Design and execution of sham-controlled endoscopic trials in acute pancreatitis: Lessons learned from the SHARP trial.

Using the ongoing NIDDK-funded multicenter randomized clinical trial, Sphincterotomy for Acute Recurrent Pancreatitis (SHARP) as an example, this article discusses the rationale and key aspects of study design that need to be considered when conducting a clinical trial of endoscopic therapy in acute pancreatitis. SHARP, the first trial using a sham ERCP in the placebo group, is designed to address a decades long controversy in clinical pancreatology, i.e. whether minor papilla sphincterotomy benefits patients with idiopathic acute recurrent pancreatitis who also have pancreas divisum. Although the trial has already enrolled and randomized over 5 times the number of subjects enrolled in the only randomized trial in this area published in 1992 (107 vs. 19), recruitment has been challenging and we are at ∼46% of target recruitment. The review discusses the challenges in the execution of the trial and strategies the SHARP team has used to address these, which investigators planning or considering treatment trials in pancreatitis may find helpful. It will also inform the general gastroenterologists the importance of discussing and referring potentially eligible subjects to centers participating in clinical trials. Developing evidence-based treatment will provide a solid scientific basis for physicians to recommend evidence-based treatments for pancreatitis.

Characteristics of Patients Undergoing Endoscopic Retrograde Cholangiopancreatography for Sphincter of Oddi Disorders.

The concept that sphincter of Oddi dysfunction (SOD) can cause attacks of biliary-type pain in postcholecystectomy patients and those with unexplained recurrent acute pancreatitis, and that endoscopic sphincterotomy can ameliorate symptoms, remains unproven. The Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction (EPISOD) study of patients without objective evidence for biliary obstruction showed no difference in outcomes between those who underwent sphincterotomy or sham treatment.1 To date, there have been no studies examining the characteristics of patients who still are being offered endoscopic retrograde cholangiopancreatography (ERCP) for SOD since the EPISOD publication, although the absolute number appears to have declined.2.

A Randomized Trial of Ketorolac vs. Sumatripan vs. Placebo Nasal Spray (KSPN) for Acute Migraine.

OBJECTIVE: To compare the efficacy of ketorolac nasal spray (NS) vs. placebo and sumatriptan NS for the acute treatment of migraine. METHODS: This was a randomized, double-blind, placebo and active-comparator, crossover study. Adult migraineurs were randomized to ketorolac NS 31.5 mg, sumatriptan NS 20 mg, or placebo to treat three moderate to severe migraine attacks and switched treatments with each attack. Patients seeking headache care at a headache center or in response to community advertisement were recruited. Adult participants with episodic migraine who experienced ≥2 migraine attacks per month were eligible for the Ketorolac vs. Sumatriptan vs. Placebo Nasal Spray migraine study. Participants were randomized to treatment arms by a research pharmacist, in a 1:1:1 ratio using computer-generated lists. The primary outcome was 2-hour pain relief. Secondary outcomes included 2-hour pain freedom and absence of migraine associated symptoms, and 24-hour sustained pain relief and pain freedom. RESULTS: Of the 72 randomized participants, 54 (75%) treated at least one attack and 49 (68%) completed all three treatments, for a total of 152 treated migraine attacks. Both ketorolac NS (72.5%, P < .001) and sumatriptan NS (69.4%, P = .001) were more effective than placebo (38.3%) for 2-hour pain relief and 2-hour pain freedom (ketorolac: 43.1%, P = .004; sumatriptan: 36.7%, P = .046; placebo: 18.4%). Ketorolac NS, but not sumatriptan NS, was more effective than placebo in 2-hour absence of nausea. Both ketorolac NS and sumatriptan NS were more effective than placebo for 24-hour sustained pain relief (ketorolac: 49%, P < .001; sumatriptan: 31%, P = .01, placebo: 20%). Only ketorolac NS was superior to placebo for 24-hour (ketorolac: 35.3%, P = .003; sumatriptan: 22.4%, P = .18, placebo: 12.2%) sustained pain freedom. Nasal burning and dysgeusia were the most common adverse effects for active treatments. CONCLUSIONS: This study supports that ketorolac NS is superior to placebo and that it is non-inferior to sumatriptan NS for the acute abortive treatment of migraine.

Sphincterotomy for Biliary Sphincter of Oddi Disorder and idiopathic Acute Recurrent Pancreatitis: THE RESPOND LONGITUDINAL COHORT.

Objective: Sphincter of Oddi Disorders (SOD) are contentious conditions in patients whose abdominal pain, idiopathic acute pancreatitis (iAP) might arise from pressurization at the sphincter of Oddi. The present study aimed to measure the benefit of sphincterotomy for suspected SOD. Design: Prospective cohort conducted at 14 U.S. centers with 12 months follow-up. Patients undergoing first-time ERCP with sphincterotomy for suspected SOD were eligible: pancreatobiliary-type pain with or without iAP. The primary outcome was defined as the composite of improvement by Patient Global Impression of Change (PGIC), no new or increased opioids, and no repeat intervention. Missing data were addressed by hierarchal, multiple imputation scheme. Results: Of 316 screened, 213 were enrolled with 190 (89.2%) of these having a dilated bile duct, abnormal labs, iAP, or some combination. By imputation, an average of 122/213 (57.4% [95%CI 50.4-64.4]) improved; response rate was similar for those with complete follow-up (99/161, 61.5%, [54.0-69.0]); of these, 118 (73.3%) improved by PGIC alone. Duct size, elevated labs, and patient characteristics were not associated with response. AP occurred in 37/213 (17.4%) at a median of 6 months post-ERCP and was more likely in those with a history of AP (30.9 vs. 2.9%, p<0.0001). Conclusion: Nearly 60% of patients undergoing ERCP for suspected SOD improve, although the contribution of a placebo response is unknown. Contrary to prevailing belief, duct size and labs are poor response predictors. AP recurrence was common and like observations from prior non-intervention cohorts, suggesting no benefit of sphincterotomy in mitigating future AP episodes.Key Messages: WHAT IS ALREADY KNOWN ON THIS TOPIC: It is not clear if the sphincter of Oddi can cause abdominal pain (Functional Biliary Sphincter of Oddi Disorder) and idiopathic acute pancreatitis (Functional Pancreatic Sphincter of Oddi Disorder), and whether ERCP with sphincterotomy can ameliorate abdominal pain or pancreatitis.WHAT THIS STUDY ADDS: Using multiple patient-reported outcome measures, most patients with suspected sphincter of Oddi disorder improve after ERCP with sphincterotomy.Duct size, elevated pancreatobiliary labs, and baseline patient characteristics are not independently associated with response.There is a high rate of recurrent acute pancreatitis within 12 months of sphincterotomy in those with a history of idiopathic acute pancreatitis.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY: Since a discrete population with a high (> 80-90%) response rate to sphincterotomy for suspected pancreatobiliary pain could not be identified, there is a need for additional observational and interventional studies that include phenotyping of patients using novel imaging or biochemical biomarkers.There remains a pressing need for quantitative nociceptive biomarkers to distinguish pancreatobiliary pain from other causes of abdominal pain or central sensitization.Discovery of blood-, bile-, or imaging-based biomarkers for occult microlithiasis and pancreatitis may be helpful in predicting who is likely to benefit from sphincterotomy.

Parent Preferences for Methods and Content of Mobile Technology-Based Asthma Medication Adherence Intervention.

OBJECTIVES: Mobile technology-based asthma medication adherence interventions can be targeted to children during periods of high risk, including the transition from hospital to home or when refill behavior suggests declining adherence. Our objective was to develop insight into parent use of mobile technology and their preferences for a mobile technology-based asthma intervention. METHODS: By using qualitative methods, 20 interviews of parents of children with asthma were conducted. The open-ended, semistructured interview guides included questions about current mobile technology use, barriers to controller medication adherence, and preferences for methods and content of a mobile technology-based asthma intervention. Using grounded theory methodology, investigators coded the transcripts and identified emerging themes. RESULTS: Twenty parents completed interviews. Half of the children were 7 to 12 years old. Eighty percent had public insurance. Sixty-five percent had a previous hospitalization. Three major themes were identified: chronic disease management assistance, distinct preferences for risk communication, and electronic reachability. Chronic disease management assistance included parents recognizing that busy lifestyles contribute to adherence challenges and welcoming a program to assist them. Distinct preferences for risk communication included a preference for 2-way communication via text message or phone call at least monthly. Under the theme of electronic reachability, all enrolled parents had smartphones and used them daily. CONCLUSIONS: Parents of children with asthma are open to communicating with asthma providers through mobile technology. This information can be used to inform the development of mobile technology-based interventions to improve care for children with asthma during periods of high risk, including the transition from hospital to home.

Body composition status and the risk of migraine: A meta-analysis.

OBJECTIVE: To evaluate the association between migraine and body composition status as estimated based on body mass index and WHO physical status categories. METHODS: Systematic electronic database searches were conducted for relevant studies. Two independent reviewers performed data extraction and quality appraisal. Odds ratios (OR) and confidence intervals (CI) were pooled using a random effects model. Significant values, weighted effect sizes, and tests of homogeneity of variance were calculated. RESULTS: A total of 12 studies, encompassing data from 288,981 unique participants, were included. The age- and sex-adjusted pooled risk of migraine in those with obesity was increased by 27% compared with those of normal weight (odds ratio [OR] 1.27; 95% confidence interval [CI] 1.16-1.37, p < 0.001) and remained increased after multivariate adjustments. Although the age- and sex-adjusted pooled migraine risk was increased in overweight individuals (OR 1.08; 95% CI 1.04, 1.12, p < 0.001), significance was lost after multivariate adjustments. The age- and sex-adjusted pooled risk of migraine in underweight individuals was marginally increased by 13% compared with those of normal weight (OR 1.13; 95% CI 1.02, 1.24, p < 0.001) and remained increased after multivariate adjustments. CONCLUSIONS: The current body of evidence shows that the risk of migraine is increased in obese and underweight individuals. Studies are needed to confirm whether interventions that modify obesity status decrease the risk of migraine.