The paradox of the novel 1 L polyethylene glycol bowel preparation: efficacy, not tolerability, is the great new!

Improving patient perception of colonoscopy plays a key role in increasing adherence to screening programs, which is crucial for screening effectiveness in colorectal cancer (CRC) prevention.

From the patient perspective, bowel preparation is recognized as the most burdensome aspect of the whole procedure, sometimes even worse than the examination itself, and this represents a major barrier to screening colonoscopy [1]. Thus, in recent years great attention has been paid to improving the tolerability of bowel preparation. Complaints regarding bowel preparation typically relate to the large volumes to be consumed within a short period of time and to the unpleasant taste.

“But postmarketing real-life data are needed to confirm the safety profile of this new product in a wider population with a range of comorbidities.”

The adoption of split-dose regimens has undoubtedly represented the most important step toward not only an increased efficacy of bowel preparation, but also an enhanced patient acceptance. Reducing the total volume of the cleansing agents, along with an attempt to improve their palatability, are also recognised as ways to improve the patient experience of colonoscopy preparation.

Although many low-volume preparations are gaining popularity at the expense of large-volume lavage solutions, many endoscopists are still skeptical of their adoption in routine practice. Concerns mainly relate to efficacy, which remains the first priority, when considering the deleterious effects of inadequate preparation on the effectiveness of colonoscopy in CRC prevention. Concern over the efficacy of low-volume bowel preparations probably reflects an endoscopist’s preconception rather than the clinical evidence. Indeed, many studies have demonstrated that low-volume preparations are not inferior to 4 L polyethylene glycol (PEG) electrolyte solutions in terms of efficacy [2], and high-quality randomized controlled trials have demonstrated that, when administered in a split regimen, they guarantee levels of efficacy over the recommended standards in the screening setting [3] [4].

In this issue of Endoscopy, data on the efficacy, safety, and tolerability of a novel 1 L PEG 3350-based bowel preparation (NER1006) for colonoscopy by two industry-funded Phase 3 studies are presented [5] [6]. These studies were two of three parallel randomized studies (also including the NOCT study carried out in the United States) [7] aimed at evaluating NER1006 in different dosing regimens, as part of the product label, compared with key leading different low-volume comparators (2LPEG with ascorbate in the MORA study, sodium picosulfate with magnesium citrate [SP + MC] in the DAYB study, and trisulfate in the NOCT study).

The three NER1006 studies share the same design, and this simplifies the interpretation and comparisons of results, which are summarized in [Table 1]. They have several strengths, including the rigorous statistical analysis, the large sample size, and above all, the use of blinded independent central readers for primary end point assessment in order to reduce the potential for bias in the subjective evaluation of bowel cleansing efficacy. In addition, right-sided cleansing was specified as a primary end point, and the efficacy primary end points were assessed for superiority by a preplanned analysis if noninferiority was demonstrated. It must be acknowledged that this is probably the first time that studies on bowel preparation have provided such robust and high quality data from a methodological point of view, and may potentially set a new quality standard for pivotal studies of new bowel cleansing products.

Table 1 Summary of efficacy primary end points in NER1006 Phase 3 trials.

	MORA (N2 D)	MORA (N1 D)	DAYB	NOCT
Study product, regimen	NER1006, split	NER1006, same day	NER1006, day before	NER1006, split
Comparator, regimen	PEG 2L + Asc, split	PEG 2L + Asc, split	SP + MC, day before	Trisulfate, split
Primary end points
Successful overall colon cleansing, HCS A + B (ITT)	noninferior[*]	noninferior[*]	noninferior[*]	noninferior[*]
Successful overall colon cleansing, HCS A + B (PP)	superior[**]	noninferior[*]	superior[**]	noninferior[*]
High-quality cleaning in the right colon, HCS score 3 + 4 (ITT)	superior[**]	superior[**]	noninferior[*]	noninferior[*]
High-quality cleaning in the right colon, HCS score 3 + 4 (PP)	superior[**]	superior[**]	superior[**]	noninferior[*]

HCS, Harefield Cleansing Scale; ITT, intention-to-treat analysis; N2 D, 2-day evening/morning split-dose regimen; N1 D, 1-day morning-only regimen; PEG, polyethylene glycol; PP, per-protocol analysis; SP + MC, sodium picosulfate + magnesium citrate.

^* Noninferiority demonstrated.

^** Superiority demonstrated.

Does this novel 1 L PEG-based preparation represent the final solution to achieve a highly effective, safe, and tolerated bowel preparation? There is no doubt that NER1006 appears to be a very effective preparation, but split dosing (or same-day regimen as an alternative) is an essential prerequisite for its success. It matters little that in the DAYB study, where both study preparations were given in day-before dosing, NER1006 met the primary end point of noninferiority efficacy vs. SP + MC, and was even superior at per-protocol analysis. The overall colon cleansing success of 62 % reported in the DAYB study is unacceptable. Conversely, the efficacy is very high, over the standards set by professional societies, when NER1006 is administered as either a split or same-day regimen. It is noteworthy that the true efficacy could probably have been even higher in the MORA study if the “runway time” had been optimized within the “golden 5 hours” [8] in a higher proportion of patients. In terms of efficacy, the most interesting, and on some level, unexpected, finding relates to the quality cleansing of the right colon, which is usually considered the “Achilles’ heel” of low-volume bowel preparations. In the MORA study, superiority of NER1006 vs. 2LPEG was statistically demonstrated with a split regimen at the intention-to-treat analysis and with both dose regimens at per-protocol analysis. This signal of higher cleansing efficacy in the right colon was consistent across the three studies, regardless of the administration regimen, and this suggests that it is strictly related to the properties of the product. Actually, NER1006 contains a high quantity of ascorbate components (4-fold higher than in the standard 2LPEG + Asc), which are administered in the second dose only. The increased osmotic load is thus delivered in a smaller volume and this is likely to represent the major determinant for efficacy in the proximal colon.

But when we deal with hyperosmotic cleansing agents (and NER1006 should definitely be considered as an osmotic laxative), safety is an important issue, especially in an open-access system. PEG-based bowel preparations are traditionally considered the gold standard for safety. They have been purposely developed to pass through the bowel without net absorption or secretion, and they are osmotically balanced with electrolyte solution to minimize significant fluid and electrolyte shifts. By contrast, most low-volume non-PEG regimens are hyperosmotic and this property might theoretically expose frail patients who are at risk of fluids shift (i. e. patients with renal insufficiency or congestive heart failure) to an even greater risk.

Nevertheless, safety data from more than 1000 patients receiving NER1006 are reassuring, as no major safety issue seems to have been revealed by the three studies. Median changes in electrolytes and renal function from baseline were mild, transient, and without any clinically relevant sequelae. However, serum sodium levels higher than normal were seen in a substantial number of patients, and this might suggest that patients need to be instructed to take in more free water than the 1 L currently recommended with NER1006 in order to prevent hypernatremia.

By reducing the volume to only 1 L of active solution, it was expected that NER1006 would improve the patient experience of colonoscopy preparation, but instead the novel low-volume preparation failed just where expectations were higher. The overall patient tolerability and acceptability were comparable between NER1006 and 2LPEG + Asc, and no significant differences were found with other comparators either. Moreover, nausea and vomiting – probably related to the high osmolality – albeit not common, were more frequent with NER1006 than with the other study products, and this may have mitigated the benefit of the smaller volume on patient tolerance. However, it should be considered that the study design somewhat downgraded the assessment of tolerability, as each patient was randomized to only one product, and patient evaluation was mostly subjective.

In conclusion, NER1006 in split or same-day regimens will probably represent the new reference standard for efficacy among the low-volume bowel preparations. As efficacy is the priority from the endoscopist’s perspective, this novel preparation might be more than welcome among them. And there is no doubt that patients, whose main concerns about colonoscopy usually relate to the volume of product to be ingested, will also favor it. But postmarketing real-life data are needed to confirm the safety profile of this new product in a wider population with a range of comorbidities.

• References

• 1 McLachlan SA, Clements A, Austoker J. Patients’ experiences and reported barriers to colonoscopy in the screening context – a systematic review of the literature. Patient Educ Couns 2012; 86: 137-146
• 2 Xie Q, Chen L, Zhao F. et al. A meta-analysis of randomized controlled trials of low-volume polyethylene glycol plus ascorbic acid versus standard-volume polyethylene glycol solution as bowel preparations for colonoscopy. PLoS One 2014; 9: e99092
• 3 Radaelli F, Paggi S, Hassan C. et al. Split-dose preparation for colonoscopy increases adenoma detection rate: a randomised controlled trial in an organised screening programme. Gut 2017; 66: 270-277
• 4 Zorzi M, Valiante F, Germanà B. et al. Comparison between different colon cleansing products for screening colonoscopy. A noninferiority trial in population-based screening programs in Italy. Endoscopy 2016; 48: 223-231
• 5 Bisschops R, Manning J, Clayton LB. et al. Colon cleansing efficacy and safety with 1 L NER1006 versus 2 L polyethylene glycol + ascorbate: a randomized Phase 3 trial. Endoscopy 2019; 51: 60-72
• 6 Schreiber S, Baumgart D, Drenth JPH. et al. Colon cleansing efficacy and safety with 1 L NER1006 versus sodium picosulfate with magnesium citrate: a randomized Phase 3 trial. Endoscopy 2019; 51: 73-84
• 7 DeMicco MP, Clayton LB, Pilot J. et al. Novel 1 L polyethylene glycol-based bowel preparation NER1006 for overall and right-sided colon cleansing: a randomized controlled phase 3 trial versus trisulfate. Gastrointest Endosc 2018; 87: 677-687
• 8 Bucci C, Rotondano G, Hassan C. et al. Optimal bowel cleansing for colonoscopy: split the dose! A series of meta-analyses of controlled studies. Gastrointest Endosc 2014; 80: 566-576