An Evaluation of the Effectiveness of Risk Minimization Measures for Tigecycline in the European Union

Background: Risk minimization measures (RMM) were implemented from February 2011 in the European Union to address risks of superinfection, off-label use and lack of efficacy associated with tigecycline. The objective of this study was to evaluate RMM effectiveness by describing prescription patterns among adults and children treated with any dose of tigecycline for any indication pre- and post-RMM implementation; incidence proportions of superinfection and lack of efficacy among adults treated with approved doses of tigecycline for complicated intra-abdominal infection and complicated skin and soft tissue infection were also evaluated. Methods: This was an observational, retrospective chart-abstraction study, including charts from 777 patients (399 pre-RMM, 378 post-RMM) at 13 sites across Austria, Germany, Italy, Greece and the United Kingdom (UK). Potential superinfection and lack of efficacy cases among those using tigecycline for on-label indication, age, dose, and duration were adjudicated. The distribution of indications for tigecycline was analyzed overall (i.e. across both study periods) and stratified by study period. Numbers and incidence proportions of superinfection and lack of efficacy cases (potential and adjudicated) were calculated overall and by study period. Results: Off-label use (indication or age) decreased from 54.2% [95% confidence interval (95% CI): 49.0, 59.3%] pre-RMM to 35.7% (95% CI 30.4, 41.2%) post-RMM. Overall, 45.7% (95% CI 41.9, 49.5%) of patients were prescribed tigecycline off-label; the most commonly reported off-label indications were characterized as \u201cother\u201d (25.5%), hospital acquired pneumonia (8.2%), other pneumonia (6.3%), bacteremia (5.2%) and diabetic foot infection (1.5%). Across study periods, incidence proportions of definite or probable superinfection and lack of efficacy in adults treated for approved indications, authorized treatment doses and duration were 4.5% (95% CI 2.1, 8.4%) and 5.5% (95% CI 2.8, 9.7%), respectively. Conclusions: Off-label use of tigecycline decreased following RMM implementation. Overall incidence proportions of definite or probable superinfection and lack of efficacy were low. EU PAS register number: EUPAS3674

No evidence for hypogammaglobulinemia in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with ravulizumab.

IntroductionRavulizumab (ALXN1210) is a long-lasting recycling IgG monoclonal antibody with an increased affinity for the neonatal Fc receptor (FcRn). The FcRn is essential for regulating IgG homeostasis. Saturation of the FcRn pathway is seen under high IgG doses as they compete with endogenous IgG to bind the FcRn by their Fc regions, resulting in enhanced IgG clearance.Patients/methodsBetween Jan 2016 and Jun 2019 (median observation time 21.6 months (6-37.7 months)) serum IgG concentrations and IgG1-4 subclasses were evaluated over a longitudinal course (post-hoc analysis) in 12 ravulizumab-treated adult patients with paroxysmal nocturnal hemoglobinuria (PNH) (58% (7/12) males, median age 50 years (yrs) (18-70 yrs)). All patients were enrolled in one of the three ravulizumab-PNH-related trials (201-, 301-, or 302-study) at the University Hospital Essen.ResultsBaseline IgG concentrations were documented in 11 out of the 12 patients prior to ravulizumab treatment (median IgG 9.9 g/L (5-13.5 g/L)). In two female patients a clinically not relevant hypogammaglobulinemia with an associated IgG1 or a combined IgG1/IgG2 deficiency prior to treatment was documented. The data were further stratified with regard to various treatment intervals as multiple analyses were obtained. Throughout observation time IgG concentrations remained within physiologic ranges with no evidence of a treatment-related IgG depletion (median IgG at study endpoint 10.1 g/L (6-13.4 g/L)).ConclusionIn ravulizumab-treated PNH patients, IgG and IgG subclass levels which are regulated by the FcRn remained unaffected. Therefore, no treatment associated hypogammaglobulinemia is to be feared under chronic ravulizumab therapy

Clinical response and mortality in tigecycline complicated intra-abdominal infection and complicated skin and soft-tissue infection trials

An imbalance in all-cause mortality was noted in tigecycline phase 3 and 4 comparative clinical trials across all studied indications. We investigated clinical failure and mortality in phase 3 and 4 complicated skin and soft-tissue infection (cSSTI) and complicated intra-abdominal infection (cIAI) tigecycline trials using descriptive analyses of a blinded adjudication of mortality and multivariate regression analyses. Attributable mortality analyses of cSSTI revealed death due to infection in 0.1% of each treatment group (P = 1.000). In cIAI, there were no significant differences between tigecycline (1.2%) and comparator (0.7%) subjects who died due to infection (P = 0.243). For cIAI clinical failure, treatment interaction with organ dysfunction was observed with no difference observed between clinical cure for tigecycline (85.4%) and comparator (76.7%) treatment groups (odds ratio = 0.58, 95% confidence interval 0.28-1.19). Tigecycline-treated subjects had more adverse events of secondary pneumonias (2.1% vs. 1.2%) and more adverse events of secondary pneumonias with an outcome of death (0.5% vs. 0.1%). These analyses do not suggest that tigecycline is a factor either for failure (cSSTI and cIAI studies) or for death (cIAI studies)

One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naive to complement inhibitor therapy: open-label extension of a randomized study

Background: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment. Methods: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics. Results: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab-ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab-ravulizumab, 64.5%; eculizumab-ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time. Conclusion: In adult, complement inhibitor-naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control. Trial registration: ClinicalTrials.gov identifier, NCT02946463.status: publishe