1. American Journal of Gastroenterology ISSN 0002-9270
C 2007 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2007.01199.x
Published by Blackwell Publishing
A Randomized, Multicenter, Placebo-Controlled Trial
of Polyethylene Glycol Laxative for Chronic Treatment
of Chronic Constipation
Jack A. DiPalma, M.D., F.A.C.G., Mark vB. Cleveland, Ph.D., John McGowan, B.S.,
and Jorge L. Herrera, M.D., F.A.C.G.
Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, Alabama and
Braintree Laboratories, Inc., Braintree, Massachusetts
OBJECTIVES: Polyethylene glycol (PEG) 3350 (MiraLAX) is currently approved for the short-term treatment of
occasional constipation. This study was designed to compare the safety and efficacy of PEG laxative
versus placebo over a 6-month treatment period in patients with chronic constipation.
METHODS: Study subjects who met defined criteria for chronic constipation were randomized in this
double-blind, placebo-controlled, parallel, multicenter study to receive PEG laxative as a single daily
dose of 17 g or placebo for 6 months. Baseline constipation status was confirmed during a 14-day
observation period. As a primary efficacy variable, treatment success was defined as relief of
modified ROME criteria for constipation for 50% or more of their treatment weeks. Various
secondary measures were assessed. An Interactive Voice Response System (IVRS) recorded daily
bowel movement experience and study efficacy and safety information. Laboratory testing at
baseline and monthly for the study duration was analyzed for hematology, blood chemistry including
amylase, GGT, uric acid, lipids, and urinalysis.
RESULTS: A total of 304 patients were enrolled and received treatment at one of 50 centers. Successful
treatment according to the primary efficacy variable was seen in 52.0% of PEG and 11% of placebo
subjects (P < 0.001). Similar efficacy was seen in a subgroup of 75 elderly subjects. According to
the primary efficacy definition (based on individual treatment weeks), 61% of PEG treatment weeks
versus 22% of the placebo weeks were successful (P < 0.001). There were no significant differences
in laboratory findings or adverse events except for the gastrointestinal category where diarrhea,
flatulence, and nausea were the most frequent with PEG although they were not individually
statistically significant compared with placebo. Similar results were observed when analyzed for
differences due to gender, race, or age.
CONCLUSIONS: PEG laxative is safe and effective for use in patients with chronic constipation for 6 months.
(Am J Gastroenterol 2007;102:1436–1441)
INTRODUCTION
Until recently, few data have been available about chronic
treatmentofchronicconstipation(1–6).Ofthevariousconsti-
pation regimens, only tegaserod, a serotonin subtype 4 recep-
tor partial agonist (7, 8) (Zelnorm, Novartis Pharmaceutical
Corporation, East Hannover, NJ), and lubiprostone, a selec-
tive chloride channel activator (Amitiza, Takeda Pharmaceu-
ticals, Lincolnshire, IL), have FDA approval for treatment
of chronic idiopathic constipation (9). Polyethylene glycol
3350 (PEG) (MiraLAX, Braintree Laboratories, Inc, Brain-
tree, MA) has proven safety and efficacy for short-term treat-
ment of occasional constipation (6, 10, 11). This present in-
vestigation was designed to evaluate the safety and efficacy
of PEG for extended (6 month) use in patients with chronic
constipation, including a subgroup of elderly patients.
MATERIALS AND METHODS
Study Design
This was a randomized, double-blind, placebo-controlled,
parallel study enrolling patients with chronic constipation
recruited from 50 centers in the United States. Eligible study
subjects had a 14-day observational qualification period.
Study Population
Enrolled study subjects met a historical definition of consti-
pation based on modified ROME criteria (12), where each
patient was required to report a history where: on average,
for the preceding 3 months, when not taking laxatives, sat-
isfactory stool was less frequent than 3 per week and one or
more of the three remaining ROME symptom criteria were
met:
1436

2. Treatment of Chronic Constipation 1437
a. Straining in more than 25% of defecations;
b. Lumpy or hard stools in more than 25% of defecations;
c. Sensation of incomplete evacuation in more than 25% of
defecations.
Additionally, inclusion criteria required that subjects had
on average fewer than three satisfactory bowel movements
per week during a 14-day observation period. Study subjects
were in otherwise good health as judged by a physical exami-
nation and laboratory testing. Study subjects were excluded if
they had allergy or sensitivity to study medications, prior GI
surgery, known or suspected GI obstruction, ileus, heart fail-
ure, renal failure, ascites, other known chronic bowel, liver,
or cardiopulmonary disorders, if they were pregnant or lactat-
ing, or if they were taking medications known to affect bowel
function. Patients taking medications known to cause consti-
pation were excluded at screening. Patients starting on con-
stipation causing medications during the study period were
allowed to continue in the study and were analyzed in the
per protocol and intent-to-treat (ITT) populations. Patients
were excluded if loose stools were present and if there were
sufficient criteria for irritable bowel syndrome. Patients who
were currently taking or had been previously treated with
PEG were also excluded. Study subjects were enrolled at
50 centers, all of which used the same investigational pro-
tocol. Study subjects were recruited from physician prac-
tices and by local advertising. Baseline evaluations included
history and physical examinations and collection of demo-
graphic data. Laboratory testing was performed at baseline
for hematology, blood chemistry including amylase, GGT,
TSH, uric acid, lipids, and urinalysis. The investigational
protocol and informed consent materials were approved by
an Institutional Review Board before initiation of the study.
Written informed consent was obtained for all participating
patients.
Study Medication
Enrolled subjects were randomly assigned in a 2:1 ratio
(PEG to placebo) within each participating site to a treatment
schedule according to a computer-generated randomization
scheme (SAS Version 8.2, Stat Net Statistical Services Net-
work, Plaiston, NH). PEG (MiraLAX) or placebo (maltodex-
trin) was provided in identically labeled single-dose packets.
Subjects were instructed to mix the contents of one packet
(17 g) in 8 oz of juice or other beverage and drink once
daily.
Study subjects were also allowed the use of bisacodyl 5 mg
tablets as rescue medication and were instructed to take 10 mg
ofbisacodyliftheyexperiencedseverediscomfortduetotheir
constipation or if they had not had a bowel movement in 4
days. Study subjects were allowed the use of nonconstipat-
ing medications; however, the use of fiber was prohibited.
Patients were instructed to bring their remaining study drug
and rescue medication so that it could be reviewed by study
personnel for accountability.
Data Collection
Study subjects called in to an Interactive Voice Response Sys-
tem (IVRS; Interactive Clinical Technologies, Inc., Yardley,
PA) each day to report their bowel movement experiences
for that day and answered questions related to study efficacy
and safety criteria. Table 1 lists the daily and weekly global
assessment questions. Baseline laboratory evaluations were
repeated monthly and at the end of the study. Adverse events
were monitored.
Data Analysis
The primary efficacy end point was assessed on the basis
of a calculated success rate for the treatment period. This
was based on an assessment of modified ROME criteria for
each treatment week for each patient (the primary efficacy
variable). Weekly treatment success (response) was defined
according to three elements, which must all be satisfied:
1. No use of rescue laxative
2. Satisfactory stool greater than or equal to 3 per week
3. One or fewer of the remaining three ROME-based symp-
tom criteria
a. Straining in more than 25% of defecations
b. Lumpy or hard stools in more than 25% of defecations
c. Sensation of incomplete evacuation in more than 25%
of defecations.
The successful treatment week rate for each patient was
then calculated as the ratio of the number of successful weeks
(where a patient met the definition of treatment week suc-
cess described above) to the total number of weeks of actual
treatment. Overall treatment success (the primary efficacy
end point) was further defined as a 0.50 or greater rate of
successful treatment weeks. In other words, a successfully
Table 1. Interactive Voice Response System (IVRS) Questions
Daily
• How many stools did you pass today?
• How many satisfactory stools did you pass today?
• Did you have to strain to pass your stool today?
• Were your stools lumpy or hard today?
• Were your bowel movements complete?
• Did you take any laxatives, including rescue med today?
• Did you have 3 or more large watery stools today?
• Please rate the amount of cramping you experienced today
on a scale of 0 to 4 with 0 indicating no cramping and
4 indicating extreme cramping.
• Please rate the amount of gas you had today on a scale of
0 to 4 with 0 indicating no gas and 4 indicating extreme gas.
Weekly
• In the past 7 days, do you feel you have had adequate
relief of your constipation?

3. 1438 DiPalma et al.
treated patient had to have at least 50% of their treatment
weeks scored as “successful.”
Secondary efficacy end points included “Super Efficacy”
which defined a successful week as one during which a patient
reported none of the four ROME criteria without the aid of
rescue medication or prohibited laxative.
The primary analysis was based on an ITT analysis and in-
cluded all patients randomized and receiving any treatment.
Each patient in this group had a determination of overall
treatment success (responders) or failure (nonresponders) de-
scribed above as the primary end point. Secondary efficacy
end points defined in terms of successful treatment rates were
determined using analysis of variance (ANOVA).
RESULTS
Sixhundrednine(609)patientswerescreened.Threehundred
three (303) did not meet criteria or failed screening during the
14-day observation period. A total of 306 subjects were en-
rolled and randomized. One patient was randomized in error
and another was dropped for noncompliance. Neither patient
received study medication; therefore, these patients were not
included in the ITT population of 304. Seventy-five were
65 yr of age or older. One hundred seventy subjects com-
pleted all 6 months of the study. Patient withdrawals were
proportionately equivalent for each reason category, with the
exception of withdrawals for lack of efficacy. In this category,
more than twice as many subjects withdrew for lack of effi-
cacy associated with placebo treatment as did subjects receiv-
ing PEG. In the study population, the average age was 53 yr,
ranging from 20 to 92. The majority of enrollees were female
(258, 85%). The average duration of constipation reported
by all patients was over 23 yr. Eighty-four percent were Cau-
casian, 13% African American, and 6.3% were of Hispanic or
Latino ethnicity. There were no demographic related, statis-
tically significant differences between the treatment groups.
Group demographics are shown in Table 2.
Study subjects treated with PEG achieved a statistically
significant benefit (P < 0.001) over placebo in 11 of 12 pri-
mary and secondary efficacy measures. The primary respon-
der analysis for the ITT population showed a 41% difference
in treatment response (PEG 52%, placebo 11%, P < 0.001).
The elderly subpopulation achieved similar efficacy (46%
Table 2. Study Demographics
PEG Placebo
N 204 100 P
Age (yr)∗
53.1 (14.9) 54.4 (15.0) 0.46
Gender
Female 175 (86%) 83 (83%)
Male 29 17 0.56
Weight (kg)∗
74.7 (16.3) 75.1 (15.6) 0.65
Constipation (yr) 23.4 (18.7) 22.6 (19.2) 0.66
∗
Mean (standard deviation).
Table 3. Secondary End Points and Individual ROME Symptoms
(Number of Successful Weeks∗
)
Responder PEG Placebo
Definition (N = 204) (N = 100) P
Secondary end points
Primary definition†
12.0 (9.8) 3.4 (5.8) <0.001
% of weeks 61.4% 21.8%
ROME‡
12.9 (10.0) 3.8 (6.2) <0.001
% of weeks 66.2% 24.4%
Super efficacy§
9.2 (9.0) 2.2 (4.7) <0.001
% of weeks 47.3% 14.4%
Individual ROME symptoms
≥3 satisfactory BM 13.5 (9.8) 5.6 (7.4) <0.001
% of weeks 68.9% 36.4%
Straining 12.4 (9.9) 3.1 (5.6) <0.001
% of weeks 63.6% 20.1%
Hard stools 14.3 (10.1) 4.5 (6.8) <0.001
% of weeks 73.3% 29.2%
Incomplete defecation 10.6 (9.2) 4.3 (6.7) <0.001
% of weeks 54.4% 27.9%
∗
Mean (standard deviation).
†
≥3 satisfactory bowel movements, with 1 or no additional ROME criteria.
‡
ROME criteria not met.
§
No ROME symptoms.
difference favoring PEG). PEG treatment resulted in a rapid
increase in the number of successfully treated patients in the
first month, with the maximum response by the second month
and with the response remaining fairly level thereafter. The
difference between PEG and placebo was statistically signif-
icant at all study months.
Analysis of secondary efficacy end points and individual
ROME symptoms favor PEG as listed in Table 3. The num-
ber of successful treatment weeks, when applying the primary
responder definition, significantly favored PEG and this re-
sponse persisted when both groups were analyzed using only
the ROME definition. Even with the rigorous definition of
“Super Efficacy” (complete absence of ROME symptoms),
thenumberofsuccessfultreatmentweeksfavoredPEG.Anal-
ysis of the individual ROME symptom criteria (Table 3)
shows a statistically significant difference for all symptoms,
the most dramatic being “straining” and “hard stool” symp-
toms.
Other secondary measures of efficacy are shown in Table 4.
There was a difference in total bowel movements per week. In
Table 4. Secondary Efficacy Criteria∗
PEG Placebo P
N 202 100
Bowel movements/week 7.9 (4.5) 5.6 (5.5) <0.001
Satisfactory BM/week 5.4 (3.6) 2.7 (2.1) <0.001
CSBM†
5.0 (4.2) 2.1 (2.7) <0.001
Global assessment‡
12.5 (8.9) 5.2 (7.1) <0.001
Rescue tablets/week 2.8 (6.0) 3.9 (7.1) <0.138
∗
Mean (standard deviation).
†
Complete, spontaneous bowel movements.
‡
Number of weeks with adequate relief.

4. Treatment of Chronic Constipation 1439
fact, PEG resulted in nearly double the number of “satisfac-
tory” bowel movements per week (5.4) compared to placebo
(2.7). PEG also performed better for “complete, spontaneous
bowel movement.” For “Global Assessment of Efficacy,”
PEG subjects noted that 64% of their weeks were satisfactory
compared with 34% of placebo weeks (P < 0.001).
There were no treatment emergent safety differences be-
tween PEG and placebo over the course of the 6-month study
except for gastrointestinal complaints (PEG 39.7%, placebo
25%, P = 0.015). Although not individually statistically sig-
nificant, the difference was driven by abdominal distension,
diarrhea, loose stools, flatulence, and nausea. These effects
are consistent with and expected from laxative therapy. Most
of these events were mild or moderate. Two cases of diar-
rhea were rated “severe,” one resolved spontaneously, the
other upon PEG discontinuation. No statistically significant
differences in treatment emergent effects including gastroin-
testinal effects were detected in elderly patients. There were
no clinically significant laboratory changes.
DISCUSSION
This multicenter study compared PEG 3350 (MiraLAX) with
placebo in a double-blind, randomized protocol in patients
with at least a 3-month history of constipation based on
ROME criteria. To be eligible for enrollment, a patient had to
have fewer than three satisfactory bowel movements per week
duringa2-wkbaselineevaluation.Atotalof304patientswere
enrolled and treated for up to 6 months with either 17 g/day
PEG or placebo. Patient compliance with study medication
administration was excellent (>86%).
The primary efficacy variable was based on a modifi-
cation of the ROME criteria where a successful treatment
week was defined as a patient having three or more satis-
factory bowel movements and no more than one of the re-
maining three ROME symptoms, in the absence of rescue
medication or laxative use. To be successfully treated in the
study, a patient had to have 50% or more of their treatment
weeks rated as successful. By this measure, 52% of PEG
treated patients were successfully treated in the study versus
11% of placebo patients. This result was highly statistically
significant (P < 0.001). Similar results were obtained for
an analysis of the 75 elderly patients treated in the study
and no differences were noted on the basis of gender or
race.
Analyses of a number of secondary efficacy measures were
similarly highly statistically significant. PEG-treated patients
achieved an average of about one bowel movement per day.
Patients were exposed, on average, to about 2 kg of PEG
over the course of the study, representing about 75 patient-
years of exposure at the labeled dose. There were no statisti-
cally significant differences in treatment emergent effects ex-
cept for the “gastrointestinal” category where an increase in
the proportion of gastrointestinal adverse events was evident
(about 40% vs 25%, P = 0.015). The difference appears to be
driven by abdominal distension, diarrhea, loose stools, flatu-
lence, and nausea in association with PEG use (none individ-
ually statistically significant compared with placebo). These
effects are consistent with and expected from laxative therapy
(3–6) and were self-limiting and generally mild or moderate
in severity. No clinically significant changes in blood chem-
istry, particularly electrolytes, or hematology measures were
observed. Similar results were observed for the elderly and
non-Caucasian study patients.
Issues are raised about renal excretion and the need for
electrolytes with long-term use of PEG. Electrolytes are re-
quired for high volume PEG colonoscopy preparations in
order to maintain electrolyte balance and avoid potentially
dangerous adverse events such as hyponatremia and hy-
pokalemia. The development of these solutions was reported
by Davis et al. (13) and Fordtran et al. (14). However, stud-
ies performed by Hammer et al. (15) gave normal volunteers
various doses of PEG (up to 252 g) in combination with elec-
trolytes (NuLYTELY formula) in several divided doses rather
than in a single large bolus. The study subjects suffered no
ill effects except moderate diarrhea (at the higher doses) and
all electrolytes contained in the test solutions were absorbed.
Presumably, the marked difference in salt absorption be-
tween a GI lavage process and a laxative effect using the
same PEG electrolyte solution can be attributed to intesti-
nal absorptive processes, which remain active but are over-
whelmed by the very large volumes of solution ingested when
GI cleansing by lavage is desired. When lesser volumes are
ingested, or the ingestion occurs slowly, the absorptive sys-
tems are better able to remove the electrolytes.
This was confirmed in the current study by the serum
electrolyte data where no clinically or statistically significant
differences between MiraLAX and placebo were observed.
This supports the position that electrolyte supplementation is
not required for low-dose polyethylene glycol laxatives, even
when given chronically.
There were no on-study deaths. Twelve serious adverse
events were reported (6 PEG, 6 placebo) and none were con-
sidered to be related to the study medication.
This study supports the conclusion that PEG laxative is
safe and effective for treating constipation in adult and elderly
patients for up to 6 months.
ACKNOWLEDGMENTS
The authors thank the following investigators for their in-
volvement in conducting this study:
Greg Anderson, M.D., Gastroenterology Research of
Greater Cincinnati, Cincinnati
Charles F. Barish, M.D., Wake Research Associates, LLC,
Raleigh
Daniel Brune, M.D., nTouch Research, Peoria

5. 1440 DiPalma et al.
Antonio Caos, M.D., Central Florida Clinical Studies, Inc.,
Ocoee
Christopher Chappel, M.D., FPA Clinical Research,
Kissimmee
David C. Chua, M.D., Summit Center of Clinical Research,
Oakbrook Terrace
Teresa Coats, M.D., Benchmark Research, Austin
Barry Collins, M.D., Advanced Clinical Research, LLC,
Pell City
Michael Collins, M.D., Clinical Research Consultants,
Inc., Hoover
Richard Craven, M.D., East Coast Clinical Research, LLC,
Virginia Beach
Adnan Dahdul, M.D., FutureCare Studies, Inc., Springfield
Steven G. Desautels, M.D., Mountain West Gastroenterol-
ogy, Salt Lake City
Scott Becker, M.D., Austin Gastroenterology, PA, Austin
W. Travis Ellison, M.D., Radiant Research, Greer
Jack S. Faintuch, M.D., Radiant Research, Lake Worth
R. David Ferrera, M.D., Sacramento Research Medical
Group, Sacramento
Chester L. Fisher, M.D., Health Research of Hampton
Roads, Inc., Newport News
Elizabeth M. Gallup, M.D., JD, MBA, and Monica Pierson,
M.D., Radiant Research, Kansas City, Overland Park
Mark Gotfried, M.D., PACT, Glendale
Jorge L. Herrera, M.D., University of South Alabama, Mo-
bile
DarrellT.Herrington,D.O.,BenchmarkResearch,SanAn-
gelo
JohnA.Hoekstra,M.D.,Ph.D.,NationalClinicalResearch,
Richmond
Walter Hood, M.D. and Stephen Gordon, M.D., Compre-
hensive NeuroScience, Inc., Atlanta
Marvin Lawrence, M.D., Maryland Digestive Disease Re-
search, LLC, Laurel
Samuel Lederman, M.D., Radiant Research, Inc., West
Palm Beach
Michael Levine, M.D., Radiant Research, Marietta
Margarita Nunez, M.D., Comprehensive NeuroScience,
Inc., St. Petersburg
Jenny Liu, M.D., and Jeffrey Kaladas, M.D., Urgentmed,
P.C., South Bound Brook
Barry Lubin, M.D., Hampton Roads Center for Clinical
Research, Norfolk
F. Timm McCarty, D.O., Radiant Research, Scottsdale
John McNerney, M.D., Tucson Gastroenterology Special-
ists, Tucson
Mitchell D. Meyer, M.D., Wilmington Health Associates,
Wilmington
David J. Morin, M.D., Tricities Medical Research, Bristol
Michael Noss, M.D., Radiant Research, Cincinnati
Peter M. Pardoll, M.D. and Sheldon Sheinert, M.D., Center
for Digestive Diseases, St. Petersburg
Peter B. Platzer, M.D., Holston Medical Group, Kingsport
Patricia Reiff, M.D., Radiant Research, Phoenix
Dennis Riff, M.D., Advanced Clinical Research Institute,
Anaheim
John Rubino, M.D., Multi-Specialty Research Association
of North Carolina, Raleigh
Douglas Schumacher, M.D., Radiant Research, Columbus
William Seger, M.D., Benchmark Research, Fort Worth
Marc Shepard, M.D., nTouch Research, Washington
Timothy Smith, M.D., Mercy Health Research, St. Louis
Jonathan Simon Staub, M.D., Wilmington Health Asso-
ciates, Wilmington
Miguel Trevino, M.D., Innovative Research of West
Florida, Inc, Largo
Lawrence Wruble, M.D., Memphis Gastroenterology
Group, Memphis
Thomas D. Bianchi, M.D., Community Medical Plaza, Tal-
lassee
STUDY HIGHLIGHTS
What Is Current Knowledge
r Constipation is a troublesome problem.
r Few data are available concerning chronic therapy.
What Is New Here
r This study extends the experience of polyethylene gly-
col (PEG) laxative for a 6-month period.
Reprint requests and correspondence: Jack A. DiPalma, M.D.,
Gastroenterology Academic Offices, USA Pavilion at Infirmary
West, 5600 Girby Road, Mobile, AL 36693.
Received September 22, 2006; accepted February 7, 2007.
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CONFLICT OF INTEREST
Guarantor of the article: Jack A. DiPalma, M.D., F.A.C.G.
Specific author contributions:
Conception and design: Jack A. DiPalma, John McGowan,
Mark vB. Cleveland, Jorge L. Herrera.
Acquisition of data: Jorge L. Herrera, Mark vB. Cleveland,
John McGowan.
Analysis and interpretation: Jack A. DiPalma, John Mc-
Gowan, Mark vB. Cleveland, Jorge L. Herrera.
Manuscript draft: Jack A. DiPalma.
Critical revision of manuscript: Jack A. DiPalma, John Mc-
Gowan, Mark vB. Cleveland, Jorge L. Herrera.
Financial support: This work was funded by Braintree Lab-
oratories, Inc.
Potential competing interests: Dr. Jack A. DiPalma is a
medical director consultant to Braintree Laboratories and has
been a member of the Speakers Bureau and paidadvisory
group consultant for Novartis Pharma. Dr. Jorge L. Herrera
has been a paid advisory group member for Braintree Lab-
oratories. Dr. Mark vB. Cleveland and John McGowan are
employees of Braintree Laboratories.