Gastric emptying and meal-related symptoms.
After 4 weeks of prucalopride treatment, solid and liquid half emptying times were 98 ± 10 and 74 ± 3 minutes, respectively. Solid but not liquid half emptying times with prucalopride were significantly shorter than during placebo treatment (126 ± 13 minutes, P = 0.02, and 87 ± 12 minutes, not significant [NS], respectively) or at baseline (P = 0.00001 and P = 0.03, respectively) (Figure 5). No statistically significant correlation was found between the change in GCSI or PAGI-SYM scores and the change in gastric emptying rate. Meal-related total symptoms (76.3 [7.75; 110.25] vs 47.9 [1.75; 61.25], P = 0.02), postprandial fullness (17.65 [0.75; 25.0] vs 9.7 [0.0; 9.25], P = 0.03), and bloating (22.0 [1.5; 36.75] vs 12.6 [0.0; 17.75], P = 0.03) were significantly lower during prucalopride treatment compared with placebo.
Quality of life.
After 4 weeks of prucalopride treatment, the PAGI-QOL and its subscales of clothing and diet were significantly better compared with placebo (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) (Figure 4b).
Daily diaries confirmed significant improvement compared with placebo treatment of symptom severity ratings for abdominal pain, postprandial fullness, bloating, early satiation, nausea, and overall symptom severity (details not shown). Significance over placebo with prucalopride treatment was observed during weeks 3 and 4 (postprandial fullness, early satiation, upper abdominal bloating, nausea, and epigastric pain significantly better than placebo), but not during weeks 1 and 2 (only bloating scores significantly better than placebo).
The number of bowel movements per day rose from a mean of 1.21 ± 0.06 at baseline to 1.57 ± 0.09 during the first 2 weeks of prucalopride therapy (P = 0.004) to normalize back to 1.38 ± 0.09 during the second 2 weeks of prucalopride treatment (NS). The proportion of type 1 and 2 bowel movements during prucalopride treatment (8%) was significantly lower compared with placebo or baseline (22 and 13%, both P < 0.05, respectively). However, no correlation was found between the change in stool pattern (frequency or consistency) and the change in symptom pattern (GCSI total score and subscales).
Idiopathic gastroparesis subgroup
Upper GI symptoms were significantly better during prucalopride compared with placebo treatment: total GCSI (1.81 ± 0.21 vs 2.47 ± 0.19, P < 0.001) (Figure 3b) and the PAGI-SYM subscales of fullness/satiety (2.37 ± 0.29 vs 3.14 ± 0.25, P < 0.0005), bloating/distension (1.82 ± 0.31 vs 2.66 ± 0.30, P < 0.0005), nausea/vomiting (1.07 ± 0.22 vs 1.45 ± 0.25, P = 0.02), and reflux (1.38 ± 0.25 vs 1.67 ± 0.22, P = 0.02) (Figure 6a).
Gastric emptying and meal-related symptoms.
In the idiopathic subgroup, prucalopride treatment was associated with a significant improvement of solid but not liquid half emptying times (99 ± 12 and 73 ± 4 minutes, respectively) compared with placebo (137 ± 68 and 87 ± 06 minutes, respectively, P = 0.005 and NS) and baseline (P < 0.0005 and NS, respectively). Placebo had no significant effect on emptying times compared with baseline. No statistically significant correlation was found between the change in GCSI or PAGI-SYM scores and the change in gastric emptying rate. Meal-related total symptoms (87.8 [22.0; 120.0] vs 53.8 [2.0; 65.0], P = 0.01), postprandial fullness (19.8 [4.0; 29.0] vs 11.4 [0.0; 10.0], P < 0.05), and bloating (24.9 [5.0; 45.0] vs 12.5 [0.0; 16.0], P = 0.006) were significantly lower during prucalopride treatment compared with placebo (Figure 5b).
Quality of life.
In the idiopathic subgroup, the PAGI-QOL was significantly better during treatment with prucalopride compared with placebo (1.35 ± 0.18 vs 1.67 ± 0.16, P = 0.007). Prucalopride improved the subscales of clothing and diet compared with placebo (Figure 6b).
Daily diaries in the idiopathic subgroup alone confirmed that prucalopride was superior to placebo in improving severity ratings for abdominal pain, postprandial fullness, bloating, early satiation, nausea, and overall symptom severity (details not shown). Stool pattern (frequency and consistency) was not correlated with symptom improvement.
One serious adverse event occurred: 1 patient developed intestinal volvulus 18 days after the start of treatment with prucalopride. Adverse events leading to termination were 1 case of diarrhea and 1 of headache during prucalopride treatment and a case of nausea during placebo treatment.
Transient diarrhea was reported by 9 patients during prucalopride treatment, lasting 1–7 days, and in 1 patient during placebo treatment. Transient headache was reported by 8 patients during prucalopride treatment, lasting 1–7 days, and in 1 patient during placebo treatment. Abdominal cramps were reported during prucalopride and placebo treatment by 1 patient each. Cystitis occurred in 1 patient during each treatment and respiratory infection in 1 patient during prucalopride treatment.
In this study, we evaluated the efficacy of the selective 5-HT4 agonist prucalopride in a placebo-controlled crossover trial in patients with idiopathic and diabetic gastroparesis. Prucalopride treatment improved symptoms, as assessed by the GCSI, compared with placebo and baseline both in the entire population and in the idiopathic subgroup. The beneficial effect of prucalopride was present for all 3 subscales of the GCSI: nausea/vomiting, fullness/satiety, and bloating/distention. In line with the pharmacodynamic properties of 5-HT4 agonists, prucalopride treatment was also associated with improved solid gastric emptying rate compared with placebo and baseline. However, there was no correlation between the symptomatic improvement and the enhancement of gastric emptying rate. Prucalopride also improved upper abdominal pain and reflux symptoms, as assessed by the PAGI-SYM questionnaire. Finally, prucalopride improved overall QOL and the subscale of clothing. The improvement in these scales from baseline exceeds the reported minimally important differences (21,25,26).
As revealed by daily diaries, significant symptomatic benefit of prucalopride treatment occurred from week 3 onward. As shown by both the diaries and the PAGI-SYM questionnaire, this improvement included all key dimensions of gastroparesis, namely postprandial fullness/early satiation, upper abdominal bloating/distention, nausea/vomiting, and reflux subscales. This was associated with improved QOL as shown by the PAGI-QOL scale, most clearly in the dimensions of diet and clothing.
The findings are consistent with the overall stimulatory effect of prucalopride on motility, both in the upper and lower GI tract. Indeed, we found significant enhancement of gastric emptying and a (transient) increase in bowel movements during prucalopride treatment. However, the improvement of gastroparesis symptoms was not explained by changes in colonic transit, as assessed using the Bristol stool scale diaries or stool frequency, nor by changes in gastric emptying rate, as assessed by the gastric half emptying time. Gastric motility is a complex phenomenon, including gastric accommodation to store the meal, grinding of solid meal components, and titrated release to the duodenum at a rate that matches intestinal nutrient absorptive capacity. Prucalopride may affect each of these aspects, and this would not necessarily be closely reflected by the gastric half emptying time. Additional studies evaluating the effect of prucalopride on different aspects of gastric and duodenal motor function in gastroparesis seem warranted to further identify the mechanism that underlies symptom improvement.
From its use in chronic constipation, prucalopride is known to be associated with adverse events of diarrhea, headache, and nausea (8–11). The same adverse events occurred more frequently in the prucalopride arm in the present gastroparesis trial and led to a slightly higher discontinuation rate during prucalopride treatment. However, most of the adverse events of diarrhea and headache were transient, as known from prucalopride use in chronic constipation. In addition, scores for nausea/vomiting improved significantly during prucalopride treatment in the entire study population.
Although 5-HT4 agonists are often considered a preferred pharmacological class of prokinetic drugs for upper GI motility disorders, several recent studies failed to show significant benefit (2–4,27). Most recent treatment trials have focused on diabetic gastroparesis (4–7,27,28), whereas the present study included mainly patients with idiopathic gastroparesis. Subgroup analysis confirmed efficacy in the idiopathic patient group, but the diabetic patient group was too small for a meaningful analysis. It is not inconceivable that the selection of patients with idiopathic gastroparesis, where sensory neuropathy is not an issue, favored a better symptom assessment compared with patients with diabetic gastroparesis, where sensory neuropathy has a potential to confound symptom assessment (1,3,27). Larger-scale studies with prucalopride in both diabetic and idiopathic gastroparesis may clarify this possibility.
The efficacy of prucalopride as observed in this idiopathic gastroparesis trial raises the question whether the drug would also be efficacious in patients with functional dyspepsia/postprandial distress syndrome with normal gastric emptying (2,28,29). The lack of a correlation between the symptomatic benefit of prucalopride and the change in gastric emptying rate suggests that enhanced emptying is not necessarily the mechanism underlying the symptomatic beneficial effect. On the other hand, we recently demonstrated in healthy volunteers that prucalopride may inhibit gastric accommodation and sensitize the stomach to gastric distention (30). As hypersensitivity to gastric distention and impaired accommodation are key mechanisms implicated in symptom generation in functional dyspepsia, it is conceivable that delayed gastric emptying is a marker of a subgroup of patients that may respond to the strong motility stimulatory effects of the selective 5-HT4 agonist prucalopride (31,32). However, a study exploring the effects of prucalopride in patients with functional dyspepsia/postprandial distress syndrome with normal gastric emptying is worth considering.
The current study has a number of limitations. This is a proof-of-concept study in patients seen at a tertiary care center. The findings are not necessarily applicable to patients seen at other levels of care and patients with organic or drug-induced causes of gastroparesis. In addition, although efficacy can be confirmed in idiopathic gastroparesis, the diabetic subgroup is too small for separate analysis. Relatively short treatment duration of 4 weeks and the crossover design (although no significant carryover effect was found) were other limitations. On the other hand, the crossover design allowed a more accurate evaluation of changes in emptying rate and symptom pattern across treatment arms. Finally, we evaluated only one dose of prucalopride, chosen for its use in chronic constipation, but it is unclear whether this is the optimal dosing for gastroparesis.
In summary, this single-center crossover study of prucalopride showed symptomatic benefit of the drug in gastroparesis and in the subgroup of patients with idiopathic gastroparesis. These encouraging findings should be confirmed in a larger, multi-setting, parallel-group design study, and prucalopride's efficacy in postprandial distress syndrome without delayed emptying also merits studying.
CONFLICTS OF INTEREST
Guarantor of the article: Jan Tack, MD, PhD.
Specific author contributions: J.T., C.J.A., A.P. contributed to the design of the study. J.T. obtained funding. J.T., L.H., P.C., J.A., and T.V. recruited patients. L.H. contributed to data collection. F.C., K.V., E.C., and L.V. contributed to data analysis. J.T., F.C., K.V., and E.G. drafted the manuscript.
Financial support: The study was supported by a grant from Shire Pharmaceuticals, who also provided placebo and active treatment, and by a Methusalem grant from Leuven University to J.T.
Potential competing interests: J.T. has given scientific advice to AlfaWassermann, Allergan, Christian Hansen, Danone, Grünenthal, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Neutec, Novartis, Noventure, Nutricia, Shionogi, Shire, Takeda, Theravance, Tramedico, Truvion, Tsumura, Zealand and Zeria pharmaceuticals, and has served on the Speaker bureau for Abbott, Allergan, AstraZeneca, Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Truvion and Zeria. T.V. has given scientific advice to Dr. Falk, Shire, Takeda, Therachon, Tramedico and Zealand, and has served on the speaker bureau for Abbott, Kyowa Kirin, Menarini, Truvion and Will Pharma. Medication for this study was provided by Shire pharmaceuticals, Belgium.
WHAT IS KNOWN
- ✓ Gastroprokinetic agents are favored for the treatment of gastroparesis, but there is a lack of evidence for their efficacy, and there are no agents of proven efficacy available.
- ✓ Prucalopride is a selective 5-HT4 agonist, developed for the treatment of chronic constipation, which was shown to enhance the gastric emptying rate.
WHAT IS NEW HERE
- ✓ In this single-center placebo-controlled crossover trial, enrolling patients with predominantly idiopathic gastroparesis, prucalopride 2 mg daily was superior to placebo in improving symptoms, as assessed by the Gastroparesis Cardinal Index.
- ✓ Prucalopride also improved upper GI symptoms in a broad sense and QOL impact, as measured, respectively, by the PAGI-SYM and PAGI-QOL questionnaires.
- ✓ Prucalopride enhanced the gastric emptying rate.
- ✓ Prucalopride was well tolerated.
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