Trial Information

A Prospective, Randomized Controlled Trial Comparing the Efficacy and Patient Tolerability of Miralax (PEG 3350) vs. Golytely as Bowel Preparation for Screening Colonoscopy

Objective To determine whether Miralax is as efficacious for bowel cleansing as standard
Golytely for screening colonoscopy. This study is designed and powered to be an
non-inferiority study.

Primary aim: To compare the quality of bowel preparation between Miralax and Golytely

Secondary Aims:

- compare patient comfort and tolerability with each of the 2 preparation regimens

- evaluate the effects of age, gender and tolerability on bowel prep quality

- to determine if either preparation is associated with acute electrolyte disturbances

Background Colonoscopy is the standard method for luminal evaluation of the colon. Bowel
cleansing prior to colonoscopy is critical to the endoscopist obtaining optimal
visualization during the procedure and therefore plays an integral role in safety, efficacy
and diagnostic accuracy of the procedure. The bowel cleansing portion of the procedure is
often the most lamented aspect of the colonoscopy experience. This is often driven by the
large volume of liquid required to be consumed, in addition to the poor palatability of some
colon cleansing regimens. Cleansing methods are variable, and often times high volume
solutions are time consuming, inconvenient and uncomfortable, leading to poor patient
compliance. This translates into decreased effectiveness of the colonoscopy exam and often
higher costs due to the need for repeat examination. Additionally, it is unknown how much
the feared discomfort of the bowel preparation experience dissuades patients from pursuing a
screening colonoscopy for colon cancer.

An ideal bowel preparation would reliably cleanse the colon in a rapid fashion, would not
alter the colonic mucosa, result in an acceptable amount of patient discomfort, would not
cause significant shifts in electrolytes and would be inexpensive. To date, no bowel regimen
meets all of these criteria.

One of the standard bowel preparation regimens is polyethylene glycol (PEG, Golytely) lavage
solution which entails consuming 4 L of water mixed with a powder packet that contains the
main ingredient (255g polyethylene glycol 3350) along with electrolytes (22.74 g anhydrous
sodium sulfate, 6.74 g sodium bicarbonate, 5.86 g sodium chloride, 2.97 g potassium
chloride). This is a non-absorbable, iso-osmotic solution which has a mildly salty taste
that induces a diarrhea that rapidly cleanses the bowel, usually within 4 hours. This
solution was first introduced in the 1980's and is currently the most widely used bowel
cleansing regimen (1). It has proven safety and efficacy but due to its high volume, it is
often difficult for patients to tolerate (2-7). It has been estimated that at least 5-15%
of patients do not complete the preparation due to the large volume and/or poor palatability
(8, 9). The literature also confirms that patients prefer lower volume solutions for
comfort and tolerability (7, 10).

Oral sodium phosphate solutions (e.g. Fleets PhosphoSoda®) were equally efficacious and
shown to be better tolerated low volume alternatives to PEG (11). They were FDA approved for
bowel cleansing and were been used extensively in select patients prior to colonoscopy until
recently. However, on December 11, 2008, the FDA issued a statement concluding that the use
of oral sodium phosphate preparations poses a risk of serious adverse events, notably acute
phosphate nephropathy- a type of acute kidney injury- in select patients (patients over age
55, baseline kidney disease, on diuretics, angiotensin converting enzyme [ACE] inhibitors,
NSAIDs or angiotensin-receptor blockers [ARBs] etc) (12-14). As a result, the FDA has
required that manufacturers of oral sodium phosphate bowel preparations add a Boxed Warning
to their labels of these products. Subsequently, these manufacturers have voluntarily
removed their products from retail sale. There have been over 20 randomized controlled
trials in the literature searching for the "ideal" bowel preparation (11). With the removal
of oral sodium phosphate preparations from the market, the search for a better tolerated
bowel cleansing regimen continues.

Miralax (PEG 3350), polyethylene glycol powder alone without electrolytes is FDA approved
for constipation. It is mixed in 8-12 ounces of any beverage and can be used daily. Because
it lacks taste (no electrolytes) it has been used as a bowel cleanser for colonoscopy.
Generally, 255 g of Miralax is combined with 64 oz of Gatorade for bowel cleansing prior to
colonoscopy. While not FDA approved for this indication, it has been widely used and is an
accepted alternative to Golytely in numerous endoscopy centers across the country.

PEG 3350's safety and efficacy has been documented in multiple studies on children
undergoing colonoscopy (15, 16). A recent single arm feasibility study described in a
letter to the editor in the American Journal of Gastroenterology 2008 found the use of
Miralax (PEG 3350) as colonoscopic preparation to be tolerable and safe in adults (17).
Moreover the study reported high compliance. It included 29 patients who underwent screening
colonoscopy with PEG 3350 in 64 oz of Gatorade® (The Gatorade Company, Chicago, IL). A "good
prep" was described in 97% of cases; patient rated tolerance was good in 86%. Insomnia was
the most common adverse effect. Of note, 18 patients had prior 4L PEG bowel cleansing
experiences- of these, 50% reported PEG 3350 was better tolerated. Beyond this data, these
investigators at a community center (Urbana, IL) have a 3 year exclusive experience with PEG
3350 as their colon preparation; they report anecdotally better patient tolerance and
compliance over prior preparations. The inclusion of Gatorade® is to reduce the potential
for electrolyte disturbances.

In addition to its low volume, PEG 3350 (Miralax) is storied to be more palatable and easily
accessible over the counter; it is also a simple, uncomplicated regimen. Based on the
theory that greater ease of use, improved taste, lower volume and lower levels of induced
discomfort would result in better patient compliance, completion of the bowel preparation
and subsequent improvement in visualization during colonoscopy, PEG 3350 (Miralax) appears
to be promising as an "ideal" cleansing agent. To date, there has been no head to head
comparison of MiraLAX and Golytely in terms of efficacy and patient tolerability as bowel
cleansing regimens for colonoscopy.

Eligibility Criteria Inclusion criteria

- All adults undergoing average risk colon cancer screening (ages 40-75 years old)

- Able to provide informed consent

Exclusion criteria

- A history of constipation

- Patients who use medications to assist with a bowel movement such as osmotic,
stimulant, or cathartic laxatives (including "colon cleansers")

- Diabetes or glucose intolerance

- Patients with severe underlying renal or hepatic impairment

- Pregnant women - pregnancy test performed on all menstruating women before procedure.

Treatment Plan This is a prospective, randomized, endoscopist-blinded study that will be
carried out at Temple University Hospital. All adult patients undergoing outpatient
colonoscopy will be screened for enrollment in the study.

Upon completion of a history and physical, patients identified as appropriate for the study
will be approached about study participation. Informed consent by the PI will be completed
in the outpatient office and the patient will be scheduled for colonoscopy. The risks and
benefits of the exam will also be discussed. Once the patient is scheduled, the medical
assistant scheduling the exam will open an opaque envelope and assign the patient their exam
preparation. She will give a script for Golytely or Miralax. Gatorade must be purchased by
the participant. The details of the bowel preparation are below:

- All patients will be advised to have clear liquids for breakfast, lunch and dinner on
the day prior to their planned colonoscopy.

- Based on their randomization assignment, subjects will be instructed to either

1. Consume 4 L polyethylene glycol (Golytely) Or

2. Consume 255 g of PEG 3350 (Miralax) in 64 oz of yellow Gatorade. The choices will
be the Lemon-Lime , Lemonade, or All-Stars Lemon Lime flavors which are all
primarily yellow.

Study participants will be instructed to take nothing by mouth after midnight on the day of
their colonoscopy. They will also be advised to avoid discussing the details of their bowel
preparation with their endoscopist until after their colonoscopy. Upon arrival to their
scheduled colonoscopy appointment and prior to their procedure, patients will be provided a
short survey assessing their bowel preparation experience (please refer to appendix document
Patient Survey for details). Also at the time of insertion of an intravenous catheter
(which is required for all procedures) 5 cc of blood will be drawn for a complete metabolic
panel and sent to the TUH laboratory to evaluate for electrolyte disturbances.

All procedures will be performed at the Temple University Hospital Digestive Disease Center
by the PI. He will be blinded to the type of bowel preparation randomized to the patient.
Upon completion of the procedure, the endoscopist will document the adequacy of the
preparation (24). The preparation quality will be assessed for each portion of the colon
according to the following scale (see appendix):

Boston Bowel Prep Scale 0 unprepared colon segment with mucosa not seen because of solid
stool that cannot be cleared

1. portion of mucosa of the colon segment seen, but other areas of the colon segment are
not well seen because of staining, residual stool and/or opaque liquid

2. minor amount of residual staining, small fragments of stool, and/or opaque liquid, but
mucosa of colon segment is well seen

3. entire mucosa of colon segment seen well, with no residual staining, small fragments of
stool, or opaque liquid

A sum score will be calculated based on the rating in each colonic segment. In order to
assess validity and reliability in the rating scale both intra-observer and inter-observer
reliability will be assessed. This will be done by taking representative high resolution
digital photographs of all colonic segments during the withdraw phase of the colonoscopy.
The photographs will be printed and de-identified. At the end of the study the PI will
blindly grade each prep using photographs presented in a random fashion. A second
experienced colonoscopist from the Temple faculty will also grade each prep to assess
inter-observer reliability.

Risks The risks of this study include the use of a colonoscopy bowel preparation agent that
is not FDA approved for this indication as well as the inherent risk of colonoscopy. The
added risks of this study are only related to the preparation. Risks from the preparation
include failure to cleanse the colon adequately and the risk of electrolyte abnormalities,
particularly hypokalemia. The risks of undergoing colonoscopy include bleeding potentially
requiring transfusion of blood products, infection, bowel perforation possibly requiring
surgical intervention, adverse reaction to anesthesia/sedation, and missed lesions. These
risks are rare and are standard for any colonoscopic exam regardless of study participation.

Benefits The benefits afforded to study subjects would include potential early detection and
treatment of colorectal cancer, prevention of colorectal cancer by removal of pre-malignant
polyps and development of a cancer prevention or surveillance strategy based on colonoscopic
findings. Also, 50% of the patients will consume a preparation that is likely to be far more
palatable than the standard preparation, Golytely.

Alternative Treatments Cancer prevention tests should be offered to all patients meeting
criteria for CRC screening. The preferred cancer prevention test is colonoscopy. Alternative
cancer prevention tests include flexible sigmoidoscopy and computed tomography colonography.
Patients who decline colonoscopy or a cancer prevention test should be offered a cancer
detection test. The preferred cancer detection test is fecal immunochemical testing.
Alternative cancer detection tests included Hemoccult Sensa fecal guaiac based testing and
fecal DNA testing. No CRC screening is an alternative.(1)

Data Collection and Statistics Sample Size Calculation The primary objective of the study is
to compare the efficacy, tolerability and safety of the standard bowel preparation Golytely
with a novel bowel preparation agent Miralax. The study is a non-inferiority study: The
objective is to conclude that the prep quality scores of those receiving Miralax is at most
10% less than for Golytely. Thus the difference in prep scores between Miralax minus
Golytely should be greater than - 10%. If this is the case, Miralax would be considered as
non-inferior to Golytely. To calculate sample size we performed a one-sided test based on
the binomial distribution with the intent of demonstrating that Miralax is non-inferior if
the calculated one-sided p-value is less than 0.05. If the true difference between the
Miralax and Golytely is exactly 0%, then the test should give a p-value less than 0.05 with
a probability of 0.80. Since we want to conclude that the difference in responders, Miralax
minus Golytely, is greater than - 10%, we choose as the null hypothesis H0: the true
difference in proportions is less than or equal to - 0.10 and the alternative hypothesis H1:
the true difference in proportions is greater than - 0.10. Based on the study by Lai and
others (24), on a 0-9 scale the expected mean prep score with Golytely will be 6.2 with a
standard deviation of 1.5.

Below is the output from PASS 2008 (Kaysville, UT ) Power Analysis of a Non-Inferiority Test
of The Difference of Two Means Numeric Results for Non-Inferiority Test (H0: D <= -/E/; H1:
D > -/E/)

Test Statistic: T-Test:

Power N1/N2 (E) (D) (Alpha) Beta (SD1) (SD2)
0.80019 78/78 -0.600 0.000 0.05000 0.19981 1.500 1.500 Report Definitions Group
1 is the treatment group. Group 2 is the reference or standard group. N1 is the number of
subjects in the first (treatment) group. N2 is the number of subjects in the second
(reference) group.

/E/ is the magnitude of the margin of equivalence. It is the largest difference that is not
of practical significance.

D is the mean difference at which the power is computed. D = Mean1 - Mean2. Alpha is the
probability of a false-positive result. Beta is the probability of a false-negative result.
SD1 and SD2 are the standard deviations of groups 1 and 2, respectively. Summary Statements
Group sample sizes of 78 and 78 achieve 80% power to detect non-inferiority using a
one-sided, two-sample t-test. The margin of equivalence is -0.600. The true difference
between the means is assumed to be 0.000. The significance level (alpha) of the test is
0.05000. The data are drawn from populations with standard deviations of 1.500 and 1.500.
Statistical Analyses Statistical analyses will be conducted by using statistical software
(SPSS 17.0). The proportions in 2 x2 contingency tables will be compared by the chi square
test. The investigators will use a kappa statistic to evaluate for inter-observer and
intra-observer variability in the bowel preparation quality. Multivariate analysis will be
performed with multiple logistic regression to assess the impact of age and gender on bowel
preparation. The investigators plan to have complete follow up of all patients and will use
an intention to treat analysis.