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Summary

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

Background

Constipation is a common condition for which PEG 3350 is an established treatment and prucalopride has recently been approved for this indication.

Aim

To compare the efficacy, safety and impact on quality of life (QoL) of PEG 3350 plus electrolytes (PEG 3350+E) vs. prucalopride in females with chronic constipation (CC) in whom laxatives have previously failed to provide adequate relief.

Methods

In this single-centre, randomised, double-blind, double-dummy study, patients with CC [<3 spontaneous complete bowel movements (SCBM)/week] remained in a controlled environment and received either a 26 g split dose of PEG 3350+E (N = 120) or 1–2 mg prucalopride (N = 120) daily for 28 days following a 14-day run-in period. The primary endpoint was the proportion of patients having ≥3 SCBMs during the last treatment week.

Results

Non-inferiority of PEG 3350+E to prucalopride was demonstrated in the per-protocol population [difference, 10.1% (66.67% vs. 56.52%), 97.5% lower confidence interval (CI) −2.7%, above the preset margin of −20%] and approached superiority in the modified intent-to-treat population (difference, 9.8%, 97.5% lower CI, −3.1%). Statistically significant differences in favour of PEG 3350+E were observed for most secondary variables (bowel movements, stool weight, consistency, time to next SCBM, patient perception of straining and completeness of defecation). Colonic transit time was dramatically reduced in both arms. Both treatments were well tolerated.

Conclusion

PEG 3350+E was at least as effective as and generally better tolerated than prucalopride as a treatment for chronic constipation in this study population (NCT01251822; http://www.clinicaltrials.gov).


Introduction

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

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,[12] and in Europe, limited therapy guidance is available on the best options for effective relief.[7] 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.[14] PEG 3350 is more efficacious, but with comparable tolerability to laxatives such as lactulose[16, 17] and ispaghula husk,[18] 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.[20] 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.[20] 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.[24]

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.

Methods

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

Study design

This prospective, single-centre, randomised, double-blind, double-dummy, parallel-group study conducted in a Phase I unit in Romania compared PEG 3350+E and prucalopride. Following screening, patients entered an ambulatory 14-day run-in period without any laxative treatment or rescue medication, during which baseline parameters and eligibility criteria (constipation) were assessed. Eligible patients were then admitted to the unit and randomised 1:1 to receive PEG 3350+E or prucalopride and matching placebo of the alternate study treatment for 28 days in a controlled environment (including standardised fluid and food intake). Randomisation was performed centrally using a permutated block design. The investigator then allocated eligible patients a randomisation number. A predefined randomisation list was provided to the unblinded pharmacist who held a confidential master list.

The primary endpoint was the proportion (%) of patients having ≥3 spontaneous complete bowel movements (SCBMs) during the last treatment week. The study was conducted in compliance with the Declaration of Helsinki and good clinical practice guidelines and the protocol was approved by the relevant local ethics committee. All patients provided informed consent prior to study entry. Trial registration number: NCT01251822 (http://www.clinicaltrials.gov).

Patients

Patient eligibility criteria were consistent with the prucalopride approved indication. Patients were female, aged 18–75 years, with at least 6 months of CC and not satisfied with any previous laxatives. Chronic constipation was defined according to the ROME III criteria and was characterised by <3 successful BMs per week with at least one additional symptom (straining, lumpy or hard stools, sense of incomplete evacuation or anorectal blockage, or manual manoeuvres to facilitate defecation) in at least 25% of defecations. Patients were to have <3 SCBMs during the last week of run-in. Patients with insufficient documentation of CC or with diarrhoea during run-in were ineligible.

Patients were excluded if they had a history or evidence of gastrointestinal (GI) disease or surgery, abdominal pain of unknown cause, other significant disease (including secondary causes of constipation), or if they had recently taken medications which could alter the function of the GI tract. Pregnant or breastfeeding women were excluded, as were those with hypersensitivity to study medications or their excipients.

Study treatment

PEG 3350+E (Movicol; Norgine Ltd, Uxbridge, UK) was given as a powder in a sachet containing 13.13 g PEG 3350, 0.35 g sodium chloride, 0.18 g sodium bicarbonate and 0.05 g potassium chloride, reconstituted in 125 mL water. Prucalopride tablets (Resolor, Shire, Belgium), each containing 1 mg prucalopride succinate were taken with water. Placebo formulations were administered in the same manner.

Two sachets of PEG 3350+E or corresponding placebo were administered daily in a split dose. From Day 14 of study treatment, daily dose could be reduced by physician's decision to one morning sachet if stools were type 6 or 7 (Bristol Stool Chart[25]). Patients received prucalopride or matching placebo daily after the morning sachet. Patients aged ≤65 years received two prucalopride tablets, while those aged >65 years received one tablet each of prucalopride and placebo; in the latter group, the dose could be increased to two tablets of active daily from Day 14 onwards if stools were type 1 or 2. Dose modification aimed to achieve a Bristol Stool Chart type 3, 4 or 5. The selection of an initial two-sachet dose of PEG 3350+E was based on the average effective dose in a previous comparative study of PEG 3350+E and lactulose.[16]

Rescue medication (docusate sodium micro-enema, Norgalax; Norgine Ltd, UK) was allowed up to twice a day if patients had no BM for ≥3 consecutive days. Use of other oral purgatives/laxatives, prokinetics or medications which could interfere with GI tract function was prohibited.

Study assessments and endpoints

The primary endpoint was response rate [proportion of patients (%) having ≥3 SCBMs during the last treatment week]. Key secondary endpoints included mean weekly SCBM number, mean weekly SCBM increase from run-in, total stool weight and frequency per stool type, colonic transit time (CTT) and responder rate [patients with ≥3 SCBMs per week plus an increase of ≥1 SCBM(s) per week compared with run-in]. Other variables included time to SCBM, stool consistency, ease of defecation, use of rescue medication and patient satisfaction/QoL. SCBMs were nonlaxative-induced BMs, associated with a feeling of complete evacuation. Use of rescue medication in the preceding 24 h rendered a BM nonspontaneous.

Faeces were collected as individual samples and weighed throughout treatment. Additional faecal samples were collected during the run-in period. The occurrence of BMs, feeling of incomplete or complete evacuation, level of straining and stool consistency was recorded in patient diaries. Colonic transit time was measured during run-in and treatment Week 4 using radio-impenetrable pellets and X-ray analysis of faecal samples.[26]

Patients completed several validated QoL questionnaires: Patient Assessment of Constipation Symptoms (PAC-SYM),[27] Patient Assessment of Constipation QoL (PAC-QoL),[28] and the European QoL instrument (EQ-5D-3L).[29] Patient global assessments of constipation severity and treatment efficacy used 5-point Likert scales. Safety assessments included recording adverse events (AEs), laboratory tests, vital signs, electrocardiograms (ECGs), weight and physical examinations.

Statistical analysis

Primary endpoint analysis involved a two-stage hierarchic procedure comparing the difference in response rate between the two treatment groups. Non-inferiority was tested using a non-inferiority margin of 20% [per-protocol (PP) population]. Non-inferiority could be concluded if the observed lower limit of the one-sided 97.5% confidence interval (CI) for the difference in response rates (PEG 3350+E minus prucalopride) laid completely above −20% (the non-inferiority margin). If non-inferiority was confirmed, superiority was assessed and could be concluded if the lower limit of the one-sided 97.5% CI for the difference laid completely above 0 [modified intent-to-treat (mITT) population]. The mITT population consisted of all patients with stool (SCBM) data available for at least 2 of the 4 treatment weeks. The PP population included patients who completed run-in and treatment phases without a major protocol deviation.

All efficacy analyses were performed on the mITT and PP populations. Treatment comparisons were conducted using Wilcoxon rank sum test, Fishers exact test or chi-squared test (using a two-sided 5% level of significance).

Sample size was based on both steps of the hierarchic test procedure for the primary endpoint. For the assessment of non-inferiority, a PP population size of 96 per group was sufficient for the lower 97.5% CI to exceed the non-inferiority margin −0.2 with 85% power, assuming equal PEG 3350+E and prucalopride response rates of 0.7. For assessment of superiority, 110 mITT patients per group were sufficient for the lower limit of the observed one-sided CI to exceed the value 0 with 88% power, assuming response rates of 0.6 and 0.8 for PEG 3350+E and prucalopride respectively.

Results

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

Patients (baseline characteristics and disposition)

The study ran between 29 October 2010 and 6 September 2011, with 347 patients screened, 244 entering run-in and 240 with confirmed CC (<3 SCBMs in the last week of run-in) randomised to receive PEG 3350+E (N = 120) or prucalopride (N = 120). During run-in (baseline), patient and constipation characteristics were comparable between treatment arms (Table 1). Patient populations are provided in Figure 1. Overall, five patients withdrew, all in the prucalopride group, due to AEs (three patients), withdrawn consent and other reason (one patient each). Treatment compliance was over 99% in both groups and mean [± standard deviation (s.d.)] duration of solution intake was similar (PEG 3350+E, 0.40 ± 0.23 min; placebo, 0.43 ± 0.26 min). All patients in the PEG 3350+E group received the same starting dose (2 sachets) and only six patients in the PEG 3350+E group and two (1.7%) patients in the prucalopride group were aged >65 years and therefore received the lower starting dose (one tablet each of prucalopride and placebo per day). The population used for the majority of analyses was the mITT population (N = 236), which differed from the ITT population (N = 237) by only one patient. This single prucalopride-treated patient was excluded from the analysis as insufficient stool data were available.

Table 1. Patient and baseline characteristics
VariablePEG 3350+E N = 120Prucalopride N = 120
  1. BM, bowel movement; BMI, body mass index; CTT, colonic transit time; N, number of patients; SCBM, spontaneous complete bowel movement; s.d., standard deviation.

  2. a

     Few patients were aged >65 years in the PEG 3350+E and prucalopride groups (6 and 2 patients respectively).

  3. b

     As recorded in the patient stool diary.

  4. c

     No rescue medication or other laxatives were taken by patients during run-in.

Demographics [mean ± s.d. (range); Safety population]
Age (years)a

40.0 ± 14.5

(18–75)

40.5 ± 13.2

(18–70)

Weight (kg)

69.8 ± 17.5

(40–121)

69.3 ± 16.6

(44–130)

BMI (kg/m2)

26.94 ± 6.76

(16.4–46.1)

26.78 ± 6.54

(16.2–50.2)

Constipation evaluation at end of run-in [ROME III criteria; n (%); Safety population]
<3 successful BMs per week120 (100)120 (100)
Symptoms ofb
Straining in at least 25% of defecations118 (98.3)118 (98.3)
Lumpy or hard stools in at least 25% of defecations120 (100)117 (97.5)
Sense of incomplete evacuation in at least 25% of defecations115 (95.8)116 (96.7)
Sensation of anorectal blockage in at least 25% of defecations64 (53.3)70 (58.3)
Manual manoeuvres to facilitate in at least 25% of defecations18 (15.0)20 (16.7)
Run-in data (mean ± s.d.; mITT population)
Number of BMsc Run-in Week 12.4 ± 1.22.4 ± 1.1
Run-in Week 22.1 ± 0.72.3 ± 0.9
Number of SCBMsc Run-in Week 10.9 ± 0.90.8 ± 0.9
 Run-in Week 20.7 ± 0.80.7 ± 0.8
CTT (h)102.79 ± 40.37106.19 ± 40.43
Total stool weight (g)Run-in Week 1331.02 ± 170.33341.80 ± 191.71
run-in Week 2331.89 ± 182.07393.82 ± 214.15
image

Figure 1. Study flow diagram. * Safety population: all randomised patients who received at least one dose of study treatment. † mITT population: all patients with stool data for at least 2 of the 4 treatment weeks. ‡ ITT population: all patients with data for the primary efficacy variable with at least 7 treatment days. § PP population: patients who completed run-in and 28 days of treatment without a major protocol deviation. ITT, intent-to-treat; mITT, modified ITT; N, number of patients; PP, per-protocol.

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Efficacy

Primary endpoint

In treatment week 4, the proportion of patients with ≥3 SCBMs increased from none in run-in for both groups, but was 10.1% greater in the PEG 3350+E than prucalopride group for the PP population (66.67% vs. 56.52%, Table 2). Similar results were observed for PEG 3350+E in the mITT population (66.7% vs. 56.9%). These results confirmed non-inferiority of PEG 3350+E to prucalopride (PP population, 97.5% lower CI limit −2.7%, above the non-inferiority limit of −20%), with the observed treatment effect approaching statistical superiority of PEG 3350+E (mITT population, rate difference 9.8%, 97.5% lower CI limit, −3.1%, approaching the superiority limit of 0).

Table 2. Efficacy analysis: spontaneous complete bowel movements and responder rates
 PEG 3350+EPrucaloprideRate differenceCIP-value
  1. CI, confidence interval; mITT, modified intent-to-treat; N, number of patients; NA, not applicable; PP, per-protocol; SCBM, spontaneous complete bowel movements.

  2. a

     mITT population: PEG 3350+E, N = 120; prucalopride, N = 116.

  3. b

     Primary endpoint = one-sided 97.5% lower CI.

  4. c

     PP population: PEG 3350+E, N = 120; prucalopride, N = 115.

  5. d

     Patients with ≥3 SCBMs per week plus an increase of ≥1 SCBM(s) per week compared to run-in.

  6. e

     Secondary endpoint = two-sided 95% CI.

  7. f

     Statistically significant differences between (P < 0.05) groups based on the two-sided P-value of the Fisher's exact test.

Patients with ≥3 SCBMs during the last treatment week (primary endpoint)
mITT populationa80 (66.7%)66 (56.9%)9.8%−3.1%bNA
PP populationc80 (66.7%)65 (56.5%)10.1%−2.7%bNA
Responder rated (secondary endpoint; mITT populationa)
Week 145.0%22.4%22.6%9.8%; 34.7%e0.0003f
Week 254.2%41.4%12.8%−0.1%; 25.4%e0.0520
Week 365.0%44.8%19.8%6.9%; 32.1%e0.0026f
Week 466.7%56.0%10.1%−2.7%; 22.8%e0.1396
Weekly average58.3%35.3%22.7%9.9%; 35.0%e0.0007f
Secondary endpoints

Improvements over time were observed for the majority of secondary endpoints in both treatment groups (mITT population), with statistically significant differences predominantly in favour of PEG 3350+E.

Bowel movements

In both groups, mean weekly SCBM number increased each week. Increasingly statistically significant improvements in SCBM number were observed with PEG 3350+E compared with prucalopride (P < 0.01 for each week, Figure 2). Accordingly, after 4 treatment weeks, the mean (±s.d.) total SCBM number was higher in the PEG 3350+E group (13.10 ± 9.03 vs. 9.03 ± 6.45, < 0.001). In both groups, the number of SCBMs increased from run-in, with higher mean (±s.d.) weekly SCBM increases in the PEG 3350+E group for all weeks (< 0.01) and for the weekly average increase (2.52 ± 2.10 vs. 1.54 ± 1.48, < 0.001). Similarly, the PEG 3350+E patients had consistently higher responder rates compared with prucalopride (58.3% vs. 35.3%, < 0.001; Table 2).

image

Figure 2. Efficacy analysis: Mean number of SCBMs and total stool weight by week (mITT population, N = 236) (a) Mean number of SCBMs during treatment with either PEG 3350+E (gray) or prucalopride (black). Error bars represent s.d. The mean number of SCBMs increased throughout treatment in both groups and was significantly higher in the PEG 3350+E group than in the prucalopride group at each week (*< 0.01). (b) Mean total stool weight with either PEG 3350+E (gray) or prucalopride (black). Error bars represent s.d. Mean total stool weight increased throughout treatment in both groups, but to a greater extent in the PEG 3350+E group compared with the prucalopride group at each week (*< 0.0001).

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Overall, patients treated with PEG 3350+E experienced more BMs (patient assessment as complete or otherwise) than those taking prucalopride, with statistical significance observed in each treatment week (P < 0.05). Accordingly, the 4-week total number of BMs (±s.d.) was higher in the PEG 3350+E group (22.9 ± 6.2 vs. 18.5 ± 6.3, < 0.0001).

Mean (±s.d.) time to first SCBM was shorter in the PEG 3350+E group compared with the prucalopride group, although the difference was not statistically significant (114.16 ± 129.97 h vs. 120.38 ± 141.59 h, P > 0.05). Time to next SCBM was also shorter in the PEG 3350+E group for all treatment weeks (P < 0.001) and for the weekly average (62.15 ± 113.17 h vs. 79.19 ± 99.10 h, P < 0.0001).

Four-week total frequencies of acceptable (40.4% vs. 49.5%), severe (2.2% vs. 6.6%) or very severe (4.0% vs. 8.6%) straining were higher in the prucalopride group. Conversely, the proportion of BMs with no straining (53.0% vs. 35.0%) was higher in the PEG 3350+E group. These trends persisted throughout the treatment period, with treatment differences statistically significant at each week (< 0.0001). Mean severity of straining improved over time in both groups and was consistently lower in the PEG 3350+E than prucalopride group for all treatment weeks (P < 0.0001). Similarly, significantly lower proportions of BMs per patient with severe or very severe straining were observed in the PEG 3350+E group throughout treatment (P < 0.01; Table 3).

Table 3. Efficacy analysis: symptom responses (mITT population)
SymptomWeekPEG 3350+EPrucaloprideP-value
  1. BM, bowel movement; s.d., standard deviation.

  2. a

     For each BM, patients reported the degree of straining as no straining, acceptable, severe or very severe. Mean severity of straining was calculated by assigning a scale to these categories, ranging from 1 (no straining) to 3 (very severe).

  3. b

     Statistically significant differences between groups based on the two-sided value of the Wilcoxon rank sum test.

Individual percentages of bowel movements* with severe or very severe straining (mean ± s.d.)Week 111.04 ± 19.9721.26 ± 30.620.0099b
Week 25.34 ± 16.9614.75 ± 27.380.0003b
Week 34.99 ± 19.1713.25 ± 25.12<0.0001b
Week 45.18 ± 19.6511.90 ± 23.36<0.0014b
Weekly average6.33 ± 15.8514.84 ± 21.20<0.0001b
Proportion of patients with a feeling of incomplete evacuation (mean ± s.d.)Week 153.68 ± 37.3264.61 ± 34.840.0274b
Week 241.78 ± 39.6552.61 ± 37.100.0221b
Week 338.97 ± 40.0649.39 ± 35.120.0162b
Week 441.51 ± 38.2044.18 ± 35.000.4396
4-week total43.29 ± 33.8852.44 ± 28.870.0159b
Stool consistency, assessed by the patient according to Bristol Stool Chart (mean ± s.d.) Week 14.55 ± 0.813.86 ± 0.64<0.0001b
Week 24.78 ± 0.803.85 ± 0.68<0.0001b
Week 34.77 ± 0.763.97 ± 0.78<0.0001b
Week 44.84 ± 0.784.05 ± 0.76<0.0001b
Weekly average4.75 ± 0.683.95 ± 0.59<0.0001b

Compared with the prucalopride group, the mean (±s.d.) proportion of BMs per patient with a feeling of incomplete evacuation was lower with PEG 3350+E at all timepoints, with statistically significant differences at Weeks 1–3, and for the 4-week total (< 0.05; Table 3).

Stool weight, stool type and colonic transit time

After 4 weeks of treatment, mean (±s.d.) total stool weight was higher in the PEG 3350+E group compared with the prucalopride group (3844.17 ± 1089.29 g vs. 1979.17 ± 738.59 g, respectively, both < 0.0001), and consistently higher at each treatment week (< 0.0001; Figure 2). Stool types 3 and 4 were more frequently observed in the prucalopride than PEG 3350+E group, whereas types 5 and 6 were more frequent in the PEG 3350+E than prucalopride group throughout treatment. Mean stool consistency (assessed using the Bristol Stool Chart) was consistently higher in the PEG 3350+E than prucalopride group each week (< 0.0001; Table 3). After 4 weeks, in both groups, there were similar profound reductions in CTT from run-in (approximately 40% in both groups; P < 0.0001; Figure 3).

image

Figure 3. Efficacy analysis: Mean colonic transit time (mITT population, N = 236). Mean colonic transit time at run-in and during the last treatment week with PEG 3350+E (gray) and prucalopride (black). In treatment week 4, colonic transit time was significantly shorter than during run-in for both treatment groups (*< 0.0001). There was no statistically significant difference in transit time between treatments (> 0.05).

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Rescue medication and dose changes

Use of rescue medication was low in both groups [PEG 3350+E, 1 (0.8%) patient; prucalopride, four (3.4%) patients]. Dose reduction occurred in only two (1.7%) patients, both in the PEG 3350+E group, and there were no dose increases in patients from either group.

Patient assessments and QoL

More patients in the PEG 3350+E than prucalopride group rated the laxative treatment as very or extremely effective from Day 7 (< 0.005). Patient assessments of bothersomeness of constipation and satisfaction of bowel habits favoured PEG 3350+E.

Constipation symptoms (PAC-SYM) improved throughout treatment in both groups. Stool symptom scores improved more in the PEG 3350+E than prucalopride group at all timepoints (P < 0.0001 each week). Rectal symptoms and global assessment scores also improved more with PEG 3350+E than prucalopride. Differences in global scores between treatments were significant (P < 0.05) at all timepoints except Day 21 (> 0.05), while rectal symptom differences were only statistically significant after the first 7 days (< 0.01). Improvements in abdominal symptoms were greater for prucalopride compared with PEG 3350+E after the first 7 days (< 0.05) and similar between treatment groups thereafter.

Improvements in the PAC-QoL subdomain ‘satisfaction’ were greater for the PEG 3350+E than prucalopride group (< 0.05). There were no other statistically significant differences between groups, although both showed improvements over time in other subdomains. The EQ-5D-3L questionnaire showed improvements in both treatment groups, with no statistically significant differences.

Safety

Over three quarters of the safety population experienced a treatment-emergent AE (TEAE) (184/240, 76.7% patients; PEG 3350+E, 82/120, 68.3%; prucalopride, 102/120, 85.0%). Most were of moderate (PEG 3350+E, 136/187 events, 72.7%; prucalopride, 210/280 events, 75.0%) or mild intensity (PEG 3350+E, 48/187 events, 25.7%; prucalopride, 62/280 events, 22.1%), with 5.3% of the events in the PEG 3350+E group and 14.3% in the prucalopride group possibly or probably related to study treatment. The most frequently reported TEAEs occurred less often in the PEG 3350+E group compared with the prucalopride group: headache (36.7% vs. 55.0% patients respectively), dysmenorrhoea (13.3% vs. 15.8%), nausea (5.8% vs. 13.3%) and pharyngitis (5.8% vs. 10.8%). Other reported GI disorders also occurring less frequently in the PEG 3350+E group included vomiting (2.5% vs. 6.7%) and abdominal pain (2.5% vs. 5.8%). Back pain (5.0% vs. 0.0%) and urinary tract infection (3.3% vs. 0.8%) were more frequent with PEG 3350+E compared with prucalopride. Three patients in the prucalopride arm experienced moderate TEAEs leading to premature study discontinuation. Of these TEAEs, one (hypersensitivity) was considered possibly related to medication. Two serious adverse events (SAEs; GI disorder and vertigo), considered severe and possibly related to study medication, occurred in one (0.8%) patient in the prucalopride group. There were no obvious differences between treatment groups for laboratory parameters, vital signs or ECG measurements.

Discussion

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

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.[30] 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,[18] and significantly, to the 5-HT4 receptor agonist tegaserod.[38] 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).[40] 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.

Authorship

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

Guarantor of the article: M Halphen.

Author contributions: R Cinca and D Chera performed the research, D Chera collected and analysed the data, M Halphen and HJ Gruss designed the research study and wrote the manuscript. All authors have approved the submitted manuscript.

Acknowledgements

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

The authors would like to thank Neil Yadav and Wendy Critchley for their involvement in the study writing and Insight Medical Writing, Kidlington, UK, for their assistance in the preparation of this manuscript. Declaration of personal interests: M Halphen is an employee of Norgine Ltd. R Cinca, principal investigator and HJ Gruss are consultants for Pierrel Research and Norgine Ltd respectively.

Declaration of funding interests: Initial analyses were conducted by D Chera (Pierrel Research HP-RO -SRL) and funded by Norgine. The study and writing support were funded by Norgine Ltd.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgements
  9. References
  • 1
    Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 2004; 99: 7509.
  • 2
    Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol 2005; 100(Suppl. 1): S521.
    Direct Link:
  • 3
    Peppas G, Alexiou VG, Mourtzoukou E, et al. Epidemiology of constipation in Europe and Oceania: a systematic review. BMC Gastroenterol 2008; 12: 5.
  • 4
    McCrea GL, Miaskowski C, Stotts NA, et al. A review of the literature on gender and age differences in the prevalence and characteristics of constipation in North America. J Pain Symptom Manage 2009; 37: 73745.
  • 5
    Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006; 130: 137790.
  • 6
    Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006; 130: 148091.
  • 7
    Tack J, Müller-Lissner S, Stanghellini V, et al. Diagnosis and treatment of chronic constipation–a European perspective. Neurogastroenterol Motil 2011; 23: 697710.
  • 8
    McCallum IJ, Ong S, Mercer-Jones M. Chronic constipation in adults. BMJ 2009; 338: b831.
  • 9
    Dennison C, Prasad M, Lloyd A, et al. The health-related quality of life and economic burden of constipation. Pharmacoeconomics 2005; 23: 46176.
  • 10
    Belsey J, Greenfield S, Candy D, et al. Systematic review: impact of constipation on quality of life in adults and children. Aliment Pharmacol Ther 2010; 31: 93849.
  • 11
    Quigley EM. Prucalopride: safety, efficacy and potential applications. Therap Adv Gastroenterol 2012; 5: 2330.
  • 12
    Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment Pharmacol Ther 2007; 25: 599608.
  • 13
    Leung L, Riutta T, Kotecha J, et al. Chronic constipation: an evidence-based review. J Am Board Fam Med 2011; 24: 43651.
  • 14
    Norgine Ltd. Movicol Summary of Product Characteristics. May 2011. Available at: http://www.medicines.org.uk/emc/medicine/1244/SPC/Movicol+13.8g+sachet,+powder+for+oral+solution/. Accessed July 16, 2012.
  • 15
    Norgine Ltd. Movicol Paediatric Plain Summary of Product Characteristics. May 2011. Available at: http://www.medicines.org.uk/emc/medicine/14165. Accessed July 16, 2012.
  • 16
    Attar A, Lémann M, Ferguson A, et al. Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut 1999; 44: 22630.
  • 17
    Lee-Robichaud H, Thomas K, Morgan J, et al. Lactulose versus polyethylene glycol for chronic constipation. Cochrane Database Syst Rev 2010; 7: CD007570.
  • 18
    Wang HJ, Liang XM, Yu ZL, et al. A Randomised, controlled comparison of low-dose polyethylene glycol 3350 plus electrolytes with ispaghula husk in the treatment of adults with chronic functional constipation. Clin Drug Investig 2004; 24: 56976.
  • 19
    NICE. Constipation in children and young people: diagnosis and management of idiopathic childhood constipation in primary and secondary care. Clinical Guideline May 2010. Available at: http://publications.nice.org.uk/constipation-in-children-and-young-people-cg99/guidance. Accessed January 28, 2013.
  • 20
    Wong BS, Manabe N, Camilleri M. Role of prucalopride, a serotonin (5-HT(4)) receptor agonist, for the treatment of chronic constipation. Clin Exp Gastroenterol 2010; 3: 4956.
  • 21
    Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008; 358: 234454.
  • 22
    Quigley EM, Vandeplassche L, Kerstens R, et al. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation–a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2009; 29: 31528.
  • 23
    Tack J, van Outryve M, Beyens G, et al. Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut 2009; 58: 35765.
  • 24
    NICE. Prucalopride for the treatment of chronic constipation in women. NICE technology appraisal guidance 211, 2010. Dec 2010.
  • 25
    Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997; 32: 9204.
  • 26
    Cummings JH, Wiggins HS. Transit through the gut measured by analysis of a single stool. Gut 1976; 17: 21923.
  • 27
    Frank L, Kleinman L, Farup C, et al. Psychometric validation of a constipation symptom assessment questionnaire. Scand J Gastroenterol 1999; 34: 8707.
  • 28
    Marquis P, De La Loge C, Dubois D, et al. Development and validation of the patient assessment of constipation quality of life questionnaire. Scand J Gastroenterol 2005; 40: 54051.
  • 29
    The EuroQol Group. EuroQol–a new facility for the measurement of health-related quality of life. The EuroQol Group. Health Policy 1990; 16: 199208.
  • 30
    Bharucha AE, Pemberton JH, Locke GR 3rd. American gastroenterological association technical review on constipation. Gastroenterology 2013; 144: 21838.
  • 31
    Corazziari E, Badiali D, Bazzocchi G, et al. Long term efficacy, safety, and tolerability of low daily doses of isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in the treatment of functional chronic constipation. Gut 2000; 46: 5226.
  • 32
    Cleveland MV, Flavin DP, Ruben RA, et al. New polyethylene glycol laxative for treatment of constipation in adults: a randomized, double-blind, placebo-controlled study. South Med J 2001; 94: 47881.
  • 33
    DiPalma JA, Cleveland MV, McGowan J, et al. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol 2007; 102: 143641.
    Direct Link:
  • 34
    Chaussade S, Minić M. Comparison of efficacy and safety of two doses of two different polyethylene glycol-based laxatives in the treatment of constipation. Aliment Pharmacol Ther 2003; 17: 16572.
  • 35
    DiPalma JA, DeRidder PH, Orlando RC, et al. A randomized, placebo-controlled, multicenter study of the safety and efficacy of a new polyethylene glycol laxative. Am J Gastroenterol 2000; 95: 44650.
    Direct Link:
  • 36
    Lembo A, Camilleri M. Chronic Consti-pation. N Engl J Med 2003; 349: 13608.
  • 37
    Fritz E, Hammer HF, Lipp RW, et al. Effects of lactulose and polyethylene glycol on colonic transit. Aliment Pharmacol Ther 2005; 21: 25968.
  • 38
    Di Palma JA, Cleveland MV, McGowan J, et al. A randomized, multicenter comparison of polyethylene glycol laxative and tegaserod in treatment of patients with chronic constipation. Am J Gastroenterol 2007b; 102: 196471.
    Direct Link:
  • 39
    Sanchez MI, Bercik P. Epidemiology and burden of chronic constipation. Can J Gastroenterol 2011; 25(Suppl. B): 11B5B.
  • 40
    NHS Regional Drug and Therapeutics Centre (Newcastle). Cost Comparison Charts. Apr 2012.