Promelaxin Microenemas Are Non-inferior to Oral Polyethylene Glycol for the Treatment of Functional Constipation in Young Children: A Randomized Clinical Trial

Abstract

Background: Polyethylene glycol (PEG) is recommended as first-line treatment of pediatric functional constipation. However, the oral route of administration is often poorly feasible in children mostly due to poor palatability. Promelaxin microenemas exert a topical evacuative action and may offer a valuable option in pediatric FC. Aim: To assess whether Promelaxin microenemas would be non-inferior to PEG 4000 in young children with FC. Methods: This is a randomized, open-label, multi-centric, non-inferiority trial enrolling infants and young children aged 6-48 months, with FC according to Rome III criteria. After 1 week of run in, children were randomized to 2 weeks of Promelaxin or PEG, followed by a 6-week on-demand treatment period. Primary endpoint was response rate to randomized treatment, with "response" defined as at least 3 evacuations per week and an average increase of at least one evacuation per week as compared to baseline. Safety, stool consistency and the analysis of fecal microbiota were secondary endpoints. Results: Out of the 158 patients who entered the trial, 153 patients were treated (77 and 76, PEG and Promelaxin arm, respectively). In the primary analysis, the 95% confidence interval (CI) for the treatment's effect lay entirely above the non-inferiority margin in both Full Set (FAS) and Per Protocol (PP) analyses, providing evidence of the non-inferiority of Promelaxin vs. PEG 4000 [response rate difference: 16.5% (CI 1.55-31.49%) and 11.03% (CI -5.58 to 27.64%), FAS and PP analyses, respectively]. Mean compliance to the randomized treatment was >80% in both arms. Secondary endpoints did not significantly differ between the two arms, except for the average number of total days of on-demand treatment that was significantly lower in the Promelaxin arm [14.6 (12.7) vs. 9.8 (9.1), mean (SD); primary endpoint responders in PEG and Promelaxin arm, respectively; p = 0.027]. Microbiota evenness significantly increased in the PEG 4000 arm at V4 as compared to the Promelaxin arm (p < 0.05). In addition, at V5, patients treated with PEG showed a significantly decreased microbiota density as compared to patients treated with Promelaxin (p = 0.036). Conclusions: Promelaxin microenemas are non-inferior to oral PEG in children with FC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02751411.

Keywords: Promelaxin microenemas; functional constipation; medical devices based on substances; polyethylene glycol; young children.

Figure 1

Study Design. The figure depicts the design of the study, including study Visits.

Figure 2

CONSORT diagram. The figure shows the Consort Diagram of the randomized trial.

Figure 3

Primary endpoint. The differences in response rates between Promelaxin and PEG and relative 95% confidence interval (CI) are shown according to the full analysis set (FAS) and the PP analyses.

Figure 4

Response rate for combined stool frequency and consistency and average days of treatment. (A,C) show the response rate (%) for the combined stool frequency and consistency secondary endpoints at V4 and V5, respectively. (B,D) show the average days of treatment (mean ± SE) at V4 and V5, respectively. In each panel, results of separate analyses either according to the PP population or to the subgroup of PP patients evaluated as responders to the primary endpoint (Primary Endpoint Responders) are depicted. Error bars represent Standard Error. (A) Overall PP: PEG, n = 38; Promelaxin, n = 36; Primary Endpoint responders: PEG, n = 25; Promelaxin, n = 31. (B) Overall PP: PEG, n = 15; Promelaxin, n = 19; Primary Endpoint responders: PEG, n = 13; Promelaxin, n = 18. (C) Overall PP: PEG, n = 35; Promelaxin, n = 33; Primary Endpoint responders: PEG, n = 22; Promelaxin, n = 28. (D) Overall PP: PEG, n = 10; Promelaxin, n = 15; Primary Endpoint responders: PEG, n = 9; Promelaxin, n = 15. *p < 0.05.

Figure 5

Stool consistency, QoL improvement and gastrointestinal symptoms in the randomized arms. (A) Percentage of patients with improved stool consistency at V3, V4, and V5. (B) Percentage of parents with improved QoL at V3, V4, and V5. (C–E) Number of days (mean ± SD) with gastrointestinal symptoms at V3, V4, and V5. Data are reported as mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. (A) V3: PEG, n = 45; Promelaxin, n = 56; V4: PEG, n = 42; Promelaxin, n = 45; V5: PEG, n = 37; Promelaxin, n = 38; (B) V3 (Father): PEG, n = 44; Promelaxin, n = 49. V4 (Father): PEG, n = 38; Promelaxin, n = 39. V5 (Father). PEG, n = 38; Promelaxin, n = 39; (B) V3 (Mother): PEG, n = 44; Promelaxin, n = 52. V4 (Mother): PEG, n = 44; Promelaxin, n = 52. V5 (Mother): PEG, n = 44; Promelaxin, n = 52. (C–E) V3: PEG, n = 45; Promelaxin, n = 56. V4: PEG, n = 40; Promelaxin, n = 47. V5: PEG, n = 40; Promelaxin, n = 47.

Figure 6

Microbiota analysis. The figure shows individual data and box-plots as median and IQR. (A) Microbiota evenness. (B) Microbiota density. Kruskal-Wallis-test and Student T-test were used for testing differences in microbiota evenness (Pielou's index) and microbiota density, respectively. *p < 0.05.