Preparazione intestinale a basso volume per la colonscopia
Gastroenterologo, Azienda ospedaliera di rilievo nazionale Antonio Cardarelli
Colonoscopy is considered the gold standard for colonic explo- ration: it represents the most effective screening tool and the only procedure allowing simultaneous detection and removal of polyps. The success of colonoscopy is largely dependent on the level of bowel cleansing: a higher cleansing level being associated to a higher detection rate of clinically relevant neoplastic lesions. The substantial adverse consequences of inadequate or sub-optimal bowel preparation include: lower likelihood of detection of small or large adenomas, longer procedure times and, in general, more difficulties during the exam. This has inevitably a negative impact on the efficiency of colonoscopy, waiting lists and costs of screening programmes.
Polyethylene glycol (PEG) solutions are widely used in clinical practice as they are effective and safe, due to the negligible net absorption of water and electrolytes and are recommended by both the European  and American Guidelines. The conventional formulations of PEG-based bowel cleansing agents administered at high volume (4 L) are considered the gold standard for efficacy . However, the large volume and unpleasant taste may limit the gastrointestinal tolerability and decrease the compliance to the recommended dose regimen, affecting indirectly the efficacy for high-quality level of bowel preparation in clinical practice.
A novel low-volume PEG bowel cleansing agent (Clensia) (Alfa Wassermann S.p.A., Bologna, Italy) was developed to overcome the above issues with a formulation aiming to improve patient com- pliance by reducing the volume of the solution to 2L in order to minimize the volume-related gastrointestinal symptoms and discomfort. Clensia active ingredients include PEG 4000, sodium sulphate, citric acid, sodium citrate, sodium chloride, potassium chloride and simeticone. Citric acid and sodium citrate are not sys- temically absorbed and acting as osmotic agents and in synergy with PEG 4000 and sodium sulphate reduce the required solution volume and improve its taste. Simeticone was included in the for- mula due to its antifoaming properties, in order to improve the visualisation of the colonic mucosa.
Moreover, to further enhance patients’ safety, Clensia has been formulated without ascorbates and aspartame. The aim of the study was to investigate whether Clensia and the standard PEG 4 L prepa- ration are equivalent in terms of safety and efficacy for bowel cleansing. Tolerability, acceptability and compliance of both prepa- rations were also evaluated.
This was a multicentre, randomised, observer-blind, parallel group, phase-3 clinical trial designed to compare Clensia (Test) with a standard PEG 4 L solution (Reference). The study protocol was reviewed and approved by the Institutional Ethics Commit- tees of the 6 participant sites and was registered in the European Union Clinical Trial Registry (EudraCT number: 2008-007144-33). All subjects provided written informed consent. Eligible subjects, who were aged between 18 and 85 years, were scheduled for rou- tine colonoscopy. Patients were excluded if they had history of anaphylaxis to drugs or allergic reactions; known or suspected gas- trointestinal obstruction or perforation, toxic megacolon, major colonic resection, heart failure (Class III or IV NYHA), serious cardiovascular disease, severe liver failure, end-stage renal dis- ease, or relevant diseases that might interfere with the aim of the study; inability to comprehend the full nature and purpose of the study and unwillingness to co-operate with the Investiga- tor.
At baseline all subjects underwent a physical examination and blood and urine sampling for clinically relevant laboratory tests were collected. Eligible subjects were allocated to receive either Clensia or PEG 4L according to a randomisation list generated using SAS PROC PLAN. Endoscopists were unaware of the assigned treat- ments and instructed to avoid any discussion with the patient that could disclose the type of bowel preparation.
The Test preparation Clensia (Alfa Wassermann S.p.A., Bologna, Italy) is a new combination of macrogol (PEG) 4000 and electrolytes with new active ingredients that are sodium citrate, citric acid and simeticone, available as a powder for oral solution after recon- stitution with 2L of water. The schedule for bowel preparation differed according to the time of colonoscopy. When colonoscopy was scheduled before 12 a.m. patients were instructed to take 2 L of solution plus 1 L of clear fluids on the day before the colonoscopy; when colonoscopy was scheduled after 12 a.m., patients were instructed to split the dose: 1 L of solution plus 0.5 L of clear flu- ids on the day before and 1 L plus 0.5 L in the morning of the day of the colonoscopy.
Similarly, patients allocated in the Reference group (PEG 4L as SELG 1000®, Alfa Wassermann S.p.A., Bologna, Italy) were instructed to take 4L of solution on the day before when colonoscopy was scheduled before 12 a.m. and to split the dose (2L of solution on the day before and 2L in the morning of the day of the procedure when colonoscopy was scheduled after 12 a.m.).
Low residue diet was prescribed for 3 days before colonoscopy. During and after bowel preparation solid food was not allowed. There were no restrictions about either previous or concomitant treatments. 2.3. Efficacyassessments
The primary efficacy endpoint was the proportion of patients with successful colon cleansing, defined as “excellent” or “good” according to the Ottawa bowel preparation scale . This is a val- idated scale (score ranging from 0 to 14) that takes into account two aspects: the degree of segments cleaning and the amount of fluid in the entire colon. Each section of the colon (right, mid and recto-sigmoid colon) is rated according to a 5-point scale (0–4) as follows:
- Excellent:grade0=mucosaldetailclearlyvisible.Incaseanyfluid is present, it is clear. Almost no stool residue;
- Good: grade 1=some turbid fluid or stool residue but mucosal detail still visible. Washing and suctioning not necessary;
- Fair: grade 2 = turbid fluid or stool residue obscuring mucosal detail. However, mucosal detail becomes visible with suctioning. Washing not necessary;
- Poor: grade 3 = presence of stool obscuring mucosal detail con- tour. However with suctioning and washing a reasonable view is obtained;
- Unprepared: grade 4 = solid stool obscuring mucosal detail and contour despite aggressive washing and suctioning.
The overall colonic fluid was rated according to a 3-point scale (0–2) as follows: small = grade 0; moderate = grade 1; large = grade 2. The degree of bowel cleansing was categorized according to the total score (sum of single assigned scores) as follows: excellent (0–3), good (4–6), fair (7–10) and inadequate cleansing (11–14).
Secondary efficacy endpoints included the overall mucosal visibility, (graded according to a 3-grade scale: grade 0 “opti- mal”=clear imaging, no or minimal amount of bubbles or foam, which could be easily removed; grade 1 “adequate”=modest amount of bubbles and foam, which could be removed requiring additional time; grade 2 “insufficient” = presence of foam and bub- bles, which significantly decreased the clear visualization of the mucosa) and indicators of quality such as caecal intubation (full colonic examination), time to reach the caecum (intubation time) and withdrawal time from the descending-sigmoid junction to exit.
The safety of the preparations was based on adverse events (AEs) occurrence and clinical laboratory test abnormalities. AEs were monitored throughout the study. The duration and intensity of each event were recorded by the Investigators, as well as the causative relationship with study drugs, outcome and seriousness. Standard laboratory blood and urine tests were performed at baseline and at the end of the study. Tolerability was assessed inquiring on the occurrence and severity of gastrointestinal symptoms related to the consumption of bowel cleansing agent, i.e., nausea, bloating, abdominal pain/cramps and anal irritation. 2.5. Acceptabilityandcompliance
The acceptability of both products was evaluated by the subjec- tive assessment provided by patients concerning the ease of taking the solution and the willingness to repeat the intake . The ease of taking or swallowing the solution was graded as follows: severe distress = 3, moderate distress = 2, mild distress = 1, no distress = 0. Willingness to repeat the same bowel cleansing agent in the future was also collected and evaluated through a “yes or no” binary ques- tionnaire. Treatment compliance was scored according to a 3-grade scale specifying the percentage of drunk solution: “optimal”: intake of the whole solution (grade=0); “good”: intake of at least 75% of the solution (grade = 1); “poor”: intake of <75% of the solution (grade = 2).
The primary end-point of this trial was the demonstration of the equivalence of Clensia versus PEG 4 L in colon cleansing. An equiva- lence margin of 15% was set for the proportion of subjects fulfilling the definition of successful bowel preparation. The null hypothesis was tested by constructing the two-sided 95% confidence interval (CI) for the difference in the success rate: the lower limit of the CI was compared with the lower equivalence limit of −15% and the upper limit of the CI was compared with the upper equivalence limit of 15%. Sample size was calculated a priori based on the esti- mated rate of 75% successful cleansing in both treatment groups, a 15% equivalence margin, a significance level of 0.05 with a power of 84%. Given that 10% of the enrolled subjects could not be included in the efficacy evaluation (drop-out, major protocol deviations, etc.) at least 210 per group were required. As recommended by the ICH guidelines for equivalence study design, efficacy analysis was based on the “Per Protocol” (PP) population.
Baseline characteristics were summarized using mean and stan- dard deviation for continuous variables and rates for categorical variables. A 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 statistical anal- ysis was performed using SAS. All randomised subjects, who took at least a fraction of the dose of the investigational formulation were included in the “safety population”. All randomised subjects, who took at least a fraction of the dose of the investigational formulation and had at least one post-baseline efficacy evalua- tion were included in the “Intent-To-Treat” (ITT) population. All randomised subjects, who completed the whole study without any major deviations (i.e. violation of inclusion/exclusion criteria, drop-out patients, missing bowel cleansing score data and poor compliance, i.e., <75% intake of the solution) were included in the PP population. The efficacy analysis was performed on both ITT and PP population, whereas the equivalence testing was limited to the PP population. The safety analysis was performed on the safety population.
The patient flow is reported in Fig. 1. Among the 440 enrolled subjects, 421 underwent colonoscopy and completed all scheduled assessments. The safety population included 422 patients and the ITT 421 patients. A total of 29 subjects incurred in major protocol violations (25 for missing bowel cleansing scores; 3 for insuffi- cient compliance (<75%) and one violation of inclusion/exclusion criteria) and were not included in the PP analysis (392 patients).
The proportion of successful bowel preparation (excellent or good) was very similar in the Clensia and PEG 4 L groups in both ITT and PP population analysis. The efficacy of Clensia was equivalent to PEG 4 L as the 95% for the difference in proportions between the two treatment groups was entirely contained within the equivalence range −15% to 15% (Table 2). There was no significant difference between the two groups for the rate of successful cleansing of the right colon, mid and recto-sigmoid colon.
Completeness and duration of colonoscopy were similar in the two treatment groups.
The frequency of successful bowel cleansing was significantly higher with the split dose than the day before regimen after both preparations (2 test, P = 0.0026 for Clensia and P = 0.0259 for PEG).
An optimum mucosal visibility was achieved with Clensia in about 63% as compared to 55% with PEG 4 L (p = 0.12) (Table 3).
3.2. Safety and tolerability
No serious adverse events (SAEs) occurred during the study and no subject discontinued the study due to AEs. Occurrence of AEs was 8% after Clensia and 7.2% after PEG 4 L (P = NS). The most frequent AEs were headache (5.6% in Clensia group and 3.8% in PEG 4 L group) and vomiting (0.9% in Clensia group and 1.0% in PEG 4 L group). No clinically relevant changes in serum electrolytes, body weight and vital signs were observed after either treatment.
Clensia showed a significantly better gastrointestinal tolerabil- ity compared to PEG 4 L. The rate of patients with nausea, bloating, abdominal pain/cramps and anal irritation was lower with Clensia than PEG 4 L (25.4% vs 37%, P < 0.01).
The frequency of an optimal compliance was similar with either treatment in the ITT population (91.1% with Clensia vs. 90.9% with PEG 4 L; P = 0.9388).
Clensia was significantly superior to PEG 4 L for acceptability as determined by the rate of patients reporting no distress on ease of taking the preparation (72.8% for Clensia and 63% for PEG 4 L; P = 0.0314) and willingness-to-repeat the same preparation for future colonoscopy (93.9% for Clensia and 82.2% for PEG 4 L; P = 0.0002).
The results of the present study show that a new low volume combination of macrogol (PEG) 4000 with citrates and simeticone (Clensia) is equivalent to the reference high volume PEG-based solution for colonoscopy in terms of proportion of subjects achieving a successful cleansing and has a better gastrointestinal tolerability and acceptability. An adequate or optimal bowel prepa- ration has a key role in ensuring a high quality colonoscopy and minimizing the risk of missing colon polyps and neoplastic lesions [1–4]. Four-L PEG-based solution is the recommended regimen of preparation before colonoscopy [8,9]. However, this approach requires the patients to consume large volumes of liquids with an unpleasant taste, within a short period of time. When tolerability of bowel cleansing agent is a matter, acceptability and compliance are variably affected in the single patients. This issue is well known in clinical practice and cannot be easily managed since most patients do not have previous experience of bowel preparation and endo- scopic services have limited resources to support and motivate the patient in an open access system .
The results of our study evidenced the equivalence in terms of cleansing level between Clensia and a standard high-volume preparation. The 73.6% of “adequate” cleansing level observed with Clensia is comparable with that observed in previous stud- ies, suggesting its equivalence to other low-volume formulations [19,23,24].
These study results are important as the comparison of the new low volume preparation with the standard treatment of PEG 4 L was planned as an equivalence trial. The results have shown that Clensia is equally effective to standard PEG 4 L for bowel cleansing; based on the confidence interval of the difference, it is of note that a clinically important difference can be ruled out. In fact, there is a 95% chance that Clensia is no worse than 7% and no better than 10% in the rate of successful preparation as compared to PEG 4 L.
Efforts have been made to reduce patient discomfort related to bowel preparation and to increase compliance. On this basis, the development of new regimens (full or split) and formulations for bowel cleansing with a higher degree of tolerability is desirable.
Some clinical trials have shown how split-dose PEG solution results in a marked increase in tolerability which improves overall bowel preparation quality [15–18]. This effect was also observed in our study: the rate of successful bowel cleansing were signifi- cantly higher with the split-dose regimen than with the full dose the day before for both low and high volume bowel preparations. This confirms that dose regimen and timing play a crucial role for the quality of bowel cleansing and that the day before regi- men should only be used when there is no practical alternative [8,17–22]. Furthermore, the new PEG-based bowel cleansing agent with citrates and simeticone, designed with a reduced volume (2 L), should improve patient’s acceptability, minimizing volume related GI symptoms and discomfort and enhancing mucosal visibility dur- ing colonoscopy. Despite important advancements in the regimen of the preparation, in clinical practice the quality indicator of bowel preparation defined as the proportion of procedures in which the cleansing is considered adequate, remains below the standard of >90%. In fact, in our study when the category “fair” bowel prepa- ration is added to “excellent” and “good” results both solutions showed adequate cleansing rates over the standard level of 90%. This efficacy has been favored by the high compliance observed with both products.
The Clensia low volume regimen resulted more tolerable and acceptable than the high volume preparation, potentially increas- ing the long-term acceptability of colonoscopy, in terms of safety and tolerability [29,30]. In the present study the rate of patients reporting nausea, bloating, abdominal pain or anal irritation was lower with Clensia than with PEG 4 L; the difference of 12% in gas- trointestinal tolerability in favour of Clensia may have a beneficial impact on patient acceptability and compliance, and a potentially improved rate of colonoscopy completion.
Furthermore, the role of simeticone in colonic preparations, due to its role in reducing the number of bubbles and enhanc- ing mucosal visibility, is well known [11,12,25–28]. Although the present study was designed as an equivalence trial, a trend in favor of the regimen of preparation including simeticone, in terms of mucosal visibility, was observed (63% in Clensia versus 55% in the reference group).
In this new 2 L PEG-formulation, citrates are not systemically absorbed and act as osmotic agents in combination with PEG 4000 and sulphates. The results of this study support the safety of Clensia, as no serious adverse events or patient discontinuation for adverse events occurred; no clinical and laboratory events of electrolyte and fluid imbalance, which may be a concern in particular using hyper- osmotic preparations, were observed in both Clensia and PEG 4 L groups. It is important to note that about one third of patients had cardiovascular disease, diabetes or other chronic significant co-morbidities. Although patients with severe, relevant comorbidi- ties (i.e. NYHA III–IV heart failure, cardiovascular diseases and end stage renal failure) were not included in the present trial, the safety profile of Clensia, a PEG-based regimen, does not differ and seems comparable to other PEGs previously evaluated in terms of safety profile.
Notably, Clensia does not contain aspartame and ascorbates, that could potentially be harmful for some patients, namely the ones with phenylketonuria or glucose-6-phosphate dehydrogenase deficiency respectively. This could represent a significant advan- tage in some patients in an open access system.
As bowel cleansing agents are evaluated primarily for their effi- cacy to avoid the risk of missing premalignant/malignant lesions [4–6], the demonstration of equivalent efficacy but with a more favorable tolerability and acceptability profile than standard solu- tions, opens the way to a greater choice of low-volume bowel preparations.
The present study has some limitations. No investigations on the effects of the two different preparations on the adenoma detec- tion rate and/or detection of malignant lesions, which represent the main outcome of the large part of colonoscopies [6,17], were per- formed. Unfortunately this quality measure is affected, in addition to bowel preparation, by several factors which may not be under control in a multicentre clinical trial and, therefore, may be difficult to evaluate.
In conclusion, the low volume Clensia solution is equally as effective as PEG 4 L for bowel preparation in colonoscopy, with a better tolerability and acceptability profile. As the large volume and unpleasant taste of PEG-based solutions still represent an issue and burden which may reduce the willingness to undergo colonoscopy, Clensia can represent a safe and more acceptable true alternative for these patients.
Conflict of interest