Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjogren's syndrome: a randomized, phase 2, double-blind, placebo-controlled study

OBJECTIVE: The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS. METHODS: This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton’s tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes. RESULTS: The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P = 0.17 vs placebo) vs 42.3% (P = 0.16), 34.7% (P = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2. CONCLUSION: Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03100942

Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial

Objective To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-alpha inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).Methods This 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.Results The proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein <= 3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.Conclusions Filgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab.Pathophysiology and treatment of rheumatic disease

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted as the document was compiled through December 2008. Repeated literature searches were performed by the guideline development staff and writing committee members as new issues were considered. New clinical trials published in peer-reviewed journals and articles through December 2011 were also reviewed and incorporated when relevant. Furthermore, because of the extended development time period for this guideline, peer review comments indicated that the sections focused on imaging technologies required additional updating, which occurred during 2011. Therefore, the evidence review for the imaging sections includes published literature through December 2011

A multi-configurational time-dependent Hartree approach to the direct calculation of thermal rate constants

Matzkies F, Manthe U. A multi-configurational time-dependent Hartree approach to the direct calculation of thermal rate constants. JOURNAL OF CHEMICAL PHYSICS. 1997;106(7):2646-2653

Accurate quantum calculations of thermal rate constants employing MCTDH: H2+OH -> H+H2O and D2+OH -> D+DOH

Matzkies F, Manthe U. Accurate quantum calculations of thermal rate constants employing MCTDH: H2+OH -&gt; H+H2O and D2+OH -&gt; D+DOH. JOURNAL OF CHEMICAL PHYSICS. 1998;108(12):4828-4836

Accurate reaction rate calculations including internal and rotational motion: A statistical multi-configurational time-dependent Hartree approach

Matzkies F, Manthe U. Accurate reaction rate calculations including internal and rotational motion: A statistical multi-configurational time-dependent Hartree approach. JOURNAL OF CHEMICAL PHYSICS. 1999;110(1):88-96

Combined iterative diagonalization and statistical sampling in accurate reaction rate calculations: Rotational effects in O+HCl -> OH+Cl

Matzkies F, Manthe U. Combined iterative diagonalization and statistical sampling in accurate reaction rate calculations: Rotational effects in O+HCl -&gt; OH+Cl. JOURNAL OF CHEMICAL PHYSICS. 2000;112(1):130-136

Iterative diagonalization within the multi-configurational time-dependent Hartree approach: Calculation of vibrationally excited states and reaction rates

Manthe U, Matzkies F. Iterative diagonalization within the multi-configurational time-dependent Hartree approach: Calculation of vibrationally excited states and reaction rates. CHEMICAL PHYSICS LETTERS. 1996;252(1-2):71-76

Rotational effects in the H2+OH -> H+H2O reaction rate: Full-dimensional close-coupling results

Manthe U, Matzkies F. Rotational effects in the H2+OH -&gt; H+H2O reaction rate: Full-dimensional close-coupling results. JOURNAL OF CHEMICAL PHYSICS. 2000;113(14):5725-5731