BESST was a multi-center, randomized, double-masked, placebo-controlled, parallel treatment groups phase 2 trial to determine whether buspirone, a 5-HT 1a receptor agonist, improved early satiety and postprandial fullness in participants with symptoms of gastroparesis and with at least moderately severe symptoms of early satiety and/or postprandial fullness. After enrollment, participants were treated with buspirone (10 mg three times per day) or a matching placebo for 4 weeks, followed by a 2-week post-treatment washout period. The primary outcome for the study was the 4-week change (week 4 minus baseline) in the 4-item postprandial fullness/early satiety subscore (higher scores indicate worse symptoms) from the Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM) questionnaire. The study hypothesized that 10 mg t.i.d. buspirone treatment would reduce mean postprandial fullness/early satiety symptom severity subscores over 4-weeks compared to treatment with placebo.

The primary objective was to determine whether 4 weeks of treatment with buspirone, a 5-HT 1a receptor agonist, compared to treatment with placebo improved symptoms of postprandial fullness and early satiety as indicated by the change in the PAGI-SYM questionnaire’s postprandial fullness/early satiety subscore (score at 4-weeks minus score at baseline).

The secondary objectives were to determine whether 4 weeks of treatment with buspirone compared to treatment with placebo improved overall and other gastroparesis symptoms, and other participant clinical characteristics (gastric retention, anxiety, depression, quality of life), and to determine the safety and tolerability of buspirone in adult participants with gastroparesis symptoms and at least moderate symptoms of postprandial fullness and early satiety.

The primary outcome measure was the change in the postprandial fullness/early satiety subscore from baseline to 4 weeks. The secondary outcome measures included Gastroparesis Cardinal Symptom Index (GCSI) total score, PAGI-SYM questionnaire subscores and severity scores, Gastrointestinal Symptom Rating Scale (GSRS) total score, Clinical Patient Grading Assessment Scale (CPGAS) score, Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QOL) questionnaire total score, Hospital Anxiety and Depression Scale (HADS) questionnaire anxiety score and depression score, Patient Health Questionnaire 15 Somatic Symptom Severity Scale (PHQ-15) questionnaire total somatization score, SF-36v2 Quality of Life questionnaire Physical Component Score and Mental Component Score, percent gastric emptying retention at 2- and 4-hours, anthropometric measurements (Body Mass Index (BMI)/weight, waist circumference), ECG measures, laboratory measures (ALT, creatinine, glucose), and frequency of side effects and adverse events, as well as severity of adverse events.

• Age 18 to 85 years of age at the initial screening interview
• Symptoms compatible with gastroparesis or other functional gastric disorder for at least 3 months (does not have to be contiguous) prior to the initial screening interview
• Diagnosis of either diabetic or idiopathic gastroparesis
• Delayed or normal gastric emptying retention on screening 4-hour Gastric Emptying Scintigraphy test
• Symptoms of gastroparesis measured by the 9-item PAGI-SYM Gastroparesis Cardinal Symptom Index (GCSI) total score > 2.0 at enrollment
• Symptomatic with postprandial fullness/early satiety severity at enrollment using the PAGI-SYM questionnaire postprandial fullness/early satiety subscore ≥ 3
• Upper endoscopy or upper GI series without ulcers or mass lesions in the 2 years prior to enrollment

• Post-surgical gastroparesis, including prior pyloromyotomy, pyloric resection, vagotomy, bariatric surgery, or post-Nissen fundoplication
• Concurrent use of opiate narcotic analgesics more than 3 days per week
• Significant hepatic injury as defined by alanine aminotransferase (ALT) elevation of greater than 2x ULN or a Child-Pugh score of 10 or greater
• History of significant cardiac disorders (prior heart attack, prior stroke, unstable angina) or significant cardiac arrhythmias or ECG abnormalities defined as history of, or current, arrhythmias including ventricular tachycardia, ventricular fibrillation, and Torsade des Pointes and/or prolonged QTc on ECG (> 450 msec for men and > 470 for women)
• History of chronic kidney disease or on hemodialysis or peritoneal dialysis
• Impaired renal function as defined by estimated glomerular filtration rate (eGFR) < 60 ml/min/1.732 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculator
• Uncontrolled diabetes defined as HbA1c (%) of 10% or more within 60 days of enrollment
• Allergy to buspirone
• Concurrent or prior use (within 30 days) of monoamine oxidase (MAO) inhibitors, benzodiazepines, buspirone, warfarin, haloperidol, and drugs to treat seizures (e.g., phenytoin and carbamazepine)
• For women of child-bearing potential, either pregnancy, planned pregnancy, unwillingness to use effective birth control during the trial, or breast feeding

There was no between-groups difference in the 4-week early satiety/postprandial fullness primary outcome. Buspirone performed better than placebo in participants with severe to very severe bloating at baseline compared to participants with none to moderate bloating. Among individual GCSI symptoms, only bloating appeared to improve with buspirone versus placebo. For participants with moderate to severe early satiety/postprandial fullness and other symptoms of gastroparesis, they did not benefit from buspirone treatment to improve the early satiety/postprandial fullness primary outcome compared with placebo. There was a suggestion of the benefit of buspirone in participants with more severe bloating.