Efficacy and safety of prucalopride in patients with chronic idiopathic constipation stratified by age, body mass index, and renal function: a post hoc analysis of phase III and IV, randomized, placebo-controlled clinical studies

Abstract

Background: Prucalopride (1 or 2 mg once daily) is approved for treating adults with chronic idiopathic constipation (CIC).

Objectives: We determined the effect of age, body mass index (BMI), and renal function on the efficacy and safety of prucalopride in adults with CIC.

Design: Data were pooled from six 12-week, phase III-IV clinical studies in adults who received prucalopride (1 or 2 mg once daily) or placebo for CIC.

Methods: Adults were stratified by age (<50; 50-64; ⩾65 years), BMI (underweight/healthy weight, <25 kg/m²; overweight, 25 to <30 kg/m²; obese, ⩾30 kg/m²), and renal function (normal renal function, estimated glomerular filtration rate (eGFR) ⩾90 mL/min/1.73 m²; mild renal impairment, eGFR 60 to <90 mL/min/1.73 m²; moderate renal impairment, eGFR 30 to <60 mL/min/1.73 m²). The primary efficacy endpoint was the proportion of patients with a mean of ⩾3 complete spontaneous bowel movements/week over 12 weeks. Safety data were evaluated descriptively.

Results: Of 2484 patients stratified by age (prucalopride, n = 1237; placebo, n = 1247), 1402, 708, and 374 were aged <50, 50-64, and ⩾65 years, respectively. Of 2482 patients stratified by BMI (prucalopride, n = 1237; placebo, n = 1245), 1425, 713, and 344 were underweight/healthy weight, overweight, and obese, respectively. Of 2474 patients stratified by renal function (prucalopride, n = 1233; placebo, n = 1241), 1444, 869, and 161 had normal renal function, mild renal impairment, and moderate renal impairment, respectively. More prucalopride-treated than placebo-treated patients achieved the primary efficacy endpoint. The difference was significant for all subgroups, except for the obese and moderate renal impairment subgroups. More prucalopride-treated than placebo-treated patients reported treatment-related adverse events in most subgroups.

Conclusion: Prucalopride demonstrated efficacy in adults with CIC, irrespective of age, BMI, and renal function. No unexpected safety concerns were identified.

Trial registration: ClinicalTrials.gov identifiers (https://clinicaltrials.gov/): NCT01147926, NCT01424228, NCT01116206, NCT00483886, NCT00485940, NCT00488137.

Keywords: age; body mass index; chronic idiopathic constipation; pooled analysis; prucalopride; renal function.

Figure 1.

CONSORT flow diagram. ^aPatients who were randomized to receive prucalopride 4 mg during PRU-USA-11, PRU-USA-13, and PRU-INT-6 were excluded from the post hoc analysis. ^bPatients who did not complete the study were not excluded from the post hoc analysis. BMI, body mass index; CONSORT, Consolidated Standards of Reporting Trials; ITT, intention-to-treat; mITT, modified intention-to-treat.

Figure 2.

Prespecified and post hoc primary efficacy endpoints. Proportions of prucalopride-treated and placebo-treated patients with a mean frequency of at least three CSBMs per week over 12 weeks of treatment (prespecified), and a mean frequency of at least three CSBMs per week over 12 weeks and an increase of at least one CSBM per week from baseline in at least 9 out of the 12 weeks, including 3 of the last 4 weeks (post hoc), stratified by age (a^a and d^d, respectively), BMI (b^b and e^e, respectively), and renal function (c^c and f^f, respectively). BMI was classified according to the Centers for Disease Control and Prevention classification. Underweight/healthy weight, BMI <25 kg/m²; overweight, BMI 25 to <30 kg/m²; obese, BMI ⩾30 kg/m². Normal renal function, eGFR ⩾90 mL/min/1.73 m²; mild renal impairment, eGFR 60 to <90 mL/min/1.73 m². p values are based on the χ² test. ^aLess than 50 years: prucalopride, n = 704; placebo, n = 696; 50–64 years: prucalopride, n = 335; placebo, n = 373; ⩾65 years: prucalopride, n = 196; placebo, n = 178. ^bUnderweight/healthy weight: prucalopride, n = 682; placebo, n = 741; overweight: prucalopride, n = 382; placebo, n = 331; obese: prucalopride, n = 171; placebo, n = 173. ^cNormal renal function: prucalopride, n = 721; placebo, n = 722; mild renal impairment: prucalopride, n = 431; placebo, n = 437; moderate renal impairment: prucalopride, n = 79; placebo, n = 82. ^dLess than 50 years: prucalopride, n = 675; placebo, n = 674; 50–64 years: prucalopride, n = 320; placebo, n = 365; ⩾65 years: prucalopride, n = 181; placebo, n = 170. ^eUnderweight/healthy weight: prucalopride, n = 651; placebo, n = 723; overweight: prucalopride, n = 364; placebo, n = 318; obese: prucalopride, n = 161; placebo, n = 166. ^fNormal renal function: prucalopride, n = 689; placebo, n = 702; mild renal impairment: prucalopride, n = 409; placebo, n = 424; moderate renal impairment: prucalopride, n = 74; placebo, n = 78. BMI, body mass index; CSBM, complete spontaneous bowel movement; eGFR, estimated glomerular filtration rate.

Figure 3.

Change from baseline to week 12 in CSBM frequency per week in prucalopride-treated and placebo-treated patients (a),^a and the time to first CSBM after the first dose of prucalopride or placebo (b),^b stratified by age. ^aLess than 50 years (prucalopride, n = 677; placebo, n = 676); 50–64 years (prucalopride, n = 320; placebo, n = 365); ⩾65 years (prucalopride, n = 182; placebo, n = 171). p values are based on a Cochran–Mantel–Haenszel test. Prucalopride compared to placebo: <50 years, p < 0.001; 50–64 years, p < 0.001; ⩾65 years, p = 0.043. ^bLess than 50 years (prucalopride, n = 706; placebo, n = 696); 50–64 years (prucalopride, n = 335; placebo, n = 373); ⩾65 years (prucalopride, n = 196; placebo, n = 178). p values are based on a proportional hazards regression model. Prucalopride compared to placebo: <50 years, p < 0.001; 50–64 years, p < 0.001; ⩾65 years, p = 0.003. CSBM, complete spontaneous bowel movement.

Figure 4.

Change from baseline to week 12 in CSBM frequency per week in prucalopride-treated and placebo-treated patients (a),^a and the time to first CSBM after the first dose of prucalopride or placebo (b),^b stratified by BMI. BMI was classified according to the Centers for Disease Control and Prevention classification. Underweight/healthy weight, BMI <25 kg/m²; overweight, BMI 25 to <30 kg/m²; obese, BMI ⩾30 kg/m². ^aUnderweight/healthy weight (prucalopride, n = 653; placebo, n = 724); overweight (prucalopride, n = 364; placebo, n = 319); obese (prucalopride, n = 162; placebo, n = 167). p values are based on a Cochran–Mantel–Haenszel test. Prucalopride compared to placebo: underweight/healthy weight, p < 0.001; overweight, p < 0.001; obese, p = 0.134. ^bUnderweight/healthy weight (prucalopride, n = 684; placebo, n = 741); overweight (prucalopride, n = 382; placebo, n = 331); obese (prucalopride, n = 171; placebo, n = 173). p values are based on a proportional hazards regression model. Prucalopride compared to placebo: underweight/healthy weight, p < 0.001; overweight, p < 0.001; obese, p = 0.004. BMI, body mass index; CSBM, complete spontaneous bowel movement.

Figure 5.

Change from baseline to week 12 in CSBM frequency per week in prucalopride-treated and placebo-treated patients (a),^a and the time to first CSBM after the first dose of prucalopride or placebo (b),^b stratified by renal function. Normal renal function, eGFR ⩾90 mL/min/1.73 m²; mild renal impairment, eGFR 60 to <90 mL/min/1.73 m²; moderate renal impairment, eGFR 30 to <60 mL/min/1.73 m². ^aNormal renal function (prucalopride, n = 692; placebo, n = 703); mild renal impairment (prucalopride, n = 409; placebo, n = 425); moderate renal impairment (prucalopride, n = 74; placebo, n = 79). p values are based on a Cochran–Mantel–Haenszel test. Prucalopride compared to placebo: normal renal function, p < 0.001; mild renal impairment, p < 0.001; moderate renal impairment, p = 0.572. ^bNormal renal function (prucalopride, n = 722; placebo, n = 722); mild renal impairment (prucalopride, n = 432; placebo, n = 437); moderate renal impairment (prucalopride, n = 79; placebo, n = 82). p values are based on a proportional hazards regression model. Prucalopride compared to placebo: normal renal function, p < 0.001; mild renal impairment, p < 0.001; moderate renal impairment, p = 0.043. CSBM, complete spontaneous bowel movement; eGFR, estimated glomerular filtration rate.