Efficacy and Safety of PEG 3350 for Treatment of Chronic Constipation
Phase: PHASE3
Conditions: Constipation - Functional
Sponsor: Fakultas Kedokteran Universitas Indonesia

 
 
CONFIDENTIAL 
 
 
 
CLINICAL TRIAL PROTOCOL 
Ver 01. 28 January 2019 
 
 
Efficacy and Safety of PEG 3350 for Treatment of                        
Chronic Constipation 
 
 
 
 
 
      Principal Investigator 
: Prof. Dr. dr. Murdani Abdullah, SpPD-KGEH 
 
  
Co-Investigators  
 
: dr. Amanda Pitarini Utari, SpPD 
 
 
  dr. Saskia Aziza Nursyirwan, SpPD 
 
 
  dr. Rabbinu Rangga Pribadi, SpPD 
 
 
  dr. Virly Nanda Muzelina, SpPD 
 
Trial Coordinator 
 
: Prof. Arini Setiawati, PhD 
 
Trial Monitor  
 
: dr. Taruna Dibya 
 
Estimated starting date 
: April 2019 
Estimated completion date : December 2019 
 
This study is supported by : PT. Meiji Indonesia 
Under contract No.   
:  
Director   
   
: Masanobu Sato 
Address  
   
: Jl. Tanah Abang II No. 4, Jakarta Pusat, Indonesia 

1 
 
CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
 
 
 
 
 
Name 
Phone/Fax/e-mail 
Address 
 
Principal Investigator : 
Prof. Dr. dr. Murdani Abdullah, SpPD-
KGEH 
  
Email : 
murdani08@gmail.com 
 
Hp:  0812-9550-812 
 
Office: 021-3153957  
           ext 6704 
 
Departemen Gastroenterologi 
RSCM, Jl. Diponegoro no. 71, 
Jakarta 
 
Co-Investigators : 
dr. Amanda Pitarini Utari, SpPD 
dr. Saskia Aziza Nursyirwan, SpPD 
dr. Rabbinu Rangga Pribadi, SpPD 
dr. Virly Nanda Muzelina, SpPD 
  
Office: 021-3142454 
           ext 6704 
Departemen Gastroenterologi 
RSCM, Jl. Diponegoro no. 71, 
Jakarta 
 
Study Monitor : 
dr. Taruna Dibya 
 
 
 
Email: 
tarunadibya@gmail.com 
 
Phone: 0812-1160-3275 
Clinical Research Supporting 
Unit (CRSU) FKUI 
IMERI FKUI, Tower A lt. 11          
Jl. Salemba Raya 6, 
Jakarta  
 

2 
 
CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
 
Efficacy and Safety of PEG 3350 for Treatment of                        
Chronic Constipation 
  
 
 
Prof. Dr. dr. Murdani Abdullah, SpPD-KGEH 
_______________________ 
Principal Investigator 
  
 
 
Date:  
 
 
Dr. dr. Evy Yunihastuti, SpPD, K-AI   
 
_______________________ 
Study Coordinator RSCM-FMUI  
 
Date:  
 
 
Prof. Dr. dr. Dadang Makmun, SpPD, KGEH 
_______________________ 
Head of Gastroenterology Division RSCM  
Date:  
 
 
Prof. dr. Frans. D. Suyatna, PhD, SpFK  
_______________________ 
Head of CRSU FMUI 
  
 
 
Date:  
 
 
 
  
 
 
 
Prof. Arini Setiawati, PhD                   
 
_______________________ 
Clinical Trial Coordinator CRSU FMUI 
 
Date:  
 
 
  
 
 
 
 
                                             
 
Masanobu Sato 
  
 
 
_______________________ 
(PT. Meiji Indonesia)    
 
 
Date: 
 
 

Efficacy and Safety of PEG 3350 for Treatment of                        
Chronic Constipation 
 
 
1.   Introduction 
Polyethylene (PEG) 3350 is a mixture of non-absorbable, non-metabolized polymers of mean 
molecular weight (MW) 3350 (+ 10%) that act as pure osmotic agents.  It contains no more 
than 0.1% of lower MW PEGs that are absorbable and excreted unchanged by glomerular 
filtration. 
Low dose PEG has been shown to be effective for treatment of chronic constipation.  
Ingestion of a solution containing PEG 3350 at low doses for 8 days significantly increased 
stool weight.  The volume of water taken with PEG did not modify the results. 
The osmotic agent lactulose is a synthetic disaccharide that is not absorbed by the small 
intestine but is readily metabolized by colonic bacteria. It has been shown to be effective for 
treating constipation, especially in the elderly.  Intracolonic fermentation of lactulose is 
associated with production of gases and with colic, bloating, and flatulence.  Furthermore, 
chronic ingestion of lactulose may induce changes in colonic bacterial metabolism and 
reduced efficacy in the treatment of chronic constipation.  Therefore, in the present study, 
lactulose is used as comparator in short-term only1. 
Whereas PEG is osmotically active without causing colonic gas production, and it has been 
shown to be nontoxic and can be ingested in large quantities without harmful effect. 
 
2.   Study objective  
To determine the efficacy and safety of PEG 3350 for short-term treatment of chronic 
constipation in adults. 
 
3.   Study design  
– 
Parallel group design, randomized, open-label, versus comparator for 14 days.  
– 
Block randomization using random permutation blocks of size 4. 
– 
Blinded evaluation. 
 
4.  Patients  
 
4.1.  Inclusion criteria 
a. Males and females aged ≥ 18 years. 
b. BMI ≥ 18.5 
c. Organic bowel disease will be ruled out by Fecal Immunochemical Test (FIT) and/or 
colonoscopy. 
d. Must have < 2 bowel movements during a 7-day qualification period. 
e. In otherwise good health as judged by a physical examination and laboratory testing. 

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This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
f. Not taking medications known to affect bowel function in one week before study. 
g. Willing to participate in the study by signing the informed consent. 
 
 
4.2.  Exclusion criteria  
a. Hypersensitive to the study medication. 
b. obstructive ileus. 
c. IBS and/or IBD 
 
5.  Study drugs  
 
5.1. Drug presentation 
– Test drug: PEG 3350 17 g powder per sachet 
– Comparator: Lactulax syrup 15 ml (containing 10 g of lactulose) 
5.2. Drug administration 
– The content of each sachet of PEG is dissolved in 240 mL of water, drink it once daily 
at bedtime, for a duration of 14 days.  
– 15 ml of Lactulax syrup is drunk with 240 ml of water once daily at bedtime, for a 
duration of 14 days. 
5.3.  Drug supply, packaging and labelling 
a.  PEG 3350 and Lactulax syrup will be supplied by PT. Meiji Indonesia. 
b.  CRSU FMUI will package PEG sachet and Lactulax syrup for individual patient according 
to a pre-determined randomization list. Each drug package is labelled with the patient 
randomization number and dosage instruction. Each patient will receive drug supply 
for consumption at day 0 and day 7 (for 7 days each) plus a few days in excess, for 
compliance check and to allow additional days for patient visit. 
c.  Each patient receives: 
▪ Each patient receives a diary book at day -7 
▪ For 7-day Treatment of Period 1 and 7-day Treatment of Period 2: 
10 sachets of PEG 3350 or Lactulax syrup 1 bottle of 120 ml: 
– Dissolve content of 1 sachet of PEG in 240 mL of water, drink once daily at 
bedtime, or 
– 15 ml of Lactulax syrup, drink with 240 ml of water once daily at bedtime. 
▪ Study patients are instructed not to take any other laxative. 
5.4.  Drug accountability 
The investigators will be responsible for recording the receipt of study drugs from the 
Sponsor, dispensing the study drugs to each patient, and return of all unused drugs to the 
Sponsor. Any unused drug should be returned to the sponsor at the conclusion of the 
study. Forms will be made available. 

3 
 
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Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
5.5.  Drug storage 
 
The investigators are responsible for assuring that the study drugs are stored in a secure, 
limited access area, protected from extremes of light, temperature, and humidity.  
 
6.  Concomitant medication 
 
None 
 
7. Endpoints measured (by blinded evaluator) 
7.1.  For efficacy:  study patients are provided with diaries to record each bowel movement 
and associated symptoms. 
a. Primary endpoint: number of bowel movements (defecation) per 7-day period.  
b. Secondary endpoint:  
▪ 
Symptom scores:  
– Stool consistency: 0 = hard, 1 = firm, 2 = soft, 3 = loose, 4 = watery (by 
anamnesis - visual comparison) 
– Stool passage: 0 = strain, 1 = easy, 2 = loss of control (by anamnesis) 
– Cramping and rectal irritation associated with each bowel movement: 
     0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = have to discontinue 
     (by anamnesis) 
– Flatus: 0 = none, 1 = moderate, 2 = occasional, 3 = frequent, 4 = very    
frequent 
▪ 
Overall rating of effectiveness: effective / not effective. 
Effective: patients with ≥ 3 bowel movements per 7-day period. 
 
 
 
 
7.2  For safety   
 
 
a.  AEs – total and related (ADRs) 
 
 
b.  SAEs – total and related (SADRs) 
 
 
 

4 
 
CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
8.   Sample size 
Based on number of bowel movements / week: 
Number of bowel movements caused by PEG 3350 at week 2 = 4.5 + 3.02 
If PEG 3350 is considered non-inferior to the comparator lactulose, then the difference (∆) is 
assumed to be a maximum of 10% = 0.45. 
Non inferiority margin = 1 
 
 = 5% (1-sided) → Z = 1.645 
 = 10% (1-sided) → Z = 1.282 
 
 
 
 
20% DO → 1.25 x 73.34 = 92 
Total = 2 x 92 = 184 patients 
 

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CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
9. Evaluation chart 
Time Schedule of Evaluation 
 
 
Screening  
Baseline 
Treatment 
Period 1 
Treatment 
Period 2 
After 
Treatment 
Day 
-7 
0 
7 
14 
21 
Visit 
1 
2 
3 
4 
5 
Informed consent 
√ 
 
 
 
 
Demography 
√ 
 
 
 
 
Medical history 
√ 
 
 
 
 
Physical examination 
√ 
 
 
 
 
Laboratory tests: 
– Routine hematology  
 
– Liver & kidney function 
 
 
√ 
 
√ 
 
 
 
  
 
 
√ 
 
√ 
 
 
Urinalysis  
√ 
 
 
√ 
 
Stool test 
√ 
 
 
 
 
Colonoscopy 
PA colonoscopy 
√ 
 
 
 
 
Inclusion/exclusion criteria 
 
√ 
 
 
 
Study drug dispensed 
 
√ 
√ 
 
 
Collect unused study drug 
 
√ 
√ 
√ 
 
Patient diary given 
Record: 
– Number of bowel movement (BM) 
– Stool consistency 
– Stool passage 
– Cramping & rectal irritation 
– Flatus 
       → assoc. with each BM 
√ 
√ 
√ 
√ 
 
Patients diary reviewed 
 
√ 
√ 
√ 
√ 
Overall rating of effectiveness 
 
 
 
√ 
 
Adverse events 
 
√ 
√ 
√ 
√ 
Patient status 
 
 
 
√ 
 
 

6 
 
CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
10.  Patient discontinuation 
10.1. Reasons for discontinuation 
a. At the request of the patient.  
b. If a patient undergoes an acute medical condition requiring intensive treatment, the 
patient will be withdrawn from the study. 
c. If the investigator considers that a patient’s health be compromised due to adverse 
effects that occur during the study.  
d. If the patient does not comply with the investigator’s instructions. 
10.2. Data collected for discontinued patients 
a. Complete all examinations at the current visit. 
b. Complete the CRF with: 
 
- the time, date and reasons for discontinuation; 
 
- assessment of efficacy and safety of the assigned drug until the last day. 
c. If necessary, arrange alternative medical care for the discontinued patient, and 
record in the CRF any follow-up of patients who are discontinued due to adverse 
events.   
10.3. Unevaluable criteria 
Patients who are recognized after entry to be uneligible (do not meet selection criteria). 
 
 
11.  Safety assessments 
All adverse events will be recorded in the CRF: the onset date, the date resolved/ongoing, 
the severity (mild, moderate, severe), the effect on study drug dosing (reduced, interrupted, 
or discontinued), and the outcome/action taken (additional therapy, hospitalization, 
additional study visit, etc.).  The relationship with study drug will also be assessed and 
categorized as probable, possible, or unlikely. 
In order to detect all possible adverse events, questions to the patient should not be 
restricted to “How have you been feeling after the last dose?” or some similar general 
question, but some questions should also be directed to the known adverse reactions of the 
test drug. 
If a serious event occurs, the investigator must report it immediately (within 24 hours) by 
telephone to the Trial Monitor, 
 
Name of the Trial Monitor :   dr. Taruna Dibya 
 
 
Address 
:   Clinical Research Supporting Unit, Faculty of Medicine,                     
Universitas  Indonesia 
 
 
Jl. Salemba Raya 6, Jakarta 10430. 
 
 
Phone 
:  (021) 291 891 60 
 
 
 

7 
 
CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
and within 3 calendar days to the Ethics Committee regardless of treatment group or 
whether any relationship to drug is suspected. 
Serious adverse events include events which: 
▪ 
are fatal 
▪ 
are life-threatening or potentially life-threatening 
▪ 
result in permanent disability 
▪ 
require hospitalization or prolongation of a hospital stay 
▪ 
involve cancer, a congenital anomaly, or the result of a drug overdose 
▪ 
suggest significant hazard to the patient 
Any death during or within a reasonable period after a study must be reported as a serious 
event, independent of the circumstances or suspected cause.  In such a case, a summary of 
available autopsy findings must be submitted as soon as possible to the Trial Monitor. 
An intercurrent illness should also be reported immediately if regarded as serious according 
to the above criteria. 
It should be emphasized that, regardless of the above criteria, any additional adverse events 
which the investigator considers significant should be immediately reported. 
In case a female patient becomes pregnant during the study, this event should also be 
reported within 24 hours by telephone to the Trial Monitor. 
Any event that should be immediately reported are described in detail on a special Adverse 
Event Reporting Form with the assistance of the Trial Monitor.  This special form will be 
made available by the sponsor. This detailed SAE Report should be submitted within 15 
calendar days to the Sponsor and the Ethics Committee.   
The drug-related SAEs should be submitted to the NRA within 15 calendar days. 
 
 
 
 
 
 
 12.  Study management  
12.1. Study completion (PLEASE, WRITE CLEARLY !) 
The investigators will ensure that all observations and findings on each patient are 
transcribed from primary source data correctly and completely in the CRFs using black 
ballpoint pen. 
All corrections on a CRF must be made in a way which does not obscure the original 
entry (do not use eraser or tipp-ex, but cross with only one line).  The correct data 
must be inserted, initialled and dated by the investigator. 
The summary page of the CRF must be signed by the principal investigator, thereby 
stating that he/she takes responsibility for the accuracy of the data in the entire CRF . 
12.2. Study monitoring 
The Trial Monitor will visit the investigators periodically to assess the progress of the 
study and the adherence to the protocol.  The investigator should allow the Trial 
Monitor to visit and check the CRF for completeness and accuracy. 

8 
 
CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
The Trial Monitor should report all irregularities found, to the Sponsor and Trial 
Coordinator in the Clinical Research Supporting Unit Faculty of Medicine, Universitas 
Indonesia, so that corrective measures can be taken. 
The investigators should keep source documents such as: 
- medical record (complete history and physical examination, treatment given and 
results) 
- laboratory reports 
- any consultation reports 
- etc. 
for possible review by the Trial Monitor. 
12.3. Retention and disclosure of data 
a. The trial data must be retained until at least 2 years after the last approval of a 
marketing application in the region. 
b. All information obtained from the study will be regarded as confidential, at least until 
the study results have been published. 
 
If any information relative to this study will be disclosed to a third party, permission 
from the investigators and sponsor is necessary. 
13. Study Procedure 
All 184 patients will be collected from Petamburan community, Paseban community and 
RSUPN dr. Cipto Mangunkusumo.  
After signing the informed consent, the study candidates will be evaluated for enrollment: 
history of constipation, hypersensitivity to the study medication, demographics, organic 
bowel disease checking by FIT and/or colonoscopy, IBD, IBS, serum chemistry tests and 
urinalysis. Then, 7-day qualification period, before which candidates will receive one diary 
book to record how many times defecation during these 7 days. Candidates with one or two 
bowel movement (defecation) during these 7 days will continue into the treatment phase. 
Each patient will receive 10 sachets of PEG or 1 bottle of 120 ml Lactulax syrup. The content 
of each PEG sachet will be dissolved in 240 ml of water and drink it once daily at bedtime for 
7 days or 15 ml of Lactulax syrup, drink with 240 ml of water once daily at bedtime for 7 
days. During these 7 days, the stool consistency (hard, firm, soft, loose or watery) is 
compared with pictures provided, the stool passage (strain, easy or loss of control), and the 
following symptoms: cramping, rectal irritation, and flatus associated with each bowel 
movement, will be recorded in the diary book. 
After 1 week, the patient will return to the study site to return the unused drug and to show 
the dairy book. The investigator will examine the dairy book to look for any improvement of 
the constipation. The patient will again receive 10 sachets of PEG or 1 bottle of 120 ml 
Lactulax syrup for another week, and return at the end of the second week, bringing the 
unused drug and the dairy book to the investigator. 

9 
 
CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
The patients will be visited by the co-investigator on day 21 (no drug being administered 
during this last week), the intention is to have information whether any adverse event occurs 
during this week. 
14.  Data analyses 
 14.1.  Efficacy analysis 
After parallel-group design (at 7 and 14 days): 
Statistical analysis between PEG vs. Lactulose: 
▪ bowel movements frequency: use unpaired t-test or Mann-Whitney test                         
▪ symptom scores: use Mann-Whitney test 
▪ overall rating of effectiveness: use X2 test       
 
14.2.  Safety analysis 
After double-blind cross-over design: all patients who take at least one dose of the 
study drug and return at least once post-randomization, will be subject to safety 
analysis. 
 a.   Adverse events (AEs) 
All adverse events will be listed per group (PEG and comparator drug), both the 
incidence and the percentage.  No statistical test will be used for comparison.  
b. Adverse drug reactions (ADRs) 
The adverse events with possible and probable relationship to the study drug 
(ADRs) will also be listed as the incidence and the percentage per group (PEG 
and comparator drug). No statistical test will be used.  
15.  Publication 
Publication of the trial will be done after agreement of all parties and is the responsibility of 
the Principal Investigator, assisted by the Trial Coordinator in Clinical Research Supporting 
Unit, FMUI. 
 
16.  Ethical Committee Approval 
Approval from the Ethical Committee at the Faculty of Medicine Universitas Indonesia must be 
obtained before starting the trial. 
 
17.  Clinical Trial Registry 
Clinical Trial Registry Number will be sought from ClinicalTrials.gov. 
 

10 
 
CONFIDENTIAL INFORMATION 
This material is the property of the Sponsor, developed by Clinical Research Supporting Unit Faculty of Medicine University of Indonesia 
Do not disclose or use any section of the present document except as authorized in writing by PT. Meiji Indonesia and CRSU FMUI. 
18.  References 
1. 
A Attar, M Lemann, A Fergusen, M Halphen, M-C Boutron, B Flourie, et al.  Comparison of 
a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic 
constipation. Gut. 1999; 44: 226-30. 
2. 
JA DiPalma, PH DeRidder, RC Orlando, BE Kolts, MvB Cleveland.  A randomized, placebo-
controlled, multicenter study of the safety and efficacy of a new polyethylene glycol 
laxative.  Am J Gastroenterology. 2000; 95(2): 446-50. 
3. 
JA DiPalma, MvB Cleveland, J McGowan, JL Herrera.  An open-label study of chronic 
polyethylene glycol laxative use in chronic constipation.  Aliment Pharmacol Ther. 2006; 
25: 703-8. 
4. 
M vB Cleveland, DP Flavin, RA Ruben, RM Epsteins, GE Clark.  New polyethylene glycol 
laxative for treatment of constipation in adults: a randomized, double-blind, placebo-
controlled study. South Med J. 2001; 94(5): 478-81.