GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus.

BACKGROUND & AIMS: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). METHODS: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. RESULTS: One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. CONCLUSIONS: Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. CLINICALTRIALS: gov ID: NCT02966834.

Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers.

Linerixibat, an oral small-molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal absorption from the intestine (site of pharmacological action). This study characterized the pharmacokinetics, absorption, metabolism, and excretion of [14C]-linerixibat in humans after an intravenous microtracer concomitant with unlabeled oral tablets and [14C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 hours vs. 0.8 hours). The short intravenous half-life was consistent with high systemic clearance (61.9 l/h) and low volume of distribution (16.3 l). In vitro studies predicted rapid hepatic clearance via cytochrome P450 3A4 metabolism, which predicted human hepatic clearance within 1.5-fold. However, linerixibat was minimally metabolized in humans after intravenous administration: ∼80% elimination via biliary/fecal excretion (>90%-97% as unchanged parent) and ∼20% renal elimination by glomerular filtration (>97% as unchanged parent). Absolute oral bioavailability of linerixibat was exceedingly low (0.05%), primarily because of a very low fraction absorbed (0.167%; fraction escaping first-pass gut metabolism (fg) ∼100%), with high hepatic extraction ratio (77.0%) acting as a secondary barrier to systemic exposure. Oral linerixibat was almost entirely excreted (>99% recovered radioactivity) in feces as unchanged and unabsorbed linerixibat. Consistent with the low oral fraction absorbed and ∼20% renal recovery of intravenous [14C]-linerixibat, urinary elimination of orally administered radioactivity was negligible (<0.04% of dose). Linerixibat unequivocally exhibited minimal gastrointestinal absorption and oral systemic exposure. Linerixibat represents a unique example of high CYP3A4 clearance in vitro but nearly complete excretion as unchanged parent drug via the biliary/fecal route. SIGNIFICANCE STATEMENT: This study conclusively established minimal absorption and systemic exposure to orally administered linerixibat in humans. The small amount of linerixibat absorbed was eliminated efficiently as unchanged parent drug via the biliary/fecal route. The hepatic clearance mechanism was mispredicted to be mediated via cytochrome P450 3A4 metabolism in vitro rather than biliary excretion of unchanged linerixibat in vivo.

Short Physical Performance Battery: What Does Each Sub-Test Measure in Patients with Chronic Obstructive Pulmonary Disease?

OBJECTIVE: To identify phenotypic factors associated with the Short Physical Performance Battery (SPPB) and its individual sub-tests: standing balance, 4­meter gait speed (4mGS) and 5-repetition sit-to-stand (5STS). METHODS: The Evaluation of the Role of Inflammation in non-pulmonary disease manifestations in Chronic Airways disease (ERICA) study recruited adult participants with stable chronic obstructive pulmonary disease (COPD). Proportional odds models identified factors associated with the SPPB, and a principal component analysis (PCA) evaluated how much SPPB variance was explainable by each of its 3 sub-tests. RESULTS: Of 729 enrolled participants, 717 (60% male, mean age 67 years) had full SPPB data. Overall, 76% of patients had some evidence of functional limitations (SPPB total score < 12). Scores < 4 were observed in 71%, 31%, and 22% of participants for the 5STS, 4mGS, and balance sub-tests, respectively. A longer 6-minute walk test and greater quadriceps maximal voluntary contraction decreased the odds of being in a lower score category for SPPB total score and for all 3 sub-tests. Aging, self-reported hypertension and higher dyspnea increased the odds, and being married decreased the odds of being in a lower category for total score. All sub-tests contributed equally to total score. CONCLUSION: Each of the 3 sub-tests contributed independent information to the SPPB, demonstrating their usefulness for assessing COPD when considered together rather than individually. The 5STS sub-test had the greatest variation in scores and may thus have the best discriminatory power for clinical COPD studies of lower limb performance where only one SPPB test is feasible.

Real-world use of rescue inhaler sensors, electronic symptom questionnaires and physical activity monitors in COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterised by airflow obstruction and other morbidities such as respiratory symptoms, reduced physical activity and frequent bronchodilator use. Recent advances in personal digital monitoring devices can permit continuous collection of these data in COPD patients, but the relationships among them are not well understood. Methods: 184 individuals from a single centre of the COPDGene cohort agreed to participate in this 3-week observational study. Each participant used a smartphone to complete a daily symptom diary (EXAcerbations of Chronic pulmonary disease Tool, EXACT), wore a wrist-worn accelerometer to record continuously physical activity and completed the Clinical Visit PROactive Physical Activity in COPD questionnaire. 58 users of metered dose inhalers for rescue (albuterol) were provided with an inhaler sensor, which time stamped each inhaler actuation. Results: Rescue inhaler use was strongly correlated with E-RS:COPD score, while step counts were correlated with neither rescue use nor E-RS:COPD score. Frequent, unpatterned inhaler use pattern was associated with worse respiratory symptoms and less physical activity compared with frequent inhaler use with a regular daily pattern. There was a strong week-by-week correlation among measurements, suggesting that 1 week of monitoring is sufficient to characterise stable patients with COPD. Discussion: The study highlights the interaction and relevance of personal real-time monitoring of respiratory symptoms, physical activity and rescue medication in patients with COPD. Additionally, visual displays of longitudinal data may be helpful for disease management to help drive conversations between patients and caregivers and for risk-based monitoring in clinical trials.

Fibrinogen does not relate to cardiovascular or muscle manifestations in COPD: cross-sectional data from the ERICA study.

Cardiovascular and skeletal muscle manifestations constitute important comorbidities in COPD, with systemic inflammation proposed as a common mechanistic link. Fibrinogen has prognostic role in COPD. We aimed to determine whether aortic stiffness and quadriceps weakness are linked in COPD, and whether they are associated with the systemic inflammatory mediator-fibrinogen. Aortic pulse wave velocity (aPWV), quadriceps maximal volitional contraction (QMVC) force and fibrinogen were measured in 729 patients with stable, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II-IV COPD. The cardiovascular and muscular manifestations exist independently (P=0.22, χ2). Fibrinogen was not associated with aPWV or QMVC (P=0.628 and P=0.621, respectively), making inflammation, as measured by plasma fibrinogen, an unlikely common aetiological factor.

Endocarditis With Fistulization and Rupture of Aortic Root Abscess to the Left Atrium.

BACKGROUND: Infective endocarditis (IE) is a difficult emergency department (ED) diagnosis to make. Symptoms are nonspecific and diverse and the classic triad of fever, anemia, and murmur is rare. Severe IE causes considerable morbidity and mortality and should be diagnosed early. However, echocardiogram is essential but not readily available in the ED and can cause diagnostic delay. CASE REPORT: This case describes severe IE and its unique presentation, diagnostic challenges, and the use of bedside cardiac ultrasonography. A 28-year-old previously healthy male presented with intermittent fevers, arthralgias, and myalgias for 2 weeks. He had twice been evaluated and diagnosed with lumbar back pain. Physical examination revealed moderate respiratory distress, pale skin with a cyanotic right lower extremity, and unequal extremity pulses. He became hypotensive and rapidly deteriorated. Chest x-ray study showed bilateral pulmonary infiltrates with subsequent imaging demonstrating worsening septic emboli. Bedside ultrasound revealed mitral and aortic valve vegetations and a presumed diagnosis of IE with septic embolization was made. Formal echocardiography (ECHO) confirmed IE with an aortic root abscess with rupture and fistulization into the left atrium. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Clinical criteria for IE include blood cultures and ECHO, however, these are often not available to an emergency physician, making IE a diagnostic challenge even in severe cases. The role of bedside ultrasound for IE continues to evolve and its utility in the diagnosis of severe IE is distinctly demonstrated in this case.