Placebo response in pharmacological trials in patients with functional dyspepsia-A systematic review and meta-analysis.

BACKGROUND: Pharmacological trials in functional dyspepsia (FD) are associated with high placebo response rates. We aimed to identify the magnitude and contributing factors to the placebo response. METHODS: We conducted a systematic review and meta-analysis including randomized controlled trials (RCTs) with a dichotomous outcome in adult patients with FD that compared an active pharmacotherapeutic treatment with placebo. Our main outcome was identification of the magnitude of the pooled placebo response rate for the following endpoints: symptom responder, symptom-free responder, adequate relief responder, and combined endpoint responder (i.e., the primary endpoint of each specific trial regarding treatment response). Several putative moderators (i.e., patient, disease, and trial characteristics) were examined. KEY RESULTS: We included 26 RCTs in our analysis. The pooled placebo response rate was 39.6% (95% CI 30.1-50.0) using the symptom responder definition, 20.5% (12.8-31.0) using the symptom-free responder definition, 38.5% (33.8-43.6) using the adequate relief responder definition, and 35.5% (31.6-39.7) using the combined endpoint responder definition. A lower overall baseline symptom score was significantly associated with a higher placebo response rate. No other moderators were found to significantly impact the placebo response rate. Due to the lack of data, no analyses could be performed according to individual FD subtypes or symptoms. CONCLUSIONS AND INFERENCES: The pooled placebo response rate in pharmacological trials in FD is about 39%, depending on which responder definitions is used. Future trials should consider applying an entry criterion based on minimal level of symptom severity to decrease the placebo response. We also suggest separate reporting of core FD symptoms pending more concrete harmonization efforts in FD trials.

The Interplay Between Stress and Fullness in Patients With Functional Dyspepsia and Healthy Controls: An Exploratory Experience Sampling Method Study.

OBJECTIVE: Fullness is a cardinal symptom in functional dyspepsia (FD). The use of real-time symptom assessment might provide more insight into factors, such as daily stress, that can influence fullness. Therefore, this study aimed to use the experience sampling method (a real-time, repeated-measurement method making use of repeated questionnaires available at random moments for a limited amount of time) to assess the association between stress and fullness in patients with FD and healthy controls (HCs). METHODS: Thirty-five patients with FD (25 female, mean age = 44.7 years) and 34 HCs (24 female, mean age = 44.1 years) completed the experience sampling method (a maximum of 10 random moments per day) for 7 consecutive days. Stress and fullness were rated on an 11-point Numeric Rating Scale. Data between patients with FD and HCs were statistically compared using a Student samples t test and linear mixed-effects models with repeated measures (level 1) nested within participants (level 2). RESULTS: Average fullness scores were 2.23 (standard error = 0.37) points higher in patients with FD compared with HCs (p < .001). Average stress scores were 1.37 (standard error = 0.30) points higher in patients with FD compared with HCs (p = .002).In FD, fullness scores increased with 0.14 for every 1-point increase in concurrent stress scores (p = .010). Fullness scores at t = 0 increased with 0.12 for every 1-point increase in stress scores at t = -1 (p = .019). T = 0 stress scores were not associated with change in t = -1 fullness scores. No associations between concurrent symptom scores were found for HCs. CONCLUSIONS: Concurrent and preceding stress scores are positively associated with fullness scores in patients with FD, but not in HCs. These findings indicate that increased levels of stress may precede feelings of fullness in patients with FD. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04204421.

Digital Instruments for Reporting of Gastrointestinal Symptoms in Clinical Trials: Comparison of End-of-Day Diaries Versus the Experience Sampling Method.

BACKGROUND: Questionnaires are necessary tools for assessing symptoms of disorders of the brain-gut interaction in clinical trials. We previously reported on the excellent adherence to a smartphone app used as symptom diary in a randomized clinical trial on irritable bowel syndrome (IBS). Other sampling methods, such as the experience sampling method (ESM), are better equipped to measure symptom variability over time and provide useful information regarding possible symptom triggers, and they are free of ecological and recall bias. The high frequency of measurements, however, could limit the feasibility of ESM in clinical trials. OBJECTIVE: This study aimed to compare the adherence rates of a smartphone-based end-of-day diary and ESM for symptom assessment in IBS and functional dyspepsia (FD). METHODS: Data from 4 separate studies were included. Patients with IBS participated in a randomized controlled trial, which involved a smartphone end-of-day diary for a 2+8-week (pretreatment + treatment) period, and an observational study in which patients completed ESM assessments using a smartphone app for 1 week. Patients with FD participated in a randomized controlled trial, which involved a smartphone end-of-day diary for a 2+12-week (pretreatment + treatment) period, and an observational study in which patients completed ESM assessments using a smartphone app for 1 week. Adherence rates were compared between these 2 symptom sampling methods. RESULTS: In total, 25 patients with IBS and 15 patients with FD were included. Overall adherence rates for the end-of-day diaries were significantly higher than those for ESM (IBS: 92.7% vs 69.8%, FD: 90.1% vs 61.4%, respectively). CONCLUSIONS: This study demonstrates excellent adherence rates for smartphone app-based end-of-day diaries as used in 2 separate clinical trials. Overall adherence rates for ESM were significantly lower, rendering it more suitable for intermittent sampling periods rather than continuous sampling during longer clinical trials.

Psychometric evaluation of an experience sampling method-based patient-reported outcome measure in functional dyspepsia.

BACKGROUND: Due to important biases, conventional end-of-day and end-of-week assessment methods of gastrointestinal symptoms in functional dyspepsia (FD) are considered suboptimal. Real-time symptom assessment based on the experience sampling method (ESM) could be a more accurate measurement method. This study aimed to evaluate validity and reliability of an ESM-based patient-reported outcome measure (PROM) for symptom assessment in FD. METHODS: Thirty-five patients with FD (25 female, mean age 44.7 years) completed the ESM-based PROM (a maximum of 10 random moments per day) and an end-of-day symptom diary for 7 consecutive days. On day 7, end-of-week questionnaires were completed including the Nepean Dyspepsia Index (NDI) and Patient Assessment of Gastrointestinal Symptom Severity Index (PAGI-SYM). KEY RESULTS: Experience sampling method and corresponding end-of-day scores for gastrointestinal symptoms were significantly associated (ICCs range 0.770-0.917). However, end-of-day scores were significantly higher (Δ0.329-1.031) than mean ESM scores (p < 0.05). Comparing ESM with NDI and PAGI-SYM scores, correlations were weaker (Pearson's r range 0.467-0.846). Cronbach's α coefficient was good for upper gastrointestinal symptoms (α = 0.842). First half-week and second half-week scores showed very good consistency (ICCs range 0.913-0.975). CONCLUSION AND INFERENCES: Good validity and reliability of a novel ESM-based PROM for assessing gastrointestinal symptoms in FD patients was demonstrated. Moreover, this novel PROM allows to evaluate individual symptom patterns and can evaluate interactions between symptoms and environmental/contextual factors. ESM has the potential to increase patients' disease insight, provide tools for self-management, and improve shared decision making. Hence, this novel tool may aid in the transition toward personalized health care for FD patients.

Anaplastic Large Cell T Cell Lymphoma in a Patient With Severe Therapy-refractory Crohn's Disease on Long-standing Immunosuppressive Medication During Ustekinumab Treatment: A Case Report and Review of the Literature.

Use of ustekinumab in Crohn's disease was approved in 2016, and consequently data regarding its real-world safety are still limited. We here present a 29-year-old woman with severe therapy-refractory Crohn's disease, who developed an anaplastic large cell T cell lymphoma during treatment with ustekinumab.

Therapeutic strategies in gastroparesis: Results of stepwise approach with diet and prokinetics, Gastric Rest, and PEG-J: A retrospective analysis.

BACKGROUND: Gastroparesis is characterized by abnormal gastric motor function with delayed gastric emptying in the absence of mechanical obstruction. In our tertiary referral center, patients are treated with a stepwise approach, starting with dietary advice and prokinetics, followed by three months of nasoduodenal tube feeding with "gastric rest." When not successful, a percutaneous endoscopic gastrostomy with jejunal extension (PEG-J) for long-term enteral feeding is placed. AIM: To evaluate the effect of this stepwise approach on weight and symptoms. METHODS: Analyses of data of all referred gastroparesis patients between 2008 and 2016. KEY RESULTS: A total of 86 patients (71% female, 20-87 years [mean 55.8 years]) were analyzed of whom 50 (58%) had adequate symptom responses to diet and prokinetics. The remaining 36 (decompensated gastroparesis) were treated with three months gastric rest. Symptom response rate was 47% (17/36). Significant weight gain was seen in all patients, independent of symptom response. In the remaining 19 symptom non-responders, the enteral feeding was continued through PEG-J. Treatment was effective (symptoms) in 37%, with significant weight gain in all. In 84% of patients, the PEG-J is still in use (mean duration 962 days). CONCLUSIONS AND INFERENCES: Following a stepwise treatment approach in gastroparesis, adequate symptom response was reached in 86% of all patients. Weight gain was achieved in all patients, independent of symptom response. Diet and prokinetics were effective with regard to symptoms in 58%, temporary gastric rest in 47%, and PEG-J as third step in 37% of patients.

Development of a real-time patient-reported outcome measure for symptom assessment in patients with functional dyspepsia using the experience sampling method.

BACKGROUND: Patient-reported outcome measures (PROMs) are used to assess symptoms in patients with functional dyspepsia (FD). Current end-of-day questionnaires have several limitations including sensitivity to recall and ecological bias. The experience sampling method (ESM) is characterized by random and repeated assessments across momentary states in daily life and therefore less sensitive to these limitations. This study describes the development of a novel PROM based on ESM technology. METHODS: An initial draft of the PROM was developed based on literature. Focus group interviews with FD patients according to Rome IV criteria, and an expert meeting with international opinion leaders in the field of functional gastrointestinal disorders were conducted in order to select items for the PROM. Cognitive interviews were performed to evaluate patients' understanding of the selected items and to create the definitive PROM. KEY RESULTS: A systematic literature search revealed 59 items across four domains (ie, physical status; mood and psychological factors; context and environment; and nutrition, medication, and substance use). After patient focus group interviews and an international expert meeting, the number of items was reduced to 33. Cognitive interviews resulted in some minor linguistic changes in order to improve patients' understanding. CONCLUSIONS AND INFERENCES: A novel digital ESM-based PROM for real-time symptom assessment in patients with functional dyspepsia was developed. This novel PROM has the potential to identify individual symptom patterns and specific triggers for dyspeptic symptoms, and optimize treatment strategies.

Prospective multicenter validation of the Glasgow Blatchford bleeding score in the management of patients with upper gastrointestinal hemorrhage presenting at an emergency department.

BACKGROUND/AIMS: The Glasgow Blatchford Bleeding Score (GBS) has been developed to assess the need for treatment in patients with acute upper gastrointestinal hemorrhage (UGIH) presenting at emergency departments (EDs). We aimed (a) to determine the validity of the GBS and Rockall scoring systems for prediction of need for treatment and (b) to identify the optimal cut-off value of the GBS. METHODS: We carried out a population-based, prospective multicenter study of 520 consecutive patients presenting with acute UGIH at EDs of three hospitals. The accuracy of GBS and Rockall scores in predicting the need for treatment (i.e. endoscopic, surgical, or radiological intervention and blood transfusion) was analyzed using receiver operating characteristic curves. RESULTS: Receiver operating characteristic curve analysis showed that the GBS had a good discriminative ability to determine the need for treatment in patients with acute UGIH (area under the curve: 0.88; 95% confidence interval: 0.85-0.91). The GBS was superior to both the clinical Rockall and the full Rockall score in predicting the need for treatment (area under the curve: 0.86 vs. 0.70 vs. 0.77). At a cut-off value of up to 2, the GBS had the optimal combination of sensitivity (99.4%) and specificity (42.4%). CONCLUSION: The GBS is superior compared with both Rockall scores in predicting the need for treatment in patients with suspected acute UGIH presenting at EDs in the Netherlands. Patients with a GBS of 2 or less form a subgroup of low-risk patients. These low-risk patients are eligible for outpatient management, which might reduce hospital admissions and healthcare costs.

Does Measurement of Esophagogastric Junction Distensibility by EndoFLIP Predict Therapy- responsiveness to Endoluminal Fundoplication in Patients With Gastroesophageal Reflux Disease?

BACKGROUND/AIMS: In patients with gastroesophageal reflux disease (GERD), an increased esophagogastric junction (EGJ) distensibility has been described. Assessment of EGJ distensibility with the endoscopic functional luminal imaging probe (EndoFLIP) technique might identify patients responsive to transoral incisionless fundoplication (TIF), whereas postoperative measurement of EGJ distensibility might provide insight into the antireflux mechanism of TIF. Therefore, we investigated the value of the EndoFLIP technique in GERD patients treated by TIF. METHODS: Forty-two GERD patients underwent EGJ distensibility measurement before TIF using the EndoFLIP technique. In a subgroup of 25 patients, EndoFLIP measurement was repeated both postoperative and at 6 months follow-up. Treatment outcome was assessed according to esophageal acid exposure time (AET; objective outcome) and symptom scores (clinical outcome) 6 months after TIF. RESULTS: Multiple logistic regression analysis showed that preoperative EGJ distensibility (OR, 0.16; 95% CI, 0.03-0.78; P = 0.023) and preoperative AET (OR, 0.62; 95% CI, 0.42-0.90; P = 0.013) were independent predictors for objective treatment outcome but not for clinical outcome after TIF. The best cut-off value for objective outcome was 2.3 mm(2)/mmHg for preoperative EGJ distensibility and 11% for preoperative AET. EGJ distensibility decreased direct postoperative from 2.0 (1.2-3.3) to 1.4 (1.0-2.2) mm(2)/mmHg (P = 0.014), but increased to 2.2 (1.5-3.0) at 6 months follow-up (P = 0.925, compared to preoperative). CONCLUSIONS: Preoperative EGJ distensibility and preoperative AET were independent predictors for objective treatment outcome but not for clinical outcome after TIF. According to our data, the EndoFLIP technique has no added value either in the preoperative diagnostic work-up or in the post-procedure evaluation of endoluminal antireflux therapy.

Effect of transoral incisionless fundoplication on reflux mechanisms.

OBJECTIVES: Transoral incisionless fundoplication (TIF) is a new endoscopic treatment option for gastroesophageal reflux disease (GERD). The mechanisms underlying the anti-reflux effect of this new procedure have not been studied. We therefore conducted this explorative study to evaluate the effect of TIF on reflux mechanisms, focusing on transient lower esophageal sphincter relaxations (TLESRs) and esophagogastric junction (EGJ) distensibility. METHODS: GERD patients (N = 15; 11 males, mean age 41 years, range 23-66), dissatisfied with medical treatment were studied before and 6 months after TIF. We performed 90-min postprandial combined high-resolution manometry and impedance-pH monitoring and an ambulatory 24-h pH-impedance monitoring. EGJ distensibility was evaluated using an endoscopic functional luminal imaging probe before and directly after the procedure. RESULTS: TIF reduced the number of postprandial TLESRs (16.8 ± 1.5 vs. 9.2 ± 1.3; p < 0.01) and the number of postprandial TLESRs associated with reflux (11.1 ± 1.6 vs. 5.6 ± 0.6; p < 0.01), but the proportion of TLESRs associated with reflux was unaltered (67.6 ± 6.9 vs. 69.9 ± 6.3 %). TIF also led to a decrease in the number and proximal extent of reflux episodes and an improvement of acid exposure in the upright position; conversely, TIF had no effect on the number of gas reflux episodes. EGJ distensibility was reduced after the procedure (2.4 ± 0.3 vs. 1.6 ± 0.2 mm(2)/mmHg; p < 0.05). CONCLUSIONS: TIF reduced the number of postprandial TLESRs, the number of TLESRs associated with reflux and EGJ distensibility. This resulted in a reduction of the number and proximal extent of reflux episodes and improvement of acid exposure in the upright position. The anti-reflux effect of TIF showed to be selective for liquid-containing reflux only, thereby preserving the ability of venting gastric air.