Leflunomide, alone or in combination, has potential utility in treatment of complex CMV syndromes and in long-term suppression of viremia. The optimal duration of therapy and the balance of risks and benefits are not yet known.
Objective:
In the primary analysis of the phase 2b VESTA study, oral fezolinetant reduced frequency and severity of menopausal vasomotor symptoms (VMS) compared with placebo. This secondary analysis evaluates effects of fezolinetant on responder rates and patient-reported outcomes (PROs).
Methods:
In this 12-week, double-blind study, postmenopausal women with moderate/severe VMS were randomized to fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo. Proportion of responders was based on reductions in VMS from daily diary records.
P
values for comparisons between active treatment and placebo were calculated using logistic regression. Changes from baseline in PROs (Menopause-Specific Quality of Life questionnaire, Hot Flash-Related Daily Interference Scale, Greene Climacteric Scale) were conducted using a mixed model for repeated measurements and compared post hoc with published minimally important differences (MIDs).
Results:
Of 356 women randomized, 352 were treated and analyzed. A greater proportion of women receiving fezolinetant versus placebo met definitions of response at week 12. For all doses, mean changes from baseline in Menopause-Specific Quality of Life questionnaire VMS scores exceeded the MID (1.2) at weeks 4 (placebo: −1.8; fezolinetant: range, −1.9 to −3.6) and 12 (placebo: −2.3; fezolinetant: range, −2.9 to −4.4). Mean changes in Hot Flash-Related Daily Interference Scale at weeks 4 (placebo: −2.2; fezolinetant: range, −2.5 to −3.8) and 12 (placebo: −2.9; fezolinetant: range, −3.3 to −4.3) exceeded the MID (1.76). Greene Climacteric Scale-VMS domain scores improved for most fezolinetant doses versus placebo (week 4, placebo: −1.7; fezolinetant: range, −2.1 to −3.3; week 12, placebo: −2.1; fezolinetant: range, −2.7 to −3.6).
Conclusions:
Oral fezolinetant was associated with higher responder rates than placebo and larger improvements in QoL and other PRO measures, including a reduction in VMS-related interference with daily life.
Introduction: This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients.Methods: Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using leastsquares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE? (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE? were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. Results: In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE? in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE? : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE? (HR 1.13,
Background
Cytomegalovirus (CMV) is a complication of allogeneic haematopoietic cell transplantation (allo-HCT). ASP0113, a DNA-based vaccine, contains two plasmids encoding human CMV glycoprotein B and phosphoprotein 65 (pp65). We assessed ASP0113 in CMV-seropositive allo-HCT recipients.
Methods
In this phase 3, randomised, placebo-controlled study, CMV-seropositive allo-HCT recipients were randomly assigned (1:1) via interactive response technology to receive five injections of 1 mL of 5 mg/mL ASP0113 or placebo. The pharmacist and designated staff were unblinded. Masked syringes maintained the blind for patients and study personnel. Efficacy and safety analyses included patients who received ≥1 dose of ASP0113/placebo. The primary efficacy endpoint was the proportion of allo-HCT recipients with composite all-cause mortality and adjudicated CMV end-organ disease (EOD) by 1 year post-transplant. ClinicalTrials.gov: NCT01877655 (not recruiting).
Findings
Patients were recruited between Sept 11, 2013 and Sept 21, 2016. Overall, 501 patients received ≥1 dose of ASP0113 (
n
= 246) or placebo (
n
= 255). The proportion of patients with composite all-cause mortality and adjudicated CMV EOD by 1 year post-transplant was 35.4% (
n
= 87) with ASP0113 and 30•2% (
n
= 77) with placebo (odds ratio 1.27; 95% confidence interval: 0.87 to 1.85;
p
= 0.205). Incidence of injection site-related treatment-emergent adverse events (TEAEs) was higher with ASP0113 than placebo. Overall incidence and severity of other TEAEs was similar between groups. T-cell response to pp65 increased over time and was greater with placebo than ASP0113 (
p
= 0.027).
Interpretation
ASP0113 did not reduce overall mortality or CMV EOD by 1 year post-transplant. Safety findings were similar between groups.
Funding
Astellas Pharma Global Development, Inc .
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