Introduction
Gastroparesis is defined as delayed gastric emptying, in the absence of mechanical obstruction, that may cause nausea, vomiting, and other upper gastrointestinal (GI) tract symptoms [
1,
2]. It is diagnosed on the basis of a combination of patient-reported symptoms—which commonly include nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain—and an objective evaluation of gastric emptying [
1‐
5]. Gastroparesis may be idiopathic or associated with diabetes. It has been estimated to affect up to 40% of patients with type 1 diabetes and 30% of patients with type 2 diabetes [
6]. Diabetic gastroparesis (DGP) is hypothesized to be caused by impaired neural control of gastric motility, and vagal neuropathy is also a prominent feature [
1,
7]. Patients with DGP may experience slowed gastric emptying and altered absorption of oral hypoglycemic drugs [
7].
Gastroparesis is associated with clinical complications including malnutrition, esophagitis, and Mallory–Weiss tears [
7], and may result in adverse impacts on patients’ lives, such as decreased social interaction, diminished work functioning, and anxiety or depression [
1,
8]. Further, as with other chronic GI disorders, the impact of gastroparesis may be underappreciated; the prevalence may be underreported because of, in part, underdiagnosis; and the long-term consequences of gastroparesis are an opportunity for further study [
9].
In 2015, the Food and Drug Administration (FDA) released draft guidance for industry with recommendations regarding the clinical evaluation of medications to treat gastroparesis [
7]. On the basis of a review of the literature, the guidance specifies five clinically significant signs and symptoms of gastroparesis: nausea, vomiting, early satiety, postprandial fullness, and upper abdominal pain. The guidance also concludes that currently there is no comprehensive patient-reported outcome measure that is appropriate to support labeling claims pertaining to the treatment of gastroparesis.
A recently completed phase 2 clinical trial to assess the efficacy and safety of a new guanylate cyclase C receptor agonist treatment for DGP provided an opportunity for in-depth exploration of patients’ symptoms and perceptions of treatment (NCT02289846) [
10]. Patients eligible for participation in the clinical trial had diagnosed DGP (type 1 or 2) without any history or evidence of mechanical obstructions, reported DGP symptoms for at least 3 months before the trial, and had evidence of delayed gastric emptying via scintigraphy or breath test. Exclusion criteria ensured that patients with other GI diseases, taking medications, or having undergone surgical procedures that may have confounded the assessment of gastroparesis symptoms were ineligible for the trial. An aim of the study was to gather patient input by conducting qualitative pretreatment and end-of-treatment interviews with trial participants regarding the DGP symptoms they experienced before and during treatment to inform either the modification of an existing DGP symptom severity measure or the development of a novel instrument. Specifically, the objectives of the patient interviews were to explore patients’ experiences with DGP and identify DGP symptoms most important to treat; to inform the measurement strategy for future clinical trials in DGP; and to complement quantitative data collected during the trial via patient-reported outcome instruments, including a patient-completed diary (the primary measure of change in symptom severity). Conducting interviews in the context of a clinical trial provided the opportunity to efficiently gather input from a large number of patients and to characterize, in detail, the DGP patient experience.
Methods
Study Design and Population
This multisite, qualitative study of individuals (18 years or older) participating in the placebo-controlled, double-blinded phase 2 clinical trial was conducted through individual telephone interviews. Study site staff at each clinic invited all clinical trial participants to participate in the interviews at enrollment. At screening, clinic staff explained the purpose and procedures associated with the patient interviews at the pretreatment visit (PTV) and end-of-treatment visit (EOTV) and obtained explicit consent from patients who wished to participate in the interviews. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients who participated in the study.
Two female authors with extensive qualitative research experience (CME and SEF) conducted all interviews by telephone. During the PTV and EOTV, study site staff took interview participants to a private location within the clinic, called the designated interviewer to initiate each interview, and then left the room. To supplement the interviewers’ field notes and facilitate analysis, the interviews were audio recorded and transcribed. On completion of the interview, each participant was provided with an honorarium.
The target sample for the patient interviews included all trial participants who consented to be interviewed at the PTV and EOTV.
Interview Methods
Each interview was conducted with use of a semistructured interview guide and lasted approximately 60 min. The interviewers had access to only a unique clinical trial identification number for each interview participant; no personally identifiable data or detailed demographics were collected.
The PTV interviews began with introductions, an overview of the interview objectives, and a description of the interview process. The interviewers (CME and SEF) then asked general, open-ended questions designed to identify the DGP symptoms relevant to each participant. More targeted questions followed to ensure the reporting of a comprehensive set of DGP symptoms and to elicit patients’ perceptions and descriptions of symptom severity, the impact of DGP on patients’ lives, the bothersomeness (0–10 scale, 10 being the most bothersome) and relative importance of each symptom, and what patients would need to experience to feel that a medication was working for them. If specific symptoms associated with gastroparesis in the literature and/or in existing patient-reported outcome measures were not mentioned spontaneously, interview participants were asked if they had experienced them. Interview participants were also asked to describe how their lives were impacted by their DGP symptoms.
The EOTV interviews focused on patients’ experiences during the clinical trial, particularly any symptoms that had changed (regardless of treatment assignment); participants were also asked about the timing and importance of any changes they experienced. If none were mentioned spontaneously, interview participants were asked if they had experienced a change in any of the symptoms they reported during the PTV interview. In addition, the Gastroparesis Cardinal Symptoms Index–Daily Dairy [
11] was briefly reviewed during the interview; these results are not reported herein.
Data Analysis
Analysis of the interview data was guided by a content analytic plan developed before conduct of the interview, was completed primarily by the interviewers (CME and SEF), and was facilitated by the use of qualitative software (ATLAS.ti version 7.5; Thomas Muhr, Scientific Software Development, 2013). While the analysis plan included an initial coding structure focused on symptoms and impacts of DGP, new codes were added (as needed) throughout the analysis process to ensure comprehensive and systematic coding of concepts and reporting of themes and patterns in patients’ descriptions of experiences before and during the clinical trial. Given the sampling plan (i.e., invitation of all clinical trial participants), the achievement of concept saturation was anticipated but not specifically monitored.
In addition to conceptual coding, each interview was rated by quality: “green” indicated that the interview participant was able to understand the interview questions and provide highly relevant data, “yellow” indicated that the interview participant was able to understand most interview questions and provide relevant data, and “red” indicated that the interview participant did not understand most questions. In the analysis and reporting of frequencies, only unique mentions per code (concept) per patient were counted, and only the data resulting from interviews rated “green” or “yellow” were used.
Discussion
This study identified a comprehensive set of symptoms that are both bothersome and important to treat from the perspective of patients with DGP. The same symptoms likely would have been identified in qualitative research conducted outside the clinical trial setting. However, this study’s larger sample size, the rigor with which participants were screened, and the details that were documented regarding participants’ medical profile contribute to the robustness and generalizability of the results across the target patient population.
Nausea, vomiting (both frequency and severity), stomach fullness, bloating, upper abdominal pain, constipation, and heartburn were consistently identified and described as important symptoms. Specifically, these symptoms were most often reported spontaneously, identified as most bothersome, and cited as an indication that a DGP medication was working during the PTV interviews. Reductions in these symptoms during the trial were also described as important improvements by EOTV interview participants. Taken together, these results strongly suggest that, at a minimum, each of these symptoms should be measured in future DGP clinical trials.
The findings from this study also provide context for the interaction of DGP symptoms. For example, participants in this study rarely described abdominal discomfort as a unique symptom, but rather described it in reference to other abdominal symptoms (e.g., pain or bloating), suggesting that discomfort may overlap with or be caused by other symptoms. Although abdominal pain and bloating were among the DGP symptoms most frequently reported spontaneously, less than a quarter of the sample spontaneously reported abdominal discomfort. These findings suggest that abdominal discomfort may not be as salient to patients or as important to measure so as to obtain a comprehensive assessment of abdominal symptoms in future DGP clinical trials.
The results of this study are largely consistent with the FDA’s draft gastroparesis guidance [
7], which identifies nausea, vomiting, early satiety, postprandial fullness, and upper abdominal pain as the core gastroparesis symptoms. The primary point of departure is that, whereas most interview participants spontaneously reported stomach fullness as both bothersome and an important treatment target, they were far less likely to report early satiety and postprandial fullness as distinct symptoms. Instead, stomach fullness generally encompassed both early satiety and postprandial fullness among interview participants. The conceptual distinction between these symptoms lies in the time point at which the patient senses stomach fullness relative to when the patient stops stop eating, and eating behavior may vary for reasons unrelated to DGP symptom severity. Although the potential to assess early satiety and postprandial fullness separately should be explored further, it is possible that a single item addressing the feeling of stomach fullness may perform better than separate items.
Not only does some overlap across DGP symptoms exist, as suggested by the interview results, but the literature and the FDA acknowledge that the signs and symptoms of gastroparesis overlap considerably with those of other GI conditions (e.g., functional dyspepsia, irritable bowel syndrome, colonic motility) [
7,
12]. However, despite the exclusion of patients with GI conditions other than DGP from the clinical trial, bloating, constipation, and heartburn (none of which are considered core symptoms in the FDA’s guidance) were common among interview participants. The interview results suggest that even if these three symptoms are not included in a primary efficacy end point in DGP treatment trials, they should likely be measured to demonstrate (at a minimum) a lack of worsening.
The results of the PTV and EOTV interviews also provide substantial insight into how to measure reduction in DGP symptoms. Modification of an existing measure or development of a new, DGP-specific symptom measure, informed by observations from this study, would appear necessary to support approval and labeling claims in future DGP trials. An additional objective of the current study was to complement and enrich quantitative trial data, providing insight into the impact of treatment on DGP symptoms. The patient diary and other patient-reported outcome measures administered during the trial offered a standard evaluation of treatment benefit, whereas these interviews offered an opportunity to more fully explore the impact of DGP symptoms and changes that occurred with treatment. For example, had unexpected changes occurred (reductions or worsening), the EOTV interview method may more likely have identified those changes given that the interviews were more open in nature than the diary assessments.
The results of this study should be considered within the context of its limitations. A potentially important limitation relates to the conduct of interviews via telephone rather than in person. In-person interviews typically encourage rapport and maximize participant engagement. In this context, because participants were enrolled in the study on an ongoing basis, in-person interviews would have been logistically challenging. However, the interviews were led by qualitative researchers who are experienced interviewers, and participants were generally forthcoming and engaged in the interviews despite the telephone-based method. As such, the study results likely would not have been substantially different had the interviews been conducted face-to-face. An additional limitation is that interview participants were self-selected clinical trial participants, and the results of the current study may not be generalizable to other patients with DGP. Finally, the interviews were conducted in English. The level of English-language proficiency required for participants to enter the trial may not have aligned with interview participants’ ability to communicate richly about their trial experience.
Acknowledgements
Sponsorship for this study, article processing charges, and the open access fee were funded by Ironwood Pharmaceuticals. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for the manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.
The authors gratefully acknowledge Melissa Villoldo, formerly of Ironwood Pharmaceuticals and currently of Revance Therapeutics, for her contributions to the design and operationalization of the study, and Diana Goss of RTI Health Solutions for the day-to-day management of the interview study. Kate Lothman of RTI Health Solutions provided medical writing services, which were funded by Ironwood Pharmaceuticals.