
Whatever the level of classification, if a subject experiences multiple episodes of an event 
within the given time reference, then the event is only counted once. Further, for summaries 
by severity or causality, the most severe event is chosen for a subject if that subject 
experiences multiple episodes of the same event. 
In this study, faecal impaction and bone fractures will be captured as AEs. The events of faecal 
impaction will be used for the analysis of the faecal impaction frequency during the study (see 
Section 8.6.2.6). 
AEs with onset dates after administration of the first dose of study medication or prior to the 
last day of treatment + 7 days will be considered treatment-emergent. Events with completely 
or partially missing onset dates will be included in the tabulations, unless the available partial 
date information clearly indicates that the event happened outside of the treatment period. 
P-values from Fisher’s exact test or chi-square test will be presented in the AE summary tables. 
The test will be performed to compare incidence rates at the SOC and “At Least One Event” 
level between the two treatment groups. 
8.5.3 
Clinical Laboratory Tests 
For clinical laboratory data, mean changes from pre-treatment to post-treatment visits will be 
summarized using descriptive statistics. Cross-tabulations analysis will be performed for 
laboratory parameters with reference normal ranges. The laboratory data will be categorized 
as low, within, and above the reference normal ranges. The summary tables will tabulate the 
number and percentage of subjects with pre-treatment values below/within/above the normal 
reference range versus minimum/maximum/final post-treatment values below/within/above the 
normal reference range. Normal reference ranges will also be provided in the summary display. 
Laboratory parameters that are not specified in the protocol will not be included in the analysis, 
but they will be provided in the individual subject listings. 


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8.5.4 
Physical Examinations  
Subjects with changes from normal at baseline to abnormal during the treatment period in any 
organ system will be identified and listed. Shift tables, which indicate incidence rates of 
changes from (normal, abnormal) at baseline to (normal, abnormal) values at each visit, will 
be presented. 
8.5.5 
Bone Growth Assessments 
Bone growth will be assessed on the DXA subgroup population (i.e., those subjects who were 
aged 6 to 9 or 14 to 17 at the time of enrolment into the SAG/0211PFC-1131 study, and who 
were qualified to participate and enrolled in the DXA substudy). Bone-related DXA endpoints 
will include:  
 
Percent changes from baseline in BMD and BMC;  
 
Change from baseline in BMD Z-scores and in height-adjusted Z-scores;  
 
Changes from baseline in height and weight Z-scores. 
Details on analyses by age, race, and gender subgroups are provided in the SAP. 
8.5.6 
Vital Signs 
Descriptive statistics will be provided to evaluate the changes from baseline for any vital signs, 
including height and weight, measured during the study. 
8.5.7 
Pharmacokinetic Evaluations 
A population pharmacokinetic analysis will be performed using the concentration-time data 
from the sparse PK samples in this study. The analysis may include data from other studies 
with lubiprostone in adults, paediatric subjects, or healthy volunteers. A separate analysis plan 
for the population pharmacokinetic analysis will be prepared prior to database lock. 
8.5.8 
Subgroup and Exploratory Analyses 
Upon completion of pivotal phase 3 studies, analyses of any under-represented subgroups 
such as males and non-whites will be performed on the pooled data from the pivotal studies. 
Details pertaining to these analyses will be specified in the SAP. 
8.6 
Analysis of Efficacy 
8.6.1 
General Inferential Principles 
The following principles apply for all inferential analyses of efficacy: All tests are two-tailed at 
a significance level of α = 0.05.  
8.6.1.1 Missing Data 
Details on handling of missing data are described in the SAP. 


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8.6.1.2 Multiplicity 
No interim analyses will be performed and therefore no multiplicity adjustments will need to be 
made to account for them. 
8.6.1.3 Multicentre Studies 
Region and/or centre effects will be explored as detailed in the SAP. 
8.6.2 
Efficacy Endpoints 
8.6.2.1 Overall and Monthly Change from Baseline in BM and SBM Frequency 
Changes from baseline in BM and SBM frequency will be analysed overall, and at each month 
from Months 1 through Month 9. A month is defined as a 4-week period; e.g., Month 1 is Weeks 
1-4; Month 2 is Weeks 5-8; Month 3 is Weeks 9-12. The SBM frequency rate per week will be 
computed as specified in Section 8.6.2.1. The analyses of the months will utilize the same 
methods as those used in the analysis of weeks. 
8.6.2.2 Overall and Monthly Change from Baseline in Incontinence Frequency 
This analysis will be performed for subjects who are fully toilet-trained and for the subset of 
subjects presenting with incontinence at baseline. Change from baseline in incontinence 
frequency will be analysed overall, and at each month during Months 1 through 9 as described 
in Section 8.6.2.2. 
8.6.2.3 Overall and Monthly Change from Baseline in Production of Large Diameter Stool 
Frequency 
This analysis will be performed for subjects who are fully toilet-trained. Change from baseline 
in the production of large diameter stool frequency will be analysed overall, and at Months 1 
through 9 as described in Section 8.6.2.2. 
8.6.2.4 Overall and Monthly Change from Baseline in Proportion of BMs and SBMs in Toilet 
This analysis will be performed for subjects who are fully toilet-trained. Change from baseline 
in the proportion of BMs and SBMs in the toilet will be analysed overall, and at each month 
during Months 1 through 9 as described in Section 8.6.2.2. 
8.6.2.5 Overall and Monthly Change from Baseline in Frequency of Faecal Impaction 
Change from baseline in faecal impaction frequency will be analysed overall, and at each 
month during Months 1 through 9 as described in Section 8.6.2.2. 
8.6.2.6 Overall and Monthly Change from Baseline in Frequency of Retentive Posturing or 
Excessive Volitional Stool Retention 
Change from baseline in retentive posturing or excessive volitional stool retention frequency 
will be analysed overall, and at each treatment month during Months 1 through 9 as described 
in Section 8.6.2.2. 


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8.6.2.7 Overall and Monthly Change from Baseline in Constipation Signs and Symptoms 
Mean changes from baseline will be generated based on subject reported data as to the degree 
of: 
 
Straining associated with SBMs; 
 
Stool consistency of SBMs; 
 
Abdominal pain associated with SBMs; and 
 
Constipation severity. 
The following rating scales will be used: 
Stool consistency: Modified Bristol Stool Form Scale (5-point scale); 
Bowel straining: 0=Not at all, 1=A little, 2=Some, 3=Quite a bit, 4=Extremely 
Constipation severity and abdominal pain: 0=Absent, 1=Mild, 2=Moderate, 3=Severe, 4=Very 
severe. 
The overall change from baseline will be calculated as the baseline value subtracted from the 
average of all diary ratings, where the baseline value will represent the average rating during 
the 2-week screening period of the previous study (SAG/0211PFC-1131). The change from 
baseline for a week (7-day period) or month (4-week period) will also be calculated as the 
baseline value subtracted from the average of all diary ratings during a week or month. 
Stool Consistency 
The analysis of stool consistency will focus on consistency assessments associated with 
SBMs. The average stool consistency rating will be calculated for each month (4-week period), 
excluding measurements recorded within 24 hours after rescue medication intake. 
Analyses will be based on the change from baseline, where the baseline value will represent 
the average stool consistency rating from all SBMs during the 2- week screening period of the 
previous study (SAG/0211PFC-1131). The van Elteren test using the change from baseline 
stratified by pool centre and stratified by study for the pooled group will be used. 
Straining 
Bowel straining will be analysed in a method similar to stool consistency. 
Constipation Severity 
The changes from baseline in mean constipation severity ratings at each month during Months 
1 through 9 will be analysed. The change from baseline will be calculated as the baseline value 
subtracted from the average of all diary ratings during the given month. For these daily diary 
assessments, each month will be defined by 4-week intervals beginning with the day of the 
first dose of study medication (Day 1). For example, Month 1 will start with the daily 
assessment on Day 1 and end with the daily assessment on Day 29 (Week 4), Month 2 will 
start with the daily assessment on Day 30 and end with the daily assessment on Day 57 (Week 


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8), and Month 3 will start with the daily assessment on Day 58 and end with the daily 
assessment on Day 85 (Week 12). Each week will be defined by 7-day intervals beginning with 
the day of the first dose of study medication (Day 1).  
The van Elteren test using the change from baseline stratified by pooled centre for the 
individual studies and stratified by study for the pooled group will be used. 
Abdominal Pain 
Abdominal pain will be analysed similarly to constipation severity. Summary tables for the 
monthly change from baseline will also be presented. 
8.6.2.8 Monthly SBM Response 
A monthly responder is defined as a subject who is a weekly responder for 3 of 4 weeks per 
month. A weekly responder is defined as a subject who has a frequency rate of ≥ 3 SBMs/week 
and an increase from baseline of ≥ 1 SBM/week for that week. Analyses of the frequency rates 
of SBMs per month will be performed using the van Elteren test, stratified by pooled centres. 
8.6.2.9 Treatment Effectiveness 
Measurements of treatment effectiveness will be collected via the diary at weekly intervals as 
well as overall using the following scale: 0 = Not at all effective, 1 = A little bit effective, 2 = 
Moderately effective, 3 = Quite a bit effective, 4 = Extremely effective. 
8.6.2.10 Health-related Quality of Life 
Health-related quality of life will be measured using the PedsQL™ questionnaire.  
The PedsQL™ questionnaire has 4 subscales: physical functioning, emotional functioning, 
social functioning, and school functioning; in addition, there is a total score. Summary 
evaluations of response for every domain and total score at each timepoint will be provided by 
treatment arm. For each subscale and for the total score, the change from baseline at each 
visit will be analysed. 
8.7 
Data Quality Assurance 
Steps to be taken to assure the accuracy and reliability of data include the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the Investigator 
and associated personnel prior to the study, and periodic monitoring visits by the Sponsor or 
designee. Compliance will be achieved through a combination of study specific audits of 
investigational sites and audits at regular intervals of the Sponsor’s systems for data handling, 
analysis, and reporting. eCRFs will be reviewed for accuracy and completeness by the 
Sponsor or designee during on-site monitoring visits and any discrepancies will be resolved 
with the Investigator or designees, as appropriate. The data will be entered into the clinical 
study database and verified for accuracy. 
This study will be organised, performed, and reported in compliance with the Sponsor’s 
Standard Operating Procedures, protocols and working practice documents, and the 
requirements of national and international GCP guidelines.  


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8.8 
Data Collection 
Original source data will be collected via source documents.  Final data for this study will be 
collected using electronic case report forms (eCRFs). Data must be entered onto the eCRFs 
in English. All eCRFs must be completed in a timely manner before the Sponsor or designee 
performs a monitoring visit. The Principal Investigator will be required to electronically sign the 
eCRFs casebook for each subject. Laboratory reports must be reviewed, signed, and dated by 
an appropriate Investigator and filed with the source documents. Any laboratory findings out 
of the normal range should indicate the clinical significance (clinically significant [CS] or not-
clinically significant [NCS]) of the results on both the source document and the corresponding 
eCRF. 
The eCRFs are to be completed as soon as possible from the time of the subject’s visit, with 
the exception of results of tests performed outside the Investigator’s office, so that they always 
reflect the latest observations on the subjects participating in the study. 
All eCRF corrections are to be made or reviewed by the Investigator or other authorized study 
site personnel.  
Automatically generated queries will be answered by site personnel during the eCRF 
completion process. 
The dates of the monitoring visits will be recorded by the monitor in a study site visit log to be 
kept at the site. The first post initiation visit will usually be made as soon as possible after 
enrolment has begun. At these visits, the monitor will compare the data entered into the eCRFs 
with the hospital or clinic records (source documents). Source documentation must be 
available to substantiate proper informed consent procedures, adherence to protocol 
procedures, adequate reporting and follow-up of AEs, administration of concomitant 
medication, medication receipt/dispensing/return records, and study medication administration 
information. Specific items required as source documents will be reviewed with the Investigator 
prior to the study. Findings from this review of eCRFs and source documents will be discussed 
with the Investigator. The Sponsor expects that, during monitoring visits, the Investigator and 
study coordinator, will be available, the original source documentation, regardless of media, 
will be available, and a suitable environment will be provided for review of study-related 
documents. 
 


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9. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study will be conducted in accordance with current applicable regulations, International 
Conference on Harmonisation (ICH), European Union (EU) Directive 2001/20/EC17 and local 
ethical and legal requirements. 
9.1 
Sponsor’s Responsibilities 
9.1.1 
GCP Compliance 
The Sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their roles for this study in compliance with all applicable 
regulations, ICH GCP Guideline E614and EU Directive 2001/20/EC.17 
Visits to Investigator sites will be conducted by representatives of the Sponsor to inspect study 
data, subjects’ medical records and CRFs in accordance with current GCP and the respective 
local and national government regulations and guidelines. Records and data may additionally 
be reviewed by auditors, interested commercial parties or by regulatory authorities. 
9.1.2 
Regulatory Approval 
The Sponsor will ensure that Local Regulatory Authority requirements are met before the start 
of the study. The Sponsor (or a nominated designee) will be responsible for the preparation, 
submission and confirmation of receipt of any Regulatory Authority approvals required prior to 
release of investigational product for shipment to the study site. 
9.1.3 
Indemnity/liability and Insurance 
Sponsor will adhere to the recommendations of the Association of British Pharmaceutical 
Industry (ABPI) Guidelines. If appropriate, a copy of the Indemnity document will be supplied 
to the Investigator before study initiation. 
Sponsor will ensure that suitable insurance cover is in place prior to the start of the study. 
9.1.4 
Protocol Management 
All protocols and amendments will be prepared by The Sponsor. If it becomes necessary to 
issue a protocol amendment during the course of the study, the Sponsor will notify the 
Investigators and collect documented Investigator Agreement to the amendment. 
9.1.5 
End of Trial Notification 
With respect to investigational sites within the EU, the Sponsor will submit an end of trial 
notification to individual Member States and IECs within 90 days of the end of the trial in 
accordance with EU Directive 2001/20/EC.17 
The end of trial notification should be made when: 
 
the trial ends in the territory of the member state(s) concerned; and 


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 
the complete trial has ended in all participating centres in all countries within and outside 
the EU. 
For the purposes of this notification, the end of the complete trial will be defined as the last 
subject/last visit in all participating centres in all countries within and outside the EU and the 
end of trial in a member state will be defined as the last subject last visit in that member state. 
However, if recruitment into the trial as a whole is on-going and there is a possibility that further 
subjects may be recruited into the trial in a member state where there are currently no active 
subjects, the end of trial notification for that member state will be deferred until it is certain that 
no further subjects will be recruited into the study in that member state. 
9.1.6 
Submission of Summary of Clinical Study Report to Competent Authorities of 
Concerned Member States and IECs 
The Sponsor will provide a summary of the Clinical Study Report within one year of the end of 
the complete trial to the competent authority of the concerned Member State(s) as required by 
the regulatory requirement(s) and to comply with the Community guideline on Good Clinical 
practice. The Sponsor will provide the IECs with a copy of the same summary. 
9.2 
Investigator’s Responsibilities 
9.2.1 
GCP Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E614, EU Directive 2001/20/EC17, and the applicable regulatory requirements. A copy of the 
guidelines will be available in the Investigator Site File. 
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources 
are available at the study site prior to commitment to participate in this study. The Investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number 
of suitable subjects within the agreed recruitment period. 
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant trial-related tasks. An up-to-date copy of the curriculum vitae for the 
Investigator, Sub-investigator(s) and essential study staff will be provided to the Sponsor (or 
designee) before starting the study. 
If the subject has a primary physician the Investigator should, with the subject’s consent, inform 
them of the subject’s participation in the trial. 
A Coordinating Principal Investigator will be appointed as soon as possible, but prior to the end 
of the study, to review the final Clinical Study Report for multicentre studies. Agreement with 
the final Clinical Study Report will be documented by the signed and dated signature of the 
Coordinating Principal Investigator (multicentre study), in compliance with Directive 
2001/83/EC and ICH E3.18 


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9.2.2 
Protocol Adherence and Investigator Agreement 
The Investigator must adhere to the protocol as detailed in this document. The Investigator will 
be responsible for enrolling only those subjects who have met protocol eligibility criteria. The 
Investigators will be required to sign an Investigator Agreement to confirm acceptance and 
willingness to comply with the study protocol. The Investigator should accurately and regularly 
document all incidents of scientific misconduct or deviation from the protocol in the source 
documents and eCRFs or any other documents stipulated in the protocol. 
For investigational sites outside the EU, it is the Investigator’s responsibility to communicate 
with their local IRB/IEC to ensure accurate and timely information is provided at all phases 
during the study; for investigational sites within the EU, this can be done by the Sponsor, the 
Investigator or for multicentre studies the Coordinating Principal Investigator, according to 
national provisions. In particular the appropriate approvals must be in place prior to 
recruitment, notification of any SAEs during the study must take place and the IRB/IEC must 
be informed of study completion. 
9.2.3 
Documentation and Retention of Records 
9.2.3.1 Case Report Forms 
Data for this study will be collected using electronic data capture (EDC). eCRFs will be 
accessible via the internet for each subject’s study completion information.  
The Investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information will be transcribed onto eCRFs which have been designed to record 
all observations and other data pertinent to the clinical investigation. eCRFs should be filled 
out completely by the Investigator or delegate as stated in the Site Delegation List. 
Data must be entered into the eCRFs in English. All eCRFs must be completed in a timely 
manner and electronically submitted. The Principal Investigator will be required electronically 
sign and date specified screens of the eCRF. Laboratory reports must be reviewed, signed 
and dated by an appropriate Investigator.  
The eCRFs are to be completed as soon as possible from the time of the subject’s visit, with 
the exception of results of tests performed outside the Investigator’s office, so that they always 
reflect the latest observations on the subjects participating in the study. 
All eCRF corrections are to be made or reviewed by the Investigator or other authorized study 
site personnel.  
Completed eCRFs will be continuously submitted in the EDC system database, and reviewed 
by the Sponsor to determine their acceptability. Automatically generated queries will be 
answered by site personnel during the eCRF completion process.   
9.2.3.2 Recording, Access and Retention of Source Data 
Source data to be reviewed during this study will include, but is not limited to: subject’s medical 
file, subject diary cards, original laboratory reports, histology and pathology reports. 


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All key data must be recorded in the subject’s medical records. 
The Investigator must permit authorised representatives of the Sponsor, the respective 
national, local or foreign regulatory authorities, the IRB/IEC, auditors and interested 
commercial parties to inspect facilities and original records relevant to this study. 
The monitor (auditors, IRB/IEC or regulatory inspectors) may check the CRF entries against 
the source documents. The consent form will include a statement by which the subjects allow 
the monitor/auditor/inspector from the Sponsor or its representatives, national or local 
regulatory authorities or the IRB/IEC access to source data (e.g., subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.) which substantiate information 
recorded in the CRFs. These personnel, bound by professional secrecy, will not disclose any 
personal information or personal medication information. 
As described in the ICH GCP Guidelines, ‘essential documents’, including CRFs, source 
documents, consent forms, laboratory test results and investigational product inventory 
records, should be retained by the Investigator until at least 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. These documents should 
be retained for a longer period however if required by the applicable regulatory requirements 
or by an agreement with the Sponsor. The Investigator must obtain written permission from 
the Sponsor prior to the destruction of any study document. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by a properly authorised representative of the US Food and Drug Administration 
(FDA) in accordance with the US Code of Federal Regulations 21 CFR 312.6819 or other 
national or foreign regulatory authorities in accordance with regulatory requirements. 
9.2.3.3 Investigational Product Accountability 
All investigational product required for completion of this study will be provided by the Sponsor. 
The recipient will acknowledge receipt of the investigational product indicating shipment 
content and condition. Damaged supplies will be replaced. Accurate records of all 
investigational product dispensed, used and returned will be maintained. 
9.2.3.4 Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
US national and local regulatory authorities), the UK Medicines and Healthcare products 
Regulatory Agency (MHRA) and other foreign regulatory authorities, the Sponsor or its 
representatives, interested commercial parties and the IRB/IEC for each study site. 
9.2.3.5 Financial Disclosure 
The Investigator will be required to disclose any financial arrangement whereby the value of 
the compensation for conducting the study could be influenced by the outcome of the study. 
The following information will be collected: any significant payments of other sorts from the 
Sponsor such as a grant to fund ongoing research, compensation in the form of equipment, 


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retainer for ongoing consultation or honoraria; any proprietary interest in lubiprostone; any 
significant equity interest in Sucampo Pharmaceuticals, Inc., or Takeda Pharmaceuticals as 
defined in 21 CFR 54 2(b).20 
In consideration of participation in the study, the Sponsor will pay the Investigator or nominated 
payee the sums set out in the payment schedule attached to the Investigator agreement. 
9.3 
Ethical Considerations 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, the note for Guidance on Good Clinical Practice (Committee for Proprietary 
Medicinal Products/ICH/135/95)21, and with applicable local regulatory requirements. These 
documents set forth that the informed consent of the subjects is an essential precondition for 
participation in the clinical study. 
9.3.1 
Informed Consent 
It is the responsibility of the Investigator to obtain written Informed Consent from subjects, or 
if under the age of consent, from their Legally Authorised Representative (LAR; e.g., 
parent/legal guardian). Assent should be obtained, in accordance with applicable local 
requirements, from minor subjects.  
All consent and assent documentation must be in accordance with applicable regulations and 
GCP. Each subject or the subject’s LAR, where applicable, is requested to sign the IRB/IEC 
approved Subject Informed Consent Form after the subject/LAR has received and read the 
written subject information and received an explanation of what the study involves, including 
but not limited to: the objectives, potential benefits and risk, inconveniences and the subject’s 
rights and responsibilities. A copy of the informed consent documentation (Consent Form or 
Subject Information and the Consent/Assent Form, as applicable) must be given to the subject 
or the subject’s LAR.  
Informed consent documentation will be approved in the local language. If translation is 
required into other languages, they must be certified and approved by the IRB/IEC for use. 
Signed consent/assent forms must remain in each subject’s study file and must be available 
for verification by Study Monitors at any time. 
For investigational sites outside the EU, the Principal Investigator will provide the sponsor with 
a copy of the IRB/IEC approved consent/assent forms, and a copy of the IRB/IEC’s written 
approval, prior to the start of the study. For investigational sites within the EU, submission and 
obtaining IEC approval of the informed consent documentation can be the responsibility of the 
Sponsor, the Investigator or for multi-centre studies the Coordinating Principal Investigator, 
according to national provisions. Additionally, if the IRB/IEC required modification of the 
sample Subject Information and Consent/Assent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor. 
The sponsor reserves the right to delay initiation of the study at a site where the informed 
consent (and assent where applicable) forms do not meet the standards of applicable 
regulations and ICH GCP. 


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9.3.2 
Institutional Review Board or Independent Ethics Committee approval 
For investigational sites outside the EU, it is the responsibility of the Investigator to submit this 
protocol, the informed consent/assent document (approved by the Sponsor or its designate), 
relevant supporting information and all types of subject recruitment information to the IRB/IEC 
for review, and all must be approved prior to site initiation. For investigational sites within the 
EU, the applicant for an IEC opinion can be the Sponsor, the Investigator or for multi-centre 
studies the Coordinating Principal Investigator, according to national provisions. In addition, 
advertisements must be approved by the IRB/IEC prior to use at the site. Prior to implementing 
changes in the study, the Sponsor and the IRB/IEC must also approve any revised informed 
consent/assent documents and amendments to the protocol. 
On the approval letter, the trial (title, protocol number and version), the documents reviewed 
(protocol, informed consent material, [and amendments, if applicable]) and the date of review 
and actions taken should be clearly stated. 
Investigational product supplies will not be released and the subject recruitment will not begin 
until this written approval has been received by the Sponsor. 
For investigational sites outside the EU, the Investigator is responsible for keeping the IRB/IEC 
appraised of the progress of the study and of any changes made to the protocol, but in any 
case at least once a year; for investigational sites within the EU, this can be done by the 
Coordinating Principal Investigator, according to national provisions. The Investigator must 
also keep the local IRB/IEC informed of any serious and significant adverse events. 
9.3.3 
Measures for Reduction of Stress and Pain in Paediatric Subjects 
In consideration of the responsibility to ensure that children are enrolled in clinical research 
that is both scientifically necessary and ethically sound,22  the Sponsor has implemented the 
following measures to reduce the burden and stress of participation in this placebo-controlled 
trial: 
 
Use of experienced Investigators and research personnel to appropriately 
assent/consent study participants. Site staff will be trained at an Investigator Meeting and 
at Site Initiation Visits; 
 
Use of sparse PK sampling (population PK) to reduce the number of PK blood samples 
collected from each subject; 
 
Minimization of clinic visit frequency for blood chemistry, haematology, and urinalysis 
collection during the study; 
 
Minimization of cohorts of patients (to 6-9 and 14-17 year olds) to be subjected to DXA 
scans;  
 
Allowing the use of protocol-specified rescue medication for the duration of the study; 
 
Allowing for dose reduction in cases where subjects are experiencing specific adverse 
events; and 
 
Use of a DSMB for monitoring of safety for the duration of the study. 
 


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9.4 
Confidentiality 
All US-based investigational sites and laboratories or entities providing support for this study, 
must, where applicable, comply with the Health Insurance Portability and Accountability Act of 
1996 (HIPAA). An investigational site that is not a Covered Entity, as defined by HIPAA, must 
provide documentation of this fact to the Sponsor. 
Data collected during this study may be used to support the development, registration or 
marketing of lubiprostone. The Sponsor will control all data collected during the study, and will 
abide by the EU Directive on Data Privacy (Directive 95/46/EC) concerning the processing and 
use of subjects’ personal data. For the purpose of data privacy legislation, Sucampo Pharma 
Europe, Ltd. will be the data controller. 
After subjects have consented to take part in the study their medical records and the data 
collected during the study will be reviewed by the Sponsor and/or its representatives. These 
records and data may, in addition, be reviewed by the following: independent auditors who 
validate the data on behalf of the Sponsor; third parties with whom the Sponsor may develop, 
register or market lubiprostone; national or local regulatory authorities and the IRB(s)/IEC(s) 
which gave its/their approval for this study to proceed. 
Although subjects will be known by a unique number, their age and month and year of birth 
will also be collected and used to assist the Sponsor to verify the accuracy of the data, for 
example, that the laboratory results are assigned to the correct subject. The results of this 
study containing the unique number, age, month and year of birth and relevant medical 
information including ethnicity may be recorded and transferred to and used in other countries 
throughout the world, which may not afford the same level of protection that applies within the 
EU. The purpose of any such transfer would be to support regulatory submissions made by 
the Sponsor in order to market lubiprostone in other countries. 
9.5 
Publication Policy 
Sucampo abides by the clinical trial registration and results submission requirements to 
ClinicalTrials.gov described in Section 801 of the Food and Drug Administration Amendments 
Act (FDAAA 801). 
 


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10. 
APPENDICES  
 




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[X will be equal to the other medicine 
selected in prior item response.] 
 
Did your child take this today or 
yesterday? 
Today 
Yesterday 
Observer only 
item 
X  
 
Please record the time of this dose. 
[spinner xx:xx] 
Observer only 
item 
Confirm you would like to report a 
Bowel Movement your child had today 
or yesterday: 
 
Today’s Date: DD Mon YYYY 
Yesterday’s Date: DD Mon YYYY 
Yes 
No 
Observer only 
item 
Did this bowel movement occur today or 
yesterday? 
Today 
Yesterday 
Observer only 
item 
Please record the time of this bowel 
movement. 
[spinner xx:xx] 
Observer only 
item 
Did your child have this bowel 
movement in the toilet?  
Yes 
No 
I don't know 
Observer only 
item 
Did the bowel movement clog the toilet? 
Yes 
No 
I don't know 
Observer only 
item 
Is your child with you right now and 
available to answer questions about this 
bowel movement? 
Yes 
No 
Observer only 
item 




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STUDY MEDICATION 
 
Over the past week, how well did your 
child’s study medicine help? 
0 – not at all effective 
1 – a little bit effective 
2 – moderately effective 
3 – quite a bit effective 
4 – extremely effective 
Observer only 
item 
Over the past week, how many 
episodes of retentive posturing did your 
child have?  
 
[continuous numeric; not applicable] 
Observer only 
item  
 


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APPENDIX 2 
PEDIATRIC BLOOD PRESSURE LEVELS 
 
 


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APPENDIX 3 
PEDIATRIC HEART RATE RANGES 
Normal Heart Rate Values for Age of Pediatric Patients* 
Age 
Heart Rate (bpm) 
Newborn 
90-180 
1-5 months 
100-180 
6-11 months 
100-150 
1 year 
100-150 
2-3 years 
65-150 
4-5 years 
65-140 
6-9 years 
65-120 
10-12 years 
65-120 
13 + years 
55-110 
* Adapted from Silverman BK. Practical information In: Textbook of Pediatric Emergency Medicine 2006.24 
 
 
 
 


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11. 
REFERENCES 
1. Baker SS, Liptak GS, Colletti RB, Croffie JM, Di Lorenzo C, Ector W, Nurko S. Constipation 
in infants and children: evaluation and treatment. A medical position statement of the North 
American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 
1999 Nov;29(5):612–26. 
2. Biggs WS, Dery WH. Evaluation and treatment of constipation in infants and children. Am 
Fam Physician 2006 Feb;73(3):469–77. 
3. Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, Walker LS. 
Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology 2006 
Apr;130(5):1527–37. 
4. van den Berg MM, Benninga MA, Di Lorenzo C, et al. Epidemiology of childhood 
constipation: a systematic review. Am J Gastroenterology 2006;101:2401–2409. 
5. van Ginkel R, Reitsma JB, Buller HA, et al. Childhood constipation: longitudinal follow-up 
beyond puberty. Gastroenterology 2003;125:357–363. 
6. Loening-Baucke V. Chronic constipation in children. Gastroenterology 1993;105:1557–
1564. 
7. Staiano A, Andreotti MR, Greco L, et al. Long term follow-up of children with chronic 
idiopathic constipation. Dig Dis Sci 1994;39:561–564. 
8. van den Berg MM, van Rossum CH, de Lorijn F, et al. Functional constipation in infants: a 
follow-up study. J Pediatr 2005;147:700–704. 
9. Bongers ME, Benninga MA, Maurice-Stam H, Grootenhuis MA. Health-related quality of life 
in young adults with symptoms of constipation continuing from childhood into adulthood. Health 
Qual Life Outcomes. 2009;7:20. 
10. Chamberlain SM, Rao SS. Safety evaluation of lubiprostone in the treatment of constipation 
and irritable bowel syndrome. Expert Opin Drug Saf. 2012 Sep;11(5):841-50. 
11. Tucker ME. Lubiprostone provides capsule option for constipation in kids. Digestive 
Disorders. January 2010;52. 
12. Hyman PE, Di Lorenzo C, Prestidge LL, et al.. An open-label, multicentre, safety and 
effectiveness study of lubiprostone for the treatment of functional constipation in children. J 
Pediatr Gastroenterol Nutr 2013; Sep 16. [Epub ahead of print]. 
13. Varni, J.W., Seid, M., & Kurtin, P.S.  PedsQL 4.0: Reliability and validity of the Pediatric 
Quality of Life Inventory Version 4.0 Generic Core Scales in healthy and patient populations.  
Medical Care 2001; 39:800-812. 
14. ICH GCP Guideline E6 – ICH Topic E6 (R1) Guideline for Good Clinical Practice. 
15. 21 CFR 312.32 – IND Safety Reports. 
16.  ICH Guideline E1 – The Extent of Population Exposure to Assess Clinical Safety for Drugs 
Intended for Long-term Treatment of Non-life Threatening Conditions. 27 October 1994. 
17. Directive 2001/20/EC of the European Parliament and the Council on the approximation of 
the laws, regulations and administrative provisions of the Member States relating to the 


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implementation of good clinical practice in the conduct of clinical trials on medicinal products 
for human use. April 2001. 
18. ICH Guidance E3 – Structure and Content of Clinical Study Reports. 
19. 21 CFR 312.68 – Inspection of Investigator’s Records and Reports. 
20. 21 CFR 54 2(b) – Definitions; Significant equity interest in the sponsor of a covered study. 
21. CPMP/ICH/135/95 - Note for Guidance on Good Clinical Practice. 
22. Roth-Cline MD, Gerson J, Bright P, et al. Ethical considerations in conducting pediatric 
research. In Pediatric Clinical Pharmacology 2008. 
23. Chumpitazi et al. Creation and initial evaluation of a stool form scale for children. J 
Pediatr 2010; October; 157(4): 594–597. 
24. Silverman BK. Practical information In: Textbook of Pediatric Emergency Medicine 
2006. 
 


Sucampo AG 
 
SAG/0211PFC-11S1-01 
 
 
CONFIDENTIAL 
 
16.1.1.2 
Protocol Amendment Summaries 


 
 
LUBIPROSTONE: CLINICAL PROTOCOL   
SAG/0211PFC-11S1 
 
 
Protocol Amendment 3 
CONFIDENTIAL 
Page 73 of 77 
Summary of Changes; Version 1.0; 19 November 2015 
 
Sucampo Pharma Americas, LLC. 
 
Protocol SAG/0211PFC-11S1 Amendment 3 (Summary of changes) 
Date:  XX November 2015 
 
Protocol Version 4.0 will incorporate Amendment 3. 
 
The purpose of this amendment is to revise Protocol SAG/0211PFC-11S1 to reflect the following changes: 








 
 
 
 
 
LUBIPROSTONE: CLINICAL PROTOCOL   
SAG/0211PFC-11S1 
 
 
 
Protocol Amendment 2 
CONFIDENTIAL 
Page 1 of 1 
Amendment Date: 10th December 2013 
 
Sucampo AG 
Protocol SAG/0211PFC-11S1 Summary of changes for  
Amendment 2 
Date:  10 December 2013 
 
Protocol Version 3.0 will incorporate Amendment 2. 
 
The purpose of this amendment is to revise Protocol SAG/0211PFC-11S1 to reflect the 
following changes: 
 
Amendment 1 Revisions to Protocol SAG/0211PFC-11S1 
Page, Section  
Number, and Title 
 
Planned Revisions 
1 
Pages 13-14, Protocol 
Synopsis, Objectives, Study 
Medication and Dose 
Regimen; and 
Pages 21, Section 2.1, 
Objectives  
Previously: To assess the long-term safety, efficacy, and pharmacokinetics of oral 
lubiprostone 12 or 24 mcg capsules dosed twice daily (BID) when administered orally for 
36 weeks in paediatric subjects with functional constipation. 
 
Revised: To assess the long-term safety, efficacy, and pharmacokinetics of oral 
lubiprostone 12 or 24 mcg capsules dosed twice daily (BID) when administered orally for 
36 weeks in paediatric subjects with functional constipation. Evaluation of lubiprostone 
safety is the primary objective of this study. 
2 
Pages 13-14, Protocol 
Synopsis, Safety 
Evaluation/Efficacy 
Evaluation; 
Page 21-22, Section 2.2, 
Endpoints; and 
Pages 49-53, Sections 8.5 and 
8.6 
Previously: Efficacy endpoints were presented before safety endpoints. 
 
Revised: Safety endpoints are now presented before efficacy endpoints.  
 
 


 
 
 
 
 
LUBIPROSTONE: CLINICAL PROTOCOL   
SAG/0211PFC-11S1 
 
 
 
Protocol SAG/0211PFC-11S1 Summary of changes for  
Amendment 1 
Date:  26 November 2013 
 
Protocol Version 2.0 will incorporate Amendment 1. 
 
The purpose of this amendment is to revise Protocol SAG/0211PFC-11S1 to reflect the 
following changes: 
 
Amendment 1 Revisions to Protocol SAG/0211PFC-11S1 
Page, Section  
Number, and Title 
 
Planned Revisions 
1 
Page 13, Protocol Synopsis, 
Exclusion Criteria Number 5 
and 
Page 26, Section 4.2, 
Exclusion Criteria Number 5 
Previously: Subject (female of childbearing potential) has a positive pregnancy test, or 
refuses/unwilling to undergo pregnancy testing. 
 
Revised: Subject (female of childbearing potential) has a positive pregnancy test, 
refuses/unwilling to undergo pregnancy testing, and/or does not agree to use protocol-
specified contraceptive measures for the duration of the study. 
 
2 
Page 26, Section 4.4, 
Contraception Specifications  
 
Added New Section: Female subjects of child-bearing potential must agree to remain 
abstinent or to use adequate contraception during study participation. The type of 
contraception being used by the subject shall be recorded in the source document. 
Adequate contraception is defined as use of any of the following: 
• 
Oral Contraceptives– must have been used for at least 3 months prior to the 
Screening Visit (Visit 1); 
• 
Intrauterine Device (IUD); or 
• 
Double barrier method. 
 
3 
Section 6.1, Study Procedures 
by Visit (specifically Page 35, 
Section 6.1.2; Page 36, Section 
6.1.3.1; Page 37, Section 
6.1.3.3; Page 38, Section 
6.1.3.4; and Page 39, Section 
6.1.4.1) 
Added total blood volume to be collected at each relevant study visit for clinical 
laboratory and pharmacokinetic (PK) analyses, as follows: 
 
Visit 9: 5.5 mL for clinical laboratory samples and 16 mL for  PK samples 
Randomization visit (Visit 2): 16 mL 
Visits 10, 12, 14, 16, and 17: 5.5 mL 
 
4 
Page 59, Section 9.3.3, 
Measures for Reduction of 
Stress and Pain in Pediatric 
Patients  
 
Added New Section: In consideration of the responsibility to ensure that children are 
enrolled in clinical research that is both scientifically necessary and ethically sound,22  the 
Sponsor has implemented the following measures to reduce the burden and stress of 
participation in this placebo-controlled trial: 
• 
Use of experienced Investigators and research personnel to appropriately 
assent/consent study participants. Site staff will be trained at an Investigator Meeting 
and at Site Initiation Visits; 
• 
Use of sparse PK sampling (population PK) to reduce the number of PK blood 
samples collected from each subject; 
• 
Minimization of regular blood chemistry, haematology, and urinalysis collection during 
the study (optional collection given at Week 8 visit); 
• 
Allowing the use of protocol-specified rescue medication for the duration of the study; 
• 
Allowing for dose reduction in cases where subjects are experiencing specific 
adverse events; and 
• 
Use of a DSMB for monitoring of safety for the duration of the study. 
 
 
22 Roth-Cline MD, Gerson J, Bright P, et al. Ethical considerations in conducting pediatric 
research. In Pediatric Clinical Pharmacology, 2008. 
 
Protocol Amendment 1 
CONFIDENTIAL 
Page 1 of 1 
Amendment Date: 26 November 2013 
 
Sucampo Pharma Americas, LLC.