Abstract
PurposeFabry disease is a rare multisystemic disorder caused by functional deficiency of the lysosomal enzyme alpha-galactosidase A. Gastrointestinal (GI) signs and symptoms are among the earliest clinical manifestations in patients with Fabry disease but are often nonspecific, misdiagnosed, and untreated. No instruments have been developed specifically to assess GI signs and symptoms in Fabry disease. The FABry disease Patient-Reported Outcome-GastroIntestinal (FABPRO-GI) was developed to address this unmet need and is intended for use in clinical trials (24-h FABPRO-GI) and real-world settings (7-day FABPRO-GI).MethodsFindings from a literature review, expert advisory meetings, and patient concept elicitation interviews (CEIs) were summarized into conceptual models. These conceptual models were used to develop preliminary versions of the 24-h and 7-day FABPRO-GI. Cognitive debriefing interviews (CDIs) were conducted with additional patients to assess content validity, including understandability, relevance, and comprehensiveness of the preliminary versions of the 24-h and 7-day FABPRO-GI.ResultsLiterature review (n = 17 articles), expert advisory meetings (n = 5), and patient CEIs (n = 17) identified mostly overlapping Fabry disease-related GI signs and symptoms, including abdominal cramps, bloating, and diarrhea, and informed development of the preliminary 24-h and 7-day FABPRO-GI. CDIs (n = 15) provided evidence of content validity and informed revisions of the 24-h and 7-day FABPRO-GI.ConclusionWith evidence of content validity, the 24-h and 7-day FABPRO-GI are the first Fabry disease-specific patient-reported outcomes to assess GI signs and symptoms in patients with Fabry disease with potential for use in clinical trials and real-world settings, respectively.
Highlights
Fabry disease is an X-linked multisystemic disorder caused by pathogenic GLA variants that result in functional deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) [1, 2]
Cognitive debriefing interviews (CDIs) were conducted in person by a trained interviewer using a semi-structured CDI guide and consisted of 2 stages: a “think-aloud” stage in which the patient completed the questionnaire while verbalizing the process and a discussion stage, in which patients reported whether the instructions, items, response options, and recall periods were relevant and appropriate for the questionnaires
Five experts from the United States (n = 3) and England (n = 2) participated in advisory meetings. These individuals worked in a variety of clinical settings, had treated patients with Fabry disease for between 15 and 24 years, and reported seeing approximately 6–80 patients with Fabry disease per month. These experts reported a total of 12 GI signs and symptoms of Fabry disease: diarrhea, abdominal pain, early satiety, abdominal cramps, constipation, gas, nausea, vomiting, poor appetite, acid reflux, bloating, and weight loss (Fig. 2A)
Summary
Fabry disease is an X-linked multisystemic disorder caused by pathogenic GLA variants that result in functional deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) [1, 2]. Diarrhea, often associated with significant urgency and frequency [13], was reported in 19% of adult patients and 25% of pediatric patients from the Fabry Outcome Survey [7] and 19% of females and 12% of males enrolled in the Fabry Registry [12] Despite their negative impact on the patient’s healthrelated quality of life, GI signs and symptoms are nonspecific and often overlooked in the management of Fabry disease [11]. Postprandial pain, nausea, and vomiting substantially improved from baseline following 24 weeks of agalsidase beta treatment in an open-label study of 16 pediatric patients [24] These studies provide evidence of the effect of ERT and migalastat treatment on GI signs and symptoms, none of the survey instruments used were developed for patients with Fabry disease or validated for use in this patient population, including the GSRS [21]. 2 versions of the FABPROGI were developed: the 24-h FABPRO-GI for clinical trials and the 7-Day FABPRO-GI for real-world settings
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