Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study

Barbara Vigone,Chiara Bellocchi,Adriana Severino,Alessandro Santaniello,Monica Caronni,Anna Rita Baldassarri,Mirella Fraquelli,Gaia Montanelli,Lorenzo Beretta

doi:10.1186/s13075-017-1340-y

Barbara Vigone, Chiara Bellocchi + Show 7 more

Open Access

https://doi.org/10.1186/s13075-017-1340-y

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Abstract

BackgroundProkinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT4) receptor agonists class were withdrawn due to cardiac toxicity in relation to modest 5-HT4 receptor affinity. Prucalopride is a high-affinity 5-HT4 receptor agonist with no major cardiac issues, for which the efficacy in SSc has not yet been assessed.MethodsForty patients with self-reported mild to moderately severe enteric symptoms were enrolled in a cross-over 2 × 2 study. Subjects were randomized 1:1 to prucalopride 2 mg/day or no treatment for one month and vice versa after a 2-week washout period. Before and after each sequence the patients compiled the University of California Los Angeles gastrointestinal tract (UCLA GIT) 2.0 questionnaire and the numbers of complete intestinal movements were recorded. Oro-cecal transit time (OCTT) was evaluated by lactulose breath test in a subgroup of patients. Data were evaluated by mixed linear models corrected for the number of laxatives used during the study periods.ResultsThere were 29 subjects who completed the study; 7 subjects withdrew due to side-effects and 4 subjects were not compliant with the study procedures. As compared to dummy treatment, prucalopride was associated with more intestinal evacuations (p < 0.001), improvement of UCLA GIT constipation (-0.672 ± 0.112 vs 0.086 ± 0.115; p < 0.001), reflux (-0.409 ± 0.094 vs 0.01 ± 0.096; p < 0.005) and bloating (-0.418 ± 0.088 vs -0.084 ± 0.09; p = 0.01) scores. Treatment was ranked moderately to more than moderately effective by 22 patients (72.4%). OCTT was significantly reduced during prucalopruide consumption (prucalopride: -20.1 ± 20.1 vs no treatment: 45.8 ± 21.3 minutes; treatment effect = -65.9 minutes; p = 0.035).ConclusionsThe safety profile of prucalopride in SSc is similar to what is known from the literature. In patients with mild to severe gastrointestinal problems, prucalopride may be effective in treating dismotility symptoms, increasing the number of complete bowel movements and improving bowel transit, reducing reflux disease and bloating.Trial registrationEU Clinical Trial Registry, EudraCT2012-005348-92. Registered on 19 February 2013.

Highlights

Prokinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy
In most cases side effects were observed the first day of treatment and were considered severe enough to preclude the prosecution of the study, despite the proposal of mitigation strategies; in the remaining cases attempts were made to go on with the treatment; this was discontinued within 1 week due to the persistence of side effects
Four patients were excluded from the analysis (10%) because not they were not compliant with the study procedures, because of inadequate drug intake (n = 1) or because the patient did not attend the assessment visit (n = 1)

Summary

Introduction

Prokinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT4) receptor agonists class were withdrawn due to cardiac toxicity in relation to modest 5-HT4 receptor affinity. Cisapride has been withdrawn from the global market due to safety concerns related to cardiac toxicity [11, 12] These side-effects were linked to the lack of selectivity for the for the 5-HT4 receptor and to the blockade of the human ether-a-go-go-related gene (hERG)-encoded K+ channel. The consequences of this interaction are the prolongation of cardiac action potential repolarisation and, QT interval, leading to a clinically significant arrhythmogenic potential [12, 13]. Prucalopride does not interact with hERG channels and in large placebo-controlled studies no differences in vital signs or electrocardiogram parameters have been observed between groups [16, 17, 19]

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