514 research outputs found

    Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

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    Background and Aims: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-őī (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5¬†mg (n=89), 10¬†mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67√óupper limit of normal (ULN), ‚Č•15% ALP decrease from baseline, and total bilirubin ‚ȧ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ‚Č•4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5¬†mg: 57.1%, 10¬†mg: 78.2%) versus placebo (12.5%) (p < 0.0001). ALP normalization occurred in 5.4% (p=0.08) and 27.3% (p < 0.0001) of patients receiving 5 and 10¬†mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10¬†mg significantly reduced mean pruritus NRS versus placebo [10¬†mg: ‚ąí3.14 (p=0.02); placebo: ‚ąí1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5¬†mg: 23.4% (p=0.0008); 10¬†mg: 16.7% (p=0.03); placebo: 4%]. There were no serious treatment-related adverse events. Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10¬†mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated

    Nomenclature, Diagnosis and Management of Drug-induced Autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

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    Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarizes the major topics discussed at a joint International Conference held between Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and often resolve spontaneously after stopping the culprit drug whereas patients with AIH mostly need long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements such as Khat and Tinospora cordifolia have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow a precise diagnosis and similarly, there is no single feature which is diagnostic of AIH. A management algorithm is proposed. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterization of this condition

    Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report

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    Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition

    Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

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    Background and aimsENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-őī (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and resultsPatients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67√óupper limit of normal (ULN), ‚Č•15% ALP decrease from baseline, and total bilirubin ‚ȧ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ‚Č•4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events.ConclusionsPatients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated

    Open‚Äźlabel, clinical trial extension:Two‚Äźyear safety and efficacy results of seladelpar in patients with primary biliary cholangitis

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    SummaryBackgroundSeladelpar is a potent and selective peroxisome proliferator‚Äźactivated receptor‚Äźőī agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti‚Äźcholestatic, anti‚Äźinflammatory and anti‚Äźpruritic effects.AimsTo evaluate the¬†long‚Äźterm safety and efficacy of seladelpar in patients with PBC.MethodsIn an open‚Äźlabel, international, long‚Äźterm extension study, patients with PBC completing seladelpar lead‚Äźin studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10‚ÄČmg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non‚Äźalcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2‚ÄČyears.ResultsThere were no serious treatment‚Äźrelated adverse events observed among 106 patients treated with seladelpar for up to 2‚ÄČyears. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2‚ÄČyears of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] &lt;1.67‚ÄČ√ó‚ÄČULN, ‚Č•15% decrease in ALP, and total bilirubin ‚ȧULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2.ConclusionsSeladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017‚Äź003910‚Äź16.</jats:sec

    Rates of Asymptomatic COVID-19 Infection and Associated Factors in Olmsted County, Minnesota, in the Prevaccination Era

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    Objective: To estimate rates and identify factors associated with asymptomatic COVID-19 in the population of Olmsted County during the prevaccination era. Patients and Methods: We screened first responders (n=191) and Olmsted County employees (n=564) for antibodies to SARS-CoV-2 from November 1, 2020 to February 28, 2021 to estimate seroprevalence and asymptomatic infection. Second, we retrieved all polymerase chain reaction (PCR)-confirmed COVID-19 diagnoses in Olmsted County from March 2020 through January 2021, abstracted symptom information, estimated rates of asymptomatic infection and examined related factors. Results: Twenty (10.5%; 95% CI, 6.9%-15.6%) first responders and 38 (6.7%; 95% CI, 5.0%-9.1%) county employees had positive antibodies; an additional 5 (2.6%) and 10 (1.8%) had prior positive PCR tests per self-report or medical record, but no antibodies detected. Of persons with symptom information, 4 of 20 (20%; 95% CI, 3.0%-37.0%) first responders and 10 of 39 (26%; 95% CI, 12.6%-40.0%) county employees were asymptomatic. Of 6020 positive PCR tests in Olmsted County with symptom information between March 1, 2020, and January 31, 2021, 6% (n=385; 95% CI, 5.8%-7.1%) were asymptomatic. Factors associated with asymptomatic disease included age (0-18 years [odds ratio {OR}, 2.3; 95% CI, 1.7-3.1] and >65 years [OR, 1.40; 95% CI, 1.0-2.0] compared with ages 19-44 years), body mass index (overweight [OR, 0.58; 95% CI, 0.44-0.77] or obese [OR, 0.48; 95% CI, 0.57-0.62] compared with normal or underweight) and tests after November 20, 2020 ([OR, 1.35; 95% CI, 1.13-1.71] compared with prior dates). Conclusion: Asymptomatic rates in Olmsted County before COVID-19 vaccine rollout ranged from 6% to 25%, and younger age, normal weight, and later tests dates were associated with asymptomatic infection

    A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis

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    BACKGROUND & AIMS: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ‚Č•1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. METHODS: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8. RESULTS: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ¬Ī standard error ALP reductions from baseline were 26 ¬Ī 2.8%, 33 ¬Ī 2.6%, and 41 ¬Ī 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ‚ȧ0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP \u3c1.67xULN, ‚Č•15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. CONCLUSIONS: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores
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