Miralax (PEG 3350) vs. Golytely as Bowel Preparation for Screening Colonoscopy
Condition: Colon Cancer
MeSH terms: Colonic Neoplasms
Study type: Interventional
Phase: Phase 4

Summary: 
      A major limitation to the widespread acceptance of colonoscopy as a procedure to screen for
      colorectal cancer is the laxative preparation. Phosphate-based preps (e.g. Fleets
      Phosphosoda) are now used on a limited basis because of their known association with renal
      injury. Polyethylene glycol (PEG) mixed with a balanced electrolyte solution (e.g. Golytely)
      has been used for over two decades for colon cleansing. The mixture is not very palatable due
      to the electrolyte additives which include sodium sulfate.

      To overcome the limitation of existing preps, gastroenterologists and colorectal surgeons
      worldwide have been using PEG powder alone (same quantity as found in Golytely prep) not
      mixed with electrolytes (Glycolax or Miralax) and dissolving this into 64 ounces of Gatorade.
      Conservatively, we estimate that 25% of colonoscopies in the US are being done with this
      prep. Anecdotally there have been reports (case series) that it is far more palatable and the
      prep is equally efficacious. The active ingredient, PEG, is not changed and therefore this is
      not surprising. The issue at present is that there has never been a blinded study to confirm
      these claims.

      This study will compare the efficacy of the two preps. There is no funding. The investigators
      will charge insurance companies for the prep - this is our current practice. The procedures
      will be done on healthy individuals referred for colon cancer screening and the exam will be
      billed to their insurance. There will be no patient honorarium. The investigators will check
      electrolytes to be sure patients do not develop hypokalemia with the Gatorade prep.
    

Detailed description: 
      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.
    

Intervention name(s): PEG-3350 and Gatorade; Golytely 4 liters
Intervention type(s): Drug; Drug
Intervention description(s): 255 grams of miralax mixed with 64 ounces gatorade for colonoscopy preparation.; Golytely 4 liters
Other intervention name(s): nulytely, PEG-3350, Miralax, glycolax; polyethylene glycol/electrolytes
Intervention MeSH terms: Polyethylene glycol 3350
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: PEG-3350, polyethylene glycol, colonoscopy