Current treatments for persistent or chronic immune thrombocytopenia (ITP) are limited by inadequate response, toxicity, and impaired quality of life. The Bruton tyrosine kinase inhibitor rilzabrutinib was evaluated to further characterize safety and durability of platelet response. LUNA2 Part B is a multicenter, phase 1/2 study in adults with ITP (≥ 3 months duration, platelet count < 30 × 109/L) who failed ≥ 1 ITP therapy (NCT03395210, EudraCT 2017-004012-19). Oral rilzabrutinib 400 mg bid was given over 24 weeks, with optional long-term extension (LTE). Primary endpoints were safety and platelet counts ≥ 50 × 109/L on ≥ 8 of the last 12 weeks of main treatment without rescue medication. From 22 March2018 to 31 January2023, 26 patients were enrolled. Patients had baseline median platelet count 13 × 109/L, ITP duration 10.3 years, and six prior ITP therapies (46% splenectomized). Nine (35%) patients achieved the primary endpoint. Platelet counts ≥ 50 × 109/L or ≥ 30 × 109/L and doubling from baseline without rescue therapy were sustained for a mean 9.3 weeks. 11 (42%) LTE-eligible patients were ongoing with median LTE platelet > 80 × 109/L. Three (12%) patients received rescue medication during main treatment, none in LTE. Clinically meaningful improvements were observed in fatigue and women's health. With a median treatment duration of 167 days (main treatment), 16 (62%) patients had ≥ 1 treatment-related adverse event (AE), mainly grade 1, including diarrhea (35%), headache (23%), and nausea (15%). There was no treatment-related grade ≥ 2 bleeding/thrombotic events/infections, serious AE, or death. Rilzabrutinib continues to demonstrate durable platelet responses with favorable safety profile in previously treated ITP patients. Trial Registration: NCT03395210, EudraCT 2017-004012-19.

• MeSH
• aplikace orální MeSH
• dospělí MeSH
• idiopatická trombocytopenická purpura * farmakoterapie   MeSH
• inhibitory proteinkinas * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• inhibitory tyrosinkinasy MeSH
• lidé středního věku MeSH
• lidé MeSH
• počet trombocytů MeSH
• proteinkinasa BTK * antagonisté a inhibitory   MeSH
• pyrazoly terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH

BACKGROUND: Hyperkalemia (HK) is associated with suboptimal renin-angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase. METHODS: Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria). RESULTS: Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%). CONCLUSIONS: In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in.

• MeSH
• antagonisté mineralokortikoidních receptorů * terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin terapeutické užití   MeSH
• hyperkalemie * farmakoterapie   krev   MeSH
• inhibitory ACE terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymery * terapeutické užití   MeSH
• renin-angiotensin systém účinky léků   MeSH
• senioři MeSH
• srdeční selhání * farmakoterapie   MeSH
• tepový objem účinky léků   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.

• MeSH
• idiopatická trombocytopenická purpura * farmakoterapie   chemicky indukované   MeSH
• krvácení chemicky indukované   MeSH
• lidé MeSH
• receptory Fc MeSH
• thrombopoetin terapeutické užití   MeSH
• trombocytopenie * chemicky indukované   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH

BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disease of the peripheral nerves, with significant unmet treatment needs. Clinical trials in CIDP are challenging; thus, new trial designs are needed. We present design of an open-label phase 2 study (NCT04658472) evaluating efficacy and safety of SAR445088, a monoclonal antibody targeting complement C1s, in CIDP. METHODS: This phase 2, proof-of-concept, multicenter, open-label trial will evaluate the efficacy, and safety of SAR445088 in 90 patients with CIDP across three groups: (1) currently treated with standard-of-care (SOC) therapies, including immunoglobulin or corticosteroids (SOC-Treated); (2) refractory to SOC (SOC-Refractory); and (3) naïve to SOC (SOC-Naïve). Enrolled participants undergo a 24-week treatment period (part A), followed by an optional treatment extension for up to an additional 52 weeks (part B). In part A, the primary endpoint for the SOC-Treated group is the percentage of participants with a relapse after switching from SOC to SAR445088. The primary endpoint for the SOC-Refractory and SOC-Naïve groups is the percentage of participants with a response, compared to baseline. Secondary endpoints include safety, tolerability, immunogenicity, and efficacy of SAR445088 during 12-week overlapping period (SOC-Treated). Part B evaluates long-term safety and durability of efficacy. Data analysis will be performed using Bayesian statistics (predefined efficacy thresholds) and historical data-based placebo assumptions to support program decision-making. INTERPRETATION: This innovative trial design based on patient groups and Bayesian statistics provides an efficient paradigm to evaluate new treatment candidates across the CIDP spectrum and can help accelerate development of new therapies.

• MeSH
• Bayesova věta MeSH
• chronická zánětlivá demyelinizační polyneuropatie * farmakoterapie   MeSH
• hormony kůry nadledvin terapeutické užití   MeSH
• komplement C1s MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• ověření koncepční studie MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• kazuistiky MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

• MeSH
• aplikace orální MeSH
• idiopatická trombocytopenická purpura * farmakoterapie   MeSH
• inhibitory proteinkinas * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• počet trombocytů MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common, heterogeneous, immune-mediated neuropathy, characterized by predominant demyelination of motor and sensory nerves. CIDP follows a relapsing-remitting or a progressive course and causes substantial disability. The pathogenesis of CIDP involves a complex interplay of multiple aberrant immune responses, creating a pro-inflammatory environment, subsequently inflicting damage on the myelin sheath. Though the exact triggers are unclear, diverse immune mechanisms encompassing cellular and humoral pathways are implicated. The complement system appears to play a role in promoting macrophage-mediated demyelination. Complement deposition in sural nerve biopsies, as well as signs of increased complement activation in serum and CSF of patients with CIDP, suggest complement involvement in CIDP pathogenesis. Here, we present a comprehensive overview of the preclinical and clinical evidence supporting the potential role of the complement system in CIDP. This understanding furnishes a strong rationale for targeting the complement system to develop new therapies that could serve the unmet needs of patients affected by CIDP, particularly in those refractory to standard therapies.

• MeSH
• biopsie MeSH
• chronická zánětlivá demyelinizační polyneuropatie * diagnóza   farmakoterapie   MeSH
• lidé MeSH
• makrofágy patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

• MeSH
• antagonisté mineralokortikoidních receptorů škodlivé účinky   MeSH
• draslík MeSH
• hyperkalemie * farmakoterapie   komplikace   MeSH
• lidé MeSH
• renin-angiotensin systém MeSH
• srdeční selhání * komplikace   farmakoterapie   MeSH
• tepový objem MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND/OBJECTIVE: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) patients. METHODS: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features. RESULTS: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features. CONCLUSIONS: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

• MeSH
• analýza rozptylu MeSH
• demence s Lewyho tělísky komplikace   diagnóza   MeSH
• kognitivní poruchy diagnóza   etiologie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezinárodní spolupráce MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• záznam o duševním stavu MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

• MeSH
• dospělí MeSH
• HIV infekce farmakoterapie   virologie   MeSH
• HIV-1 účinky léků   genetika   MeSH
• inhibitory HIV-proteasy farmakologie   MeSH
• inhibitory reverzní transkriptasy farmakologie   MeSH
• látky proti HIV farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mutace MeSH
• prevalence MeSH
• virová léková rezistence genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors.

• MeSH
• epidemie statistika a číselné údaje   MeSH
• fylogeografie MeSH
• HIV infekce epidemiologie   přenos   virologie   MeSH
• HIV-1 * MeSH
• lidé MeSH
• lidské činnosti MeSH
• shluková analýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH