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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background

Low-volume bowel preparations with polyethylene glycol (PEG) have been shown to provide an equivalent cleansing with improved tolerability as compared with standard PEG bowel preparation for colonoscopy. A new iso-osmotic sulphate-free formulation of PEG-Citrate-Simethicone (PEG-CS) in combination with bisacodyl has been recently developed.

Aim

To compare the quality of bowel cleansing with PEG-CS with bisacodyl vs. PEG-Ascorbate (PEG-ASC) in adult out-patients undergoing colonoscopy.

Methods

Randomised, observer-blind, parallel group study in adult out-patients undergoing colonoscopy in five Italian centres. Both preparations were taken the evening before the procedure. Subjects were instructed to take 2–4 tablets of 5 mg bisacodyl at 16:00 hours and 2 L of PEG-CS at 20:00 hours or 2 L of PEG-ASC plus 1 L of additional water the day before colonoscopy. Bowel cleansing was evaluated according to the Boston Bowel Preparation Scale (≥6 scores were considered as ‘clinical success’), and mucosal visibility according to a 3-point scale. Tolerability, acceptability and compliance were also evaluated.

Results

Four hundred and eight patients were randomly allocated to PEG-CS and bisacodyl (n = 204, male patient 48%, mean age 59.1 years) or PEG-ASC (n = 204, male patient 51%, age 59.4 years). In the planned per-protocol analysis, the rate of successful preparation was 79.1% following PEG-CS with bisacodyl, and 70% following PEG-ASC (P < 0.05). Mucosal visibility was evaluated as optimal in 56.1% in the PEG-CS and bisacodyl and 46.3% in the PEG-ASC group (P < 0.05). There were no serious adverse events (AE) in each of the two experimental groups. Two subjects in the PEG-ASC group discontinued the study because of AE.

Conclusions

Polyethylene glycol-Citrate-Simethicone in combination with bisacodyl was more effective for bowel cleansing than PEG-ASC for out-patient colonoscopy. Tolerability, safety, acceptability and compliance of the two low-volume bowel preparations were similar.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Adequate bowel cleansing is essential for a successful examination of the mucosa during colonoscopy; the ideal preparation would allow a thorough cleansing, have no adverse effects especially fluid or electrolyte imbalance, should be easy to take and cause no patient discomfort. Osmotically balanced polyethylene glycol (PEG)-electrolyte bowel lavage solutions were introduced in 1980.[1] PEG-based bowel preparations for colonoscopy have been shown to be highly effective and safe, owing to negligible net absorption of water and electrolytes. The earliest formulations of PEG-regimens required the administration of 4-L solutions, to achieve an adequate cathartic effect. Reduced volume formulations were subsequently developed to improve patient tolerability. More specifically, a low-volume preparation that exploits the additional osmotic effect of ascorbic acid to a 2-L formulation of PEG with electrolytes (PEG-ASC) has been shown to be an effective alternative to 4-L PEG-regimens.[2-4]

However, the hyper-osmolarity of the PEG-ASC solution requires an additional litre of clear liquids, and it may be a relative contraindication in kidney/heart diseases. To improve the safety and tolerability of the low-volume preparations, a new iso-osmotic, sulphate-free, 2-L formulation of PEG-Citrate-Simethicone (PEG-CS) has been recently developed. This new formulation is administered together with oral bisacodyl, a well-established stimulant laxative, which compensates for the lack of osmotic effect related with ascorbic acid.

This study was designed to assess the efficacy, safety and tolerability of 2-L PEG-CS combined with 10–20 mg of bisacodyl tablets in comparison with the standard 2-L formulation of PEG-ASC presently available in Europe.

Patients and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study design

This multicentre, randomised, observer-blind, parallel group study was conducted in five centres in Italy from March 2010 through December 2010. The study design was defined in compliance with internationally recognised guidelines for clinical studies (Clinical Trials. Gov: NCT 01509131). Out-patients of both sexes (age 18–85 years) undergoing elective colonoscopy for various indications were enrolled. The study protocol was approved by Ethics Committee of all participant Institutions, and written informed consent was obtained from all patients.

Study population

Adult out-patients undergoing routine colonoscopy were enrolled. Patients were considered ineligible for study participation in presence of any of the following: pregnant or lactating women, known or suspected hypersensitivity to the active principle and/or formulations ingredients, known or suspected gastrointestinal obstruction or perforation, toxic megacolon, major colonic resection, heart failure (Class III or IV), serious cardiovascular disease, severe liver failure and end-stage renal insufficiency. To avoid a large variability in the interval between bowel preparation and colonoscopy, all colonoscopies were scheduled for the morning.

A complete medical history, physical examination with vital signs, previous and current medications, routine blood tests were obtained at time of enrolment. All these medical activities were performed by a physician who was not involved in the subsequent colonoscopy. A serum pregnancy test was performed for women with childbearing potential.

Study medications

The study preparation is a combination of PEG-CS and bisacodyl. PEG-CS is a new sulphate-free iso-osmotic formulation of PEG-4000 with citrates and simethicone (Lovol-esse; Promefarm, Milan, Italy) available as powder to be dissolved in 2 L of water. Subjects allocated to the study preparation were instructed to take 2–4 (based on simple constipation questionnaire) bisacodyl 5-mg tablets (Lovoldyl; Promefarm) at 16:00, followed 2–3 hours later by 2 L PEG-CS solution. The patients were instructed to drink 250 mL in 15–20 min (all solution in about 2–3 hours).

As active control, a 2-L PEG 3350 with ascorbic acid (PEG-ASC) (Moviprep; Norgine Ltd, Harefield, UK) with 1 L additional clear fluid was used (Table 1).

Table 1. Technical characteristics of the two regimens compared in the study
 PEG-CSPEG-ASC
  1. PEG-CS, PEG-citrate-simethicone; PEG-ASC, PEG with ascorbic acid.

  2. a

    It started one hour before PEG-CS group, because of the need to administer 1 additional L of water after completion of the solution intake only in this arm.

Active ingredientsPEG, citrates, simethiconePEG, ascorbates, sodium sulphate
Product description4 sachets each containing 60.7 g of PEG 4000, 1.066 g of sodium citrate, 1.25 g of citric acid, 80 mg of simethicone

2 sachets each containing 100 g of PEG 3350 and 7.5 g of sodium sulphate

2 sachets each containing 4.7 g of ascorbic acid and 5.9 g of sodium ascorbate

Total volume2-L2-L
ElectrolytesSodium chloride, potassium chlorideSodium chloride, potassium chloride
Osmolality (mosmol/kg)293553
Mixed withWaterWater
Diet prior to colonoscopyClear liquid after starting solution intakeClear liquid after starting solution intake
Timing of ingestionFull amount of solution at 20:00 hours the day prior to procedureFull amount of solution at 19:00 hours the day prior to procedurea
Additional agents2–4 bisacodyl tablets at 16:00 hours the day before starting solution intake1-L of water after completing solution intake

The preparations were dispensed by a nurse who carefully explained how the products should be taken, emphasising the importance of complete intake of the solution to ensure a safe and effective procedure. Moreover, each patient was provided with dietary instructions: low residue diet for 3 days before colonoscopy. During and after bowel preparation, solid food was not allowed. Clear liquid could be taken until 2 h before the procedure.

Randomization and blinding

A randomised computer-generated list was prepared centrally by a qualified statistician. Subjects meeting the inclusion/exclusion criteria were consecutively assigned to the next available number. The study was observer-blind: the endoscopists were not allowed to perform any activities associated with study preparation prior and after colonoscopy and had to avoid any discussion with the patients and the staff, which could disclose the type of bowel preparation.

Evaluation of bowel preparations

Efficacy

Preparation efficacy was evaluated by the blinded endoscopist per colonic segment (right, transverse, and left colon) on a 4-point scale (0–3) according to the Boston Bowel Preparation scale (BBPS).[5] In addition, overall cleansing of the colon was scored by summing up the scores of each segment. For the study, the total score ranging from 0 to 9 was divided into four different classes: excellent cleansing (total score 8–9), good cleansing,[6, 7] poor cleansing,[3-5] and inadequate cleansing (i.e. unprepared colon, 0–2). For the primary efficacy variable, excellent and good cleansing were considered as ‘successful’ and poor or inadequate as ‘failure’. Prior to study initiation, designated observers performed a calibration exercise on 20 colonoscopies using the scoring system adopted in this study (BBPS) to reach a satisfactory level of concordance among the physicians involved in the assessment of the degree of bowel cleansing.

Physicians were also asked to score the overall mucosal visibility according to the following 3- grade scale: optimal (grade 0, clear imaging with no or minimal amount of bubbles or foam, which can be easily removed), adequate (grade 1, modest amount of bubbles and foam, which can be cleared, with a bit loss of time), insufficient (grade 2, presence of foam and bubbles, which reduces significantly the clear visualisation of the mucosa).

Safety

Vital signs, complete physical examination and blood tests were performed at the time of patient enrolment and on the day of colonoscopy and included haematology and blood chemistry, including BUN, ALT, creatinine, potassium, sodium, chlorides and calcium.

Adverse events were assessed on the day of colonoscopy by direct questioning and by follow-up telephone calls 48–96 hours after colonoscopy.

All new symptoms were considered to be treatment related and have been included in the analysis. Any symptom that manifested following the treatment (except those expected and included in the evaluation of GI-tolerability) and exacerbations of preexisting symptoms were assumed to be related to the bowel preparation regimen.

Tolerability

On the morning of colonoscopy, immediately before the procedure, a nurse questioned each patient about his/her experience by using a standardised questionnaire. Patients were inquired about tolerability, additional fluid intake, acceptability and compliance. The endoscopist was not allowed to take part in the questioning or to supervise the questionnaire before colonoscopy.

Tolerability assessment was based on the recording of GI symptoms. The nurse asked each patient about the occurrence and severity of nausea, bloating, abdominal pain/cramps and anal discomfort. A 5-point Likert scale (1 = severely distressing, 2 = distressing, 3 = bothersome, 4 = mild and 5 = none) was used to score the tolerability. This scale has already been used in previous bowel cleansing studies.[6]

Acceptability and compliance

The easiness of taking or swallowing the solution was graded according to the following scale: very severe distress = 4, severe distress = 3, moderate distress = 2, mild distress = 1, no distress = 0. Willingness to repeat the same type of bowel preparation if necessary was also evaluated. Compliance was scored on a 3-grade scale according to the percentage of drunk solution (excellent: intake of the whole solution; good: intake of at least 75% of the solution; poor: intake of <75%).

Study end-points

The primary efficacy end-point was the overall colon cleansing defined as the rate of ‘successful’ cleansing (excellent and good scores in the BBPS, i.e. ≥6 points). The rate of optimal mucosa visibility (score 0) was a secondary efficacy end-point. Secondary end-points also included the proportion of patients with no predefined gastrointestinal symptoms, no distress, willingness to repeat the exam with the same bowel preparation and good-excellent compliance.

Statistical analysis

The sample size was calculated according to the assumption that the two formulations were equally effective with a rate of clinical success of 75% and an equivalence margin of +15%. Assuming the conventional levels for power and significance as 0.80 and 0.05, respectively, and considering a drop-out rate of 10% and an equal allocation to the study centres, a total number of 408 subjects was estimated to be needed to achieve the 95% confidence interval of the difference between the clinical success rates contained in the equivalence interval.

Baseline characteristics were summarised by usual descriptive statistics, such as mean and standard deviation for continuous variables and rates for categorical variables. Two-sided t-test was used to compare the means of continuous variables; likelihood ratio Chi-squared test was used to compare the rates of categorical measures. The P-values smaller than 0.05 were considered statistically significant. To demonstrate equivalence, the primary efficacy analysis was the per-protocol (PP) analysis and included patients completing the study without any major violation. According to international guidelines, intention-to-treat analysis (ITT) has been performed when the study objective was switched to superiority (‘Points to consider on switching between superiority and noninferiority’, EMEA guideline CPMP/EWP/482/99, London, 27 July 2000).

Patients withdrawing consent were excluded from the ITT population. Patients who did not undergo colonoscopy, with poor compliance (<75% intake) and those without BBPS total score for reasons independent from bowel preparations (anatomic strictures, poor tolerability) were excluded from PP analysis. This approach is in agreement with ICH statistical guideline.[7]

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Demographics and baseline

Figure 1 shows the flow of patients throughout the study. Of the 408 patients who underwent randomisation, 3 were excluded from ITT analysis (withdrawal of informed consent) and 31 from the PP analysis (colonoscopy not performed in 11, poor compliance in 9, no BBPS in 8 cases). Thus, 405 patients were included in the ITT- and 377 in the PP analysis. The baseline demographic and clinical characteristics of patients were similar for the two groups (Table 2).

image

Figure 1. Patient flow.

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Table 2. Demographic characteristics of the two study group at intention-to-treat analysis
VariablesPEG-CS & Bisacodyl N = 204PEG-ASC N = 204
Sex 
Male, N (%)98 (48.0%)105 (51.5%)
Female, N (%)106 (52.0%)99 (48.5%)
Age (years) 
Mean ± s.d.59.1 ± 12.459.4 ± 11.8
Height (cm) 
Mean ± s.d.166.4 ± 8.8166.5 ± 8.2
Missing data1
Weight (kg) 
Mean ± s.d.71.7 ± 12.871.7 ± 15.3
Missing data1
BMI 
Mean ± s.d.25.9 ± 4.225.8 ± 4.7
Missing data1

Efficacy of bowel cleansing

Adequate level of bowel cleansing (i.e. ≥6 BBPS) was observed in 79.1% (95% CI: 73.3%, 85.0%) of PEG-CS + bisacodyl and in 70.0% (95% CI: 63.5%, 76.5%) of PEG-ASC patients in the PP analysis (P = 0.042), corresponding to an absolute difference of 9.1% (95% CI: 0.4%, 17.9%). The difference between the two bowel preparations was consistent among centres ranging from +1% to +16% in favour of the PEG-CS + bisacodyl. The results were similar at ITT analysis (76.4% vs. 67.3%; P = 0.043). Details on the degrees of level of preparation according to BBPS scale are provided in Table 3. Bowel cleansing was also evaluated by colonic segment. As shown in Table 3, a statistical significant difference was found only for the transverse colon (P = 0.031), but a trend towards significance was also seen for the right colon (P = 0.051).

Table 3. Efficacy outcomes at per-protocol (PP) and intention-to-treat (ITT) analysis
VariablesPEG-CS + bisacodylPEG-ASCP-value
PP populationN = 187N = 190 
Qualitative preparation rating, N (%)
Excellent (BBPS: 8–9 pts)85 (45.5%)72 (37.9%) 
Good (BBPS: 6–7 pts)63 (33.7%)61 (32.1%) 
Poor (BBPS: 3–5 pts)36 (19.3%)51 (26.8%) 
Inadequate (BBPS: 0–2 pts)3 (1.6%)6 (3.2%) 
BBPS successful bowel cleansing (excellent & good), N (%)148 (79.1%)133 (70.0%)0.042
Point estimate and 95% CI for the difference between successful rates+9.1% (+0.4%, +17.9%)
BBPS score per segment, mean ± s.d. 
Right colon2.11 ± 0.781.95 ± 0.850.051
Transverse colon2.39 ± 0.702.23 ± 0.770.031
Left colon2.39 ± 0.752.28 ± 0.750.150
Optimum visibility degree, N (%)106 (56.1%)88 (46.3%)0.044
ITT populationN = 203N = 202 
BBPS successful bowel cleansing155 (76.4%)136 (67.3%)0.043
Point estimate and 95% CI for the difference between successful rates+9.0% (+0.3%, +17.7%)
Optimum visibility degree, N (%)110(54.2%)90(44.6%)0.052

Caecal intubation rate was similarly high in both groups (99.5% in PEG-CS + bisacodyl and 97.9% in PEG-ASC) without differences in the time required to reach the caecum (7.9 ± 3.7 min with PEG-CS + bisacodyl and 7.3 ± 3.5 min with PEG-ASC respectively).

Mucosal inspection was rated as optimal in 56.7% of PEG-CS + bisacodyl and in 46.3% in the PEG-ASC (P = 0.044).

Safety and tolerability

No serious adverse events were reported in both study groups. Two patients in PEG-ASC group had to discontinue the bowel preparation because of vomiting. The rate of specific symptoms generally associated with colonic lavage solutions is reported in Table 4. No significant differences were seen in the rate of patients with any of the specific symptoms (PEG-CS + bisacodyl: 43.8% vs. PEG-ASC: 45%), as well as in the rate of nausea, bloating, pain/cramps and anal irritation. When those symptoms were present, they were generally mild indicating that both formulations were well tolerated.

Table 4. Secondary end-points at intention-to-treat analysis
VariablesPEG-CS+bisacodyl N = 203PEG-ASC N = 202P-value
  1. BBPS, Boston bowel preparation scale.

Tolerability (ITT population) 
Presence of any of the following symptoms, N (%)89 (43.8%)91 (45.0%)0.807
Nausea60 (29.6%)57 (28.2%)0.766
Bloating47 (23.2%)43 (21.3%)0.652
Abdominal pain34 (16.7%)30 (14.9%)0.601
Anal irritation19 (9.4%)16 (7.9%)0.606
Adverse events35 
Acceptability (ITT Population) 
Ease of taking: no distress, N (%)123 (60.6%)133 (65.8%)0.273
Willingness to repeat, N (%)188 (92.6%)189 (93.6%)0.705
Compliance (ITT Population) 
Amount of solution intake ≥ 75%, N (%)193 (95.1%)192 (95.0%)0.991

No statistically significant difference between the pre and posttreatment laboratory values of kidney and liver function was found, at exception of serum chloride. However, this finding was considered of no clinical significance. There was no individual report of adverse-drug-reaction based on abnormal laboratory test results. There were no clinically significant changes in physical examination and vital signs.

Acceptability and compliance

Most patients (59.6%) were administered two bisacodyl tablets, while three and four tablets were given in 24.6% and 14.3% of cases respectively. For three patients (1.5%), data are missing. The rate of patients who declared that they would be willing to repeat the same preparation regimen if needed was similar in the two groups (PEG-CS + bisacodyl, 92.6% vs. PEG-ASC, 93.6%).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Low-volume PEG formulations represent an important alternative to standard volume PEG formulation to reduce the discomfort and inconvenience of bowel preparation for colonoscopy.[3, 8] Previous studies consistently showed the noninferior efficacy of the hyper-osmotic low-volume PEG-ASC formulation[3, 4] and iso-osmotic low-volume PEG plus bisacodyl[9-11] as compared with a 4-L PEG regimen. According to the results of our study, a new iso-osmotic, sulphate-free low-volume formulation combined with 10–20 mg bisacodyl tablets provided marginally superior bowel cleansing than PEG-ASC formulation for out-patient colonoscopy. In the context of the current uncertainty, this study provides a relevant comparison between two different low-volume PEG-based bowel preparations. The greater cleansing effect of PEG-CS + bisacodyl regimen may be related to the stimulant effect of bisacodyl on ascending colon emptying and colonic transit. Such assumption is at odds with findings from a previous mono-centric study claiming the superiority of PEG-ASC over a combination of 2-L PEG plus bisacodyl.[3] However, in Cohen et al. study,[3] a split regimen for afternoon colonoscopies was prescribed only in PEG-ASC, but not in the 2-L PEG plus bisacodyl arm, so that a confounding effect of the split/nonsplit regimen on the results of this study cannot be excluded. On the other hand, we decided to restrict all the colonoscopies in the morning, to allow for a more fair and homogeneous comparison between the two regimens. Indeed, in our study, all the patients undergoing (morning) colonoscopies were prescribed with a nonsplit administration of the two preparations, as currently recommended for low-volume PEG solutions.[4, 12] In detail, a split regimen was only recommended for high-volume PEG preparation to enhance patient tolerability.[12] A nonsplit regimen for morning colonoscopies was also widely adopted in previous studies on low-volume PEG preparation.[4, 12-15] A noticeable exception was represented by Ell et al. study,[2] in which a split regimen was adopted also for morning colonoscopies. However, such a study was performed with hospitalised patients, minimising the nuisance of ingesting part of the preparation in the very early morning of the procedure before travelling. [2] The discrepancy between our series and the previous study may be also partly related to the higher dose of bisacodyl used in the present investigation.

Our study also showed better mucosal inspection following PEG-CS + bisacodyl. Although this may be related to the increased rate of adequate preparation in patients given this formulation, it cannot be excluded that such an effect could, at least in part, be related to the simethicone, which is a component of this regimen. The antifoaming properties of simethicone and its capacity to dissolve foam bubbles in the gastrointestinal tract have been largely demonstrated. The disappearance of the mucus-surrounded gas bubbles in the colonic lumen has been already reported to improve the mucosal visibility during colonoscopy.[16, 17]

Safety and tolerability of the bowel preparations were similarly high. We did not observe clinical or laboratory events of electrolyte and fluid imbalance, which may be a concern with hyper-osmotic preparations. Compared with sodium phosphate and magnesium citrate preparations, both low-volume PEG preparations are less likely to induce clinically significant alterations of serum electrolytes and serious disturbances related to fluid and electrolyte balance.[18, 19] Similarly, no cases of ischaemic colitis were observed in this study. There have been some reports of ischaemic colitis with 2-L PEG plus bisacodyl.[20] Acceptability and compliance of the two bowel preparations were also similar.

There are limitations to this study. We did not collect the adenoma-detection rate, and therefore, we are unable to state whether the improved bowel cleansing is associated with an increased adenoma-detection rate. However, it is widely accepted that the only reliable end-point for studies on bowel preparation is represented by the quality of preparation.[12] Both the polyp- and the adenoma-detection rates are indeed affected by several variables, such as age and sex of the patient, a positive family history, colonoscopy indication, endoscopist technique, as well as by endoscopy technology, that would introduce uncertainty on the study results.[21] Moreover, the adenoma-detection rate, as a clinically relevant indicator, has been validated only in screening setting, where it has been related with a higher risk of interval cancer, but not in an unselected setting that much better represents the routine workload of endoscopy units.[22]

In conclusion, low-volume PEG-CS + bisacodyl has shown to provide better bowel cleansing and similar tolerability and acceptance compared with PEG-ASC in patients undergoing colonoscopy.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal interests: None. Declaration of funding interests: The study was sponsored by Promefarm, Italy. Medications were provided by the sponsoring company. Statistical analysis was performed by a professional statistician who was paid by the sponsoring company. Two persons working for the company were involved in drafting the study protocol and monitoring and data collection was made by the company. The funding sources had no role in the interpretation of the data, in the preparation of the manuscript, or in the decision to submit the manuscript for publication.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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