Evaluating response in gastroparesis: Patient reported outcome measures and survey instruments

Introduction

Gastroparesis is a symptomatic condition of delayed gastric emptying with no mechanical obstruction . There are several etiologies of gastroparesis, including diabetic gastroparesis and postsurgical gastroparesis. In many patients, a cause cannot be found, and the condition is termed idiopathic gastroparesis. In some of these patients, a viral etiology may be suspected due to a sudden onset of symptoms associated with a viral-like prodrome.

A variety of symptoms are reported by patients with gastroparesis . These can include nausea, vomiting, early satiety, postprandial fullness, bloating, loss of appetite, abdominal distension, and abdominal pain. Patients may experience any combination of symptoms with varying degrees of severity . The symptoms are often chronic; however, patients may also have periodic exacerbations of their symptoms . These symptoms may impair physical, emotional and social functioning and well-being, and reduce the patient’s health-related quality of life (HRQL). Many patients experience weight loss due to their symptoms.

The diagnosis of gastroparesis is made by demonstrating in a symptomatic patient delayed gastric emptying without evidence of obstruction . Delayed gastric emptying is most commonly assessed using a validated measurement of gastric emptying. At present, the best validated, and approved method of measurement is scintigraphy of the solid phase of a meal . Other ways to assess gastric emptying include wireless capsule motility and breath tests using stable C-13 isotopes. Absence of obstruction is most commonly determined by upper endoscopy. An alternative test is an upper gastrointestinal radiographic series, which can also assess the small intestine.

There is a need for new safe and effective treatments for gastroparesis with favorable benefit risk profiles. Pharmacologic treatment of gastroparesis typically involves two classes of agents: prokinetics agents and antiemetic agents. Metoclopramide, a dopamine type 2 receptor antagonist has both prokinetic and antiemetic properties, and is the only drug currently approved by the FDA for gastroparesis, specifically for diabetic gastroparesis for up to 12 weeks of treatment.

Understanding the relevant symptoms of gastroparesis is important in treating patients with this disorder. In gastroparesis, the symptom experience and severity is obtained from the patient. Consequently, patient-reported symptom scales that capture overall gastroparesis severity are necessary for evaluating treatments for gastroparesis. In the 2015 draft FDA guidance, they note that the most frequently reported symptoms associated with gastroparesis of nausea (92–96%), vomiting (68–88%), post-prandial fullness (54–77%), early satiety (42–86%), and upper abdominal pain (36–85%) . A well-defined patient reported outcome (PRO) instrument that measures clinically important signs and symptoms of gastroparesis would be a useful assessment tool for clinical trials to support labeling claims for treatment of gastroparesis.

Patient-reported outcomes in gastroparesis clinical studies

Over the past 30 years, a number of different PRO measures have been used to assess symptom severity and frequency, and the impact of symptom severity on patient physical, emotional and social functioning and well-being, or HRQL. Various different symptom measures have been included in randomized clinical trials and other clinical studies (see Table 33.1 ). The most frequently utilized symptom scales were derived from the Gastroparesis Cardinal Symptom Inventory (GCSI) . Several clinical studies have included either the original GCSI or the more recently developed GCSI Daily Diary (GCSI-DD) . Often the GCSI is administered in the complete Patient Assessment of Upper Gastrointestinal-Symptoms (PAGI-SYM) . The current version of the GCSI-DD, the ANMS GCSI-DD contains symptom severity items for nausea, early satiety, post-prandial fullness and upper abdominal pain and a vomiting frequency item .

Many studies focus on investigator developed symptom scales or a subset of gastroparesis-related symptoms depending on the treatment being evaluated or the objectives of the clinical study . Several studies focus on only nausea and vomiting . A number of studies include global assessments of symptom severity, change in symptom severity or relief in gastroparesis-related symptoms . More recently, a new diabetic gastroparesis-related scale, the Diabetic Gastroparesis Symptom Severity Diary (DGSSD) was developed. The DGSSD was developed as a daily diary and contains symptom severity items on nausea, abdominal pain, bloating, post-prandial fullness, abdominal pain, and early satiety, and a vomiting frequency item. Evidence supporting the content validity and reliability and validity of the DGSSD was recently published . Camilleri et al. reported on a 12-week phase 2b randomized clinical trial comparing relamorelin versus placebo in patients with diabetic gastroparesis. No treatment differences were observed between active and placebo treatment based on vomiting frequency and a 4-item composite score (nausea, abdominal pain, post-prandial fullness, bloating severity).

Previous clinical trials and other clinical studies have incorporated other PRO measures to characterize the impact of gastroparesis-related symptoms on patient physical, social and emotional functioning and well-being (i.e., HRQL). For example, the NIDDK Gastroparesis Clinical Research Consortium (GPCRC) includes a very comprehensive battery of HRQL and emotional well-being instruments, including the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QOL) Scale, SF-36 Health Survey, Brief Pain Inventory, Beck Depression Inventory, State-Trait Anxiety Scale, Patient Health Questionnaire-15, and several patient completed global rating scales . Other researchers have incorporated the SF-36 Health Survey, a generic measure of functioning and well-being, into gastroparesis clinical studies .

Next, we will discuss PRO instrument development and regulatory issues, then we will illustrate the development of a gastroparesis-related PRO measure, using examples from the ANMS GCSI-DD, which is undergoing qualification evaluation by the FDA as a primary or key secondary endpoint for clinical trials in diabetic and idiopathic gastroparesis. Currently, the ANMS GCSI-DD is the gastroparesis symptom endpoint with the greatest supportive evidence available on content validity and psychometric characteristics (i.e., reliability, validity, responsiveness) . The gastroparesis-related symptoms included in the ANMS GCSI-DD are also consistent with the most recent draft FDA guidance on gastroparesis related endpoints. The conceptual framework for the ANMS GCSI-DD core composite is summarized in Fig. 33.1 and for the total score in Fig. 33.2 .