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With an estimated prevalence between 1.9% and 31.7% in Western populations,[1-3] constipation is a common condition affecting around twice as many women as men and associated with increasing age.[3, 4] For the diagnosis of constipation according to the ROME III criteria, the patient must have two or more of the following symptoms: straining, lumpy or hard stools, sensation of incomplete evacuation, assistive manual manoeuvres (in at least 25% of defecations) and <3 successful bowel movements (BMs) per week. In addition, they should rarely have loose stools without laxative use and fail to fulfil the criteria for irritable bowel syndrome. Constipation is considered chronic when these criteria have been fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.[5-8] As well as a considerable impact on patient's quality of life (QoL), constipation and its sequelae represent a significant economic consideration for patients and society.[9, 10]
Various treatment options are available for constipation relief, including dietary and lifestyle modifications, pharmacological agents and surgery.[7, 11] In spite of these, patients frequently report dissatisfaction with available treatments, and in Europe, limited therapy guidance is available on the best options for effective relief. A progressive treatment regimen is generally recommended, from diet and lifestyle changes (largely increased fibre intake and activity level) to use of bulk/osmotic laxatives then stimulants.[7, 11, 13] Laxative treatments using polyethylene glycol 3350 [PEG (macrogol) 3350] have been recognised as effective, well-tolerated options in randomised trials and extensively in clinical practice. However, newer therapeutic agents are not routinely compared with established evidence-based treatment options, but mainly to placebo.
PEG 3350 plus electrolytes (PEG 3350+E) and prucalopride are distinct pharmacological agents used for the relief of chronic constipation (CC). PEG 3350+E is an established first-line osmotic laxative, widely available for the treatment of all forms of constipation in adults and children.[14, 15] PEG 3350 acts by increasing stool volume through increased hydration, triggering colon motility to improve transit of softened stools and defecation mechanics. PEG 3350 is more efficacious, but with comparable tolerability to laxatives such as lactulose[16, 17] and ispaghula husk, and in independent reviews is considered a key treatment option.[17, 19]
Unlike PEG 3350, prucalopride is a selective serotonin (5-HT4) receptor agonist, recently approved in Europe for the treatment of CC in adult females for whom previous laxative use failed to provide satisfactory relief. Prucalopride stimulates the enteric nervous system to enhance the peristaltic reflex, stimulating gut motility and accelerating colonic transit. Prucalopride improves bowel function, patient treatment satisfaction and QoL compared with placebo,[21-23] and has been suggested as a second-line treatment for relief of CC. The UK National Institute for Health and Clinical Excellence (NICE) have recommended prucalopride only in women for whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses for at least 6 months, has failed to provide adequate relief and invasive treatment for constipation is being considered.
There have been no direct comparisons of prucalopride against established pharmacological treatments for CC. This study therefore aimed to compare the efficacy, safety and impact on QoL of PEG 3350+E vs. prucalopride in patients with CC in the restricted population for whom prucalopride is indicated. The study specifically recruited females with CC in whom any laxative had previously failed to provide adequate relief. Notably, this study was conducted in the controlled environment of a Phase I unit, enabling standardisation of environmental factors (diet/liquid intake), and ensuring accurate recording/weighing of stools during treatment.
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This randomised controlled trial directly compared the efficacy, safety and impact on QoL of PEG 3350+E and prucalopride. Importantly, use of a controlled environment, aiming to standardise environmental factors, represents a novel design for studies of this type and provides a unique body of evidence. The associated and unavoidable limitations of this particular study design relate to the artificial environment of the Phase I unit compared with normal life for constipated patients. In addition, the 4-week evaluation period was shorter than would generally be expected for evaluation of CC, however, this was the maximum duration acceptable to the patients given their confinement in the Phase I unit.
In these study conditions, prucalopride showed no advantage over PEG 3350+E for the treatment of CC in female patients who were dissatisfied with previous laxative treatment. For the primary endpoint of patients having ≥3 SCBMs, the 97.5% lower CI limit of −2.7% was substantially above the non-inferiority margin of −20%, providing conclusive evidence of non-inferiority of PEG 3350+E to prucalopride in this subset of patients with CC. The study was also designed to detect superiority based on a true treatment effect of 20%; however, an estimated treatment effect of 10%, with a 95% CI indicating that the true treatment effect is unlikely to lie below −2.7% or above 32.1%, was observed. To have demonstrated a statistically significant superior treatment effect of 10% with a power of 80%, 406 patients per group would have been required. The achieved rates of 66.7% (PEG 3350+E) and 56.5% (prucalopride) are also somewhat higher and therefore had greater variability than previously reported response rates for 2 mg prucalopride (between 19.5% and 30.9%).[21-23] This disparity may reflect differences in study design, or in the severity or type of constipation, with a relatively higher proportion of patients having evacuation disorders. The greater efficacy was observed in the closely supervised controlled environment (achieving over 99% treatment compliance and full documentation of defecations). In comparison, the lower response rates were reported in ambulatory patients, where laxative effectiveness has a greater component of patient subjectivity, thus emphasising the importance of active-controlled studies. In addition, to meet the criteria for which prucalopride is currently approved, all patients in this study were female. This may also have influenced the disparity in response rates compared to results from previous studies which were in mixed gender populations.
The study population was generally comparable between treatment groups. While patients with secondary causes of constipation were excluded during screening, those with pelvic floor dysfunction and/or delayed colonic transit were not specifically identified or omitted from the study. Symptoms which may be indicative of pelvic floor dysfunction (anorectal blockade or the need for manual manoeuvres to facilitate defection) were recorded during initial patient evaluations, as was CTT, and all these variables were comparable between treatment groups at baseline. In addition, no differentiation between patients with slow or normal CTT was made in this study. Although these patients may respond disparately to treatment, recent guidelines propose that, in practice, such differentiation is not immediately useful as initial treatment options (e.g. laxatives) remain the same in both instances. Furthermore, slow CTT and defecatory disorders are not mutually exclusive and so patients may still derive benefit from these treatments. It would be of potential future interest, however, to determine the relative efficacies of these two treatments in different subpopulations of patients with CC.
While superiority over prucalopride was not conclusively demonstrated for the primary endpoint based on the selected sample size, the observed treatment effect was nevertheless clinically relevant. In addition, a number of other significant benefits associated with PEG 3350+E were observed for the majority of secondary variables. Compared to prucalopride, PEG 3350+E treatment resulted in higher weekly SCBM number, higher stool weight, greater SCBM increase from run-in and higher proportions of responders throughout treatment. Although the shorter time to first SCBM in PEG 3350+E than prucalopride-treated patients was not statistically significant, time to next SCBM was statistically significantly shorter in the PEG 3350+E group for all treatment weeks (P < 0.001). Stool weight, consistency and patient perception of straining and completeness of defecation after 4 weeks of treatment all favoured PEG 3350+E. The observed relief from constipation supports previous reports where the efficacy of PEG 3350 and prucalopride was demonstrated against placebo.[21-23, 31-33]
Interestingly, CTT reduction in the PEG 3350+E group was highly significant, and similar to that observed with prucalopride, a prokinetic laxative, although time to first SCBM was longer than previously reported for both treatments.[21, 22, 34] Measures of patient satisfaction and QoL supported the improvements observed in the PEG 3350+E group. Only the PAC-SYM subdomain abdominal symptoms showed greater improvement in the prucalopride group.
In agreement with previously published safety reports, both PEG 3350+E[31-33, 35] and prucalopride[21-23] were well tolerated. Events of back pain and urinary tract infection were higher in the PEG 3350+E group; however, the incidences were low overall (≤5% of patients). While the number of SAEs and events resulting in treatment discontinuation was low, all occurred in the prucalopride group, which also reported over twice as many possibly or probably treatment-related AEs. The incidence of headache and dysmenorrhoea was higher in this study than previously reported for either treatment.[21-23, 31-33, 35] These higher incidences may reflect the close observational nature, and thus potentially more rigorous reporting, of this study and, specifically for dysmenorrhoea, the solely female patient population. Low use of rescue medication and few dose adjustments indicate dosing was appropriate. The prevalence of stool types 5 and 6 in the PEG 3350+E group, however, indicates a lower dose may have been appropriate over time as supported by the flexible dosing recommendations of PEG 3350-based laxatives in relation to observed stool frequency/consistency.
As highlighted previously, the 4-week treatment duration reflected restrictions associated with the closely monitored in-patient stay. Maintaining patients in this controlled environment for longer would have been unfeasible. However, beneficial effects of both treatments comparable with the literature were observed, as were clear differences in patient responses. Also, patients generally respond to laxative treatment within 28 days[24, 36] making this a relevant timeframe for assessment. The efficacy of both PEG 3350+E and prucalopride has also been shown to be maintained when the products are used on a longer term basis (up to 3 months).[16, 22] The in-patient setting facilitated close scrutiny of patient responses to treatment as well as the control of environmental factors such as food and drink intake, enabling direct pharmacological treatment comparisons. A potential limitation was the subjective component of SCBM evaluation, defined as ‘spontaneous BMs associated with the feeling of complete evacuation’. However, the objective measurement of stool weight gives reassurance of the validity of the selected endpoints.
Greater benefits observed for the relief of CC in the PEG 3350+E group parallel reports comparing other constipation treatments with PEG 3350. PEG 3350 was more effective and as well tolerated as the laxatives lactulose[16, 17, 37] and ispaghula husk, and significantly, to the 5-HT4 receptor agonist tegaserod. In the latter study, more patients treated with PEG 3350 achieved statistically significant relief of constipation for ≥50% of their treatment weeks, more weekly BMs and greater improvement in constipation symptoms than those treated with tegaserod.
Significant costs are associated with treating CC[9, 39] and are an important consideration for an increasing elderly population. Prucalopride (Resolor) has a higher cost for a 14-day course compared with PEG 3350+E (Movicol). This, together with the efficacy of PEG 3350+E reported in this study, suggests that PEG 3350+E is a more cost effective treatment. However, a comparative cost-benefit analysis has not been performed on these therapies. The results of our study suggest future remedies for CC or conditions where CC has a major impact on QoL should be tested against PEG 3350+E instead of placebo in populations considered nonresponders.
In conclusion, this study confirmed the effectiveness of both PEG 3350+E and prucalopride for the relief of CC in women for whom laxatives have not previously proven satisfactory. However, prucalopride showed no advantage over PEG 3350+E under the study conditions. PEG 3350+E was as effective as and generally better tolerated than prucalopride. Importantly, PEG 3350+E has a wider treatment indication and is a lower cost treatment compared with prucalopride. Despite the emergence of new treatment options, this study suggests that PEG 3350+E should remain a first-line treatment for CC. For any new therapy, assessment of efficacy, safety and tolerability would benefit from comparison not only against placebo but also established treatments. Most clinical data available at launch are comparisons against placebo, which does not help the prescriber to establish the place of the new therapy in medicine. This prospective, active-controlled efficacy study provides strong evidence that the less expensive, established product with a long history of safe and effective use is not inferior, and has clinically relevant benefits compared with the more costly new treatment.