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Context Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. Objective This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS. Methods This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed. Results Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/day were −0.80 (0.13) and −0.39 (0.12) nmol/L vs −0.05 (0.10) nmol/L with placebo (P .10). Fezolinetant was well tolerated. Conclusion Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.

Many patients with rheumatoid arthritis (RA) are not able to achieve long-term disease remission. This phase 2a study (NCT02884635) evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of the novel, oral, gonadotropin-releasing hormone antagonist, ASP1707, in combination with methotrexate (MTX) for treatment of RA. Postmenopausal women with RA who had been receiving MTX for ≥90 days were randomized to ASP1707 30 mg twice daily or placebo for 12 weeks. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Secondary endpoints included: ACR20, ACR50, and ACR70 response rates; disease activity score (DAS)28-CRP; DAS28-ESR; Tender or Swollen Joint Counts; and remission rates. Of 105 patients screened, 72 were randomized to ASP1707 30 mg twice daily (n = 37) or placebo (n = 35). ASP1707 did not improve ACR20, ACR50, or ACR70 response rates at any time point and did not improve any secondary efficacy endpoint. Plasma luteinizing hormone (LH) concentration decreased >90% in >90% of patients receiving ASP1707, with a rapid decrease to

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to 80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

Aims To evaluate the efficacy and safety of mirabegron in children and adolescents (aged 3 to

Introduction: Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women

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 . ispartof: ECLINICALMEDICINE vol:33 ispartof: location:England status: published

Background Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune condition characterized by joint synovial inflammation. Current treatments include methotrexate (MTX), biologic agents, and Janus kinase (JAK) inhibitors. However, these agents are not efficacious in all patients and there are concerns regarding side effects and risk of infection as these treatments target immune-related pathways. Overexpression and activation of integrin alpha-9 (α9) on fibroblast-like synoviocytes are associated with RA disease onset and exacerbation. The humanized immunoglobulin G1 monoclonal antibody ASP5094 was designed to inhibit human α9 and is currently under investigation for the treatment of RA. Methods This phase 2a, multicenter, randomized, placebo-controlled, double-blind, parallel-group study (NCT03257852) evaluated the efficacy, safety, and biological activity of intravenous ASP5094 10 mg/kg in patients with moderate to severe RA that was refractory to MTX. Patients received ASP5094 or placebo every 4 weeks for a total of three administrations. Both treatment groups used concomitant MTX. The primary efficacy endpoint was the proportion of patients who responded per American College of Rheumatology 50% improvement using C-reactive protein (ACR50-CRP) after 12 weeks of treatment. Biological activity of ASP5094 was assessed via pharmacokinetics and pharmacodynamics of known downstream effectors of α9. Safety was also assessed. Results Sixty-six patients were enrolled and randomized to placebo (n = 33) or ASP5094 (n = 33). In the primary efficacy analysis, ACR50-CRP response rates were 6.3% and 18.2% at week 12 in the ASP5094 and placebo groups, respectively; a difference of − 11.9, which was not significant (2-sided P value = 0.258). No trends in ACR50 response rates were observed in subgroups based on demographics or baseline disease characteristics, and no significant differences between placebo and ASP5094 were identified in secondary efficacy or pharmacodynamic endpoints, despite achievement of target serum concentrations of ASP5094. Most treatment-emergent adverse events were mild to moderate in severity, and ASP5094 was considered safe and well tolerated overall. Conclusion Although no notable safety signals were observed in this study, ASP5094 was not efficacious in patients with moderate to severe RA with an inadequate response to MTX. Trial registration ClinicalTrials.gov, NCT03257852. Registered on 22 Aug. 2017

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.

Cytomegalovirus (CMV) is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. ASP0113 is a DNA-based vaccine for the prevention of CMV-related mortality and end-organ disease in transplant recipients. The efficacy, safety, and immunogenicity of ASP0113 was assessed in a phase 2, double-blind, placebo-controlled study in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Transplant recipients were randomized (1:1) to receive 5 doses of ASP0113 (5 mg; n = 75) or placebo (n = 74) on Days 30/60/90/120/180 posttransplant, and they received prophylactic valganciclovir/ganciclovir 10-100 days posttransplant. The primary endpoint was the proportion of transplant recipients with CMV viremia ≥1000 IU/mL from Day 100 through to 1 year after the first study vaccine injection. There was no statistically significant difference in the primary endpoint between the ASP0113 and placebo groups (odds ratio 0.79, 95% confidence interval 0.43-1.47; P = .307). There were similar numbers of transplant recipients with treatment-emergent adverse events between groups; however, more transplant recipients reported injection site pain in the ASP0113 group compared with placebo. ASP0113 did not demonstrate efficacy in the prevention of CMV viremia in this CMV-seronegative kidney transplant population, but demonstrated a safety profile similar to placebo. ClinicalTrials.gov registration number: NCT01974206.

Summary Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

Isavuconazonium sulfate is the water‐soluble prodrug of the active triazole isavuconazole. Two phase 1 studies were conducted to identify the metabolic profile and mass balance of isavuconazole and BAL8728 (inactive cleavage product). Seven subjects in study 1 (isavuconazole mass balance) received a single oral dose of [cyano‐14C]isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridinylmethyl‐14C]isavuconazonium sulfate corresponding to 75 mg BAL8728. Pharmacokinetic parameters of radioactivity in whole blood and plasma and of isavuconazole and BAL8728 in plasma were assessed. Radioactivity ratio of blood/plasma, percentage of dose, and cumulative percentage of radioactive dose recovered in urine and feces for isavuconazole and BAL8728 were assessed. Metabolic profiling was carried out by high‐performance liquid chromatography and mass spectrometry. Mean plasma isavuconazole pharmacokinetic parameters included apparent clearance (2.3 ± 0.7 L/h), apparent volume of distribution (301.8 ± 105.7 L), and terminal elimination half‐life (99.9 ± 44.6 hours). In study 1, isavuconazole‐derived radioactivity was recovered approximately equally in urine and feces (46.1% and 45.5%, respectively). In study 2, BAL8728‐derived radioactivity was predominantly recovered in urine (96.0%). Isavuconazole (study 1) and M4 (cleavage metabolite of BAL8728; study 2) were the predominant circulating components of radioactivity in plasma.

This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (n = 12 each in groups of nonelderly males and females and elderly males and females)., This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (n = 12 each in groups of nonelderly males and females and elderly males and females). All subjects received a single oral dose of 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole). PK samples were collected for analysis of isavuconazole plasma concentrations from the predose time point up to 336 h postdose. Data were analyzed using population pharmacokinetic (PPK) analysis. The resulting PPK model included two compartments with Weibull absorption function as well as interindividual variability with respect to clearance, intercompartment clearance, volumes of central and peripheral compartments, and two Weibull absorption parameters, RA and KAMAX. The PPK analysis showed that elderly females had the highest exposure versus males (ratio of total area under the time-concentration curve [AUC], 138; 90% confidence interval [CI], 118 to 161) and versus nonelderly females (ratio of AUC, 147; 90% CI, 123 to 176). Higher exposures in elderly females were not associated with significant toxicity or treatment-emergent adverse events, as measured in this study. No dose adjustments appear to be necessary based on either age group or sex even with an increase in exposure for elderly females. (This study has been registered at ClinicalTrials.gov under registration no. NCT01657890.)

The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double‐blind study in healthy individuals who received isavuconazole (after 2‐day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post‐hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L‐type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein‐bound isavuconazole in vivo. In the phase I study (n = 161), isavuconazole shortened the QT interval in a dose‐ and plasma concentration‐related manner. There were no serious treatment‐emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study (n = 257). Isavuconazole was associated with a shortened cardiac QT interval.

This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration-time curves from time 0 to infinity of S- and R-warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S- and R-warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment-emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.

This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration-time curves (AUC0-∞ ) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (Cmax ) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cmax of mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism.

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUCτ ) during a dosing interval by 90% and maximum concentration (Cmax ) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0-∞ ) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 μg/1 mg; CYP3A4 substrate). Following coadministration, AUC0-∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.

This phase 1, open-label study evaluated the pharmacokinetic effects of coadministration of the antifungal agent, isavuconazole (administered as its water-soluble prodrug isavuconazonium sulfate), with the antiretroviral agent lopinavir/ritonavir in healthy adults. In part 1, 13 subjects were randomized to 2 arms to receive multiple doses of oral isavuconazole 100 mg either alone or with lopinavir/ritonavir 400/100 mg. In part 2, a different group of 55 subjects were randomized to 3 arms to receive multiple doses of oral isavuconazole 200 mg, either alone or with lopinavir/ritonavir 400/100 mg, or to receive oral lopinavir/ritonavir 400/100 mg alone. Mean area under the concentration-time curve (AUC) following the last dose (AUCτ ) and Cmax of isavuconazole increased by 113% and 96% in part 1 and by 96% and 74% in part 2 in the presence vs absence of lopinavir/ritonavir, respectively. Mean AUCτ and Cmax of lopinavir were 27% and 23% lower, and mean AUCτ and Cmax of ritonavir were 31% and 33% lower in the presence vs absence of isavuconazole, respectively. Mild to moderate gastrointestinal disorders were the most common adverse events experienced. These findings indicate that coadministration of lopinavir/ritonavir with isavuconazole can decrease the exposure of lopinavir/ritonavir and increase the exposure of isavuconazole. Patients should be monitored for reduced antiviral efficacy if these agents are coadministered.

This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein-1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion-transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P-glycoprotein (P-gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P-gp substrate), digoxin (0.5 mg; P-gp substrate), metformin (850 mg; OCT1, OCT2, and MATE1 substrate), or methotrexate (7.5 mg; BCRP, OAT1, and OAT3 substrate) in the presence and absence of clinical doses of isavuconazole (200 mg 3 times a day for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased mean area under the plasma concentration-time curves (90% confidence interval) of atorvastatin, digoxin, and metformin to 137% (129, 145), 125% (117, 134), and 152% (138, 168) and increased mean maximum plasma concentrations to 103% (88, 121), 133% (119, 149), and 123% (109, 140), respectively. Methotrexate parameters were unaffected by isavuconazole. There were no serious adverse events. These findings indicate that isavuconazole is a weak inhibitor of P-gp, as well as OCT1, OCT2, MATE1, or a combination thereof but not of BCRP, OATP1B1, OAT1, or OAT3.

This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration-time curves (AUC∞) and maximum concentrations (Cmax) as follows: bupropion, AUC∞ reduced 42%, Cmax reduced 31%; repaglinide, AUC∞ reduced 8%, Cmax reduced 14%; caffeine, AUC∞ increased 4%, Cmax reduced 1%; dextromethorphan, AUC∞ increased 18%, Cmax increased 17%; R-methadone, AUC∞ reduced 10%, Cmax increased 3%; S-methadone, AUC∞ reduced 35%, Cmax increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2-, CYP2C8-, or CYP2D6-mediated metabolism.

This pooled analysis evaluated the relationship of isavuconazole and voriconazole MICs of Aspergillus pathogens at baseline with all-cause mortality and clinical outcomes following treatment with either drug in the SECURE and VITAL trials. Isavuconazole and voriconazole may have had reduced efficacy against pathogens with drug MICs of ≥16 µg/ml, but there was no relationship with clinical outcomes in cases where the MIC was

Supplemental Digital Content is available in the text., Background: Amphotericin B deoxycholate (AmB-D) is standard of care treatment for neonatal invasive candidiasis (IC). Micafungin (MCA) has broad-spectrum fungicidal activity against Candida spp. We compared the efficacy and safety of intravenous MCA with intravenous AmB-D and assessed the pharmacokinetics of MCA in infants >2–120 days of age with proven IC in a phase 3, randomized, double-blind, multicenter, parallel-group, noninferiority study (NCT00815516). Methods: Infants were randomized 2:1 to MCA (10 mg/kg/d) or AmB-D (1 mg/kg/d) for ≥21 days. Primary efficacy endpoint was fungal-free survival (FFS) 1 week after last study drug dose. MCA population pharmacokinetics included simulated area under the curve (AUC) at steady state and maximum plasma concentration after 2-hour infusion. AUC pharmacodynamic target exposure was 170 µg·h/mL. Results: Thirty infants received MCA (n = 20) or AmB-D (n = 10). The trial was terminated early because of slow recruitment. FFS was observed in 12 of 20 [60%; 95% confidence interval (CI): 36%–81%] MCA-group infants and in 7 of 10 (70%; 95% CI: 35%–93%) AmB-D-group infants. The most common treatment-emergent adverse events were anemia [MCA: n = 9 (45%); AmB-D: n = 3 (30%)] and thrombocytopenia [n = 2 (10%) and n = 3 (30%), respectively]. Model-derived mean AUC at steady state for MCA was 399.3 ± 163.9 µg·h/mL (95% prediction interval: 190.3–742.3 µg/mL); steady state and maximum plasma concentration after 2-hour infusion was 31.1 ± 10.5 µg/mL (95% prediction interval: 17.0–49.7 µg/mL). MCA exposures were above the AUC pharmacodynamic target exposure. Conclusions: Within the study limitations, infants with IC treated with MCA achieved similar FFS compared with AmB-D. Both agents were safe and well tolerated.

Data regarding treatment of rare invasive fungal diseases (IFDs) are scarce. We documented the efficacy and safety of isavuconazole for treatment of uncommonly diagnosed IFDs. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily). The primary outcome was overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by rare or unidentified pathogens. Twenty-six patients with IFDs caused by rare moulds (n = 17), non-Candida yeasts (n = 2), or unidentified moulds (n = 7) were enrolled (median treatment duration [range], 114.5 [1-496]) days. Overall treatment success was observed in 11/26 (42.3%), 10/26 (38.5%), and 15/26 (57.7%) patients at Days 42, 84, and EOT, respectively. All-cause mortality rates were 2/26 patients (7.7%) at Day 42 and 4/26 patients (15.4%) at Day 84; another two patients died after Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 15 patients (57.7%) had serious TEAEs, and TEAEs led to discontinuation of isavuconazole in four patients (15.4%). Isavuconazole may be efficacious for treatment of a range of rare IFDs.

Historically, baseline neutropenia and lack of neutrophil recovery have been associated with poor outcomes in invasive aspergillosis (IA). It is unclear how treatment with the new Aspergillus-active triazoles isavuconazole and voriconazole affects outcomes in neutropenic patients with IA.A post hoc analysis of the Phase 3 SECURE trial assessed patients with neutropenia (neutrophil count0.5 × 109/L for10 days at baseline) with IA (proven/probable) who had received either isavuconazole or voriconazole. The primary endpoint was all-cause mortality (ACM) through day 42. ACM in patients with resolved versus unresolved neutropenia at day 7 and overall success at end of treatment (EOT) were also assessed.One hundred and forty-two patients with neutropenia and IA were included (isavuconazole n = 78, voriconazole n = 64). ACM through day 42 (primary endpoint), day 7 and EOT were higher for patients with unresolved versus resolved neutropenia at each timepoint (day 42, unresolved: 45.0% isavuconazole, 45.2% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; day 7, unresolved: 31.0% isavuconazole, 29.8% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; EOT, unresolved: 48.6% isavuconazole, 36.4% voriconazole; resolved: 5.0% isavuconazole, 14.3% voriconazole). ACM was significantly higher for isavuconazole-treated patients with unresolved versus resolved neutropenia (day 7, P = 0.031; day 42, P 0.001; EOT, P 0.001). In voriconazole-treated patients, ACM was significantly higher among patients with unresolved versus resolved neutropenia at day 42 (P = 0.002) and numerically higher at day 7 and EOT (P 0.05 for both).Isavuconazole had comparable efficacy and safety to voriconazole in neutropenic patients with IA. Resolution of neutropenia was associated with improved outcomes.

Background: To evaluate the psychometric properties of the newly developed seven-item Irritable Bowel Syndrome – Diarrhea predominant (IBS-D) Daily Symptom Diary and four-item Event Log using phase II clinical trial safety and efficacy data in patients with IBS-D. This instrument measures diarrhea (stool frequency and stool consistency), abdominal pain related to IBS-D (stomach pain, abdominal pain, abdominal cramps), immediate need to have a bowel movement (immediate need and accident occurrence), bloating, pressure, gas, and incomplete evacuation. Methods: Psychometric properties and responsiveness of the instrument were evaluated in a clinical trial population [ ClinicalTrials.gov identifier: NCT01494233]. Results: A total of 434 patients were included in the analyses. Significant differences were found among severity groups ( p < 0.01) defined by IBS Patient Global Impression of Severity (PGI-S) and IBS Patient Global Impression of Change (PGI-C). Severity scores for each Diary and Event Log item score and five-item, four-item, and three-item summary scores were calculated. Between-group differences in changes over time were significant for all summary scores in groups stratified by changes in PGI-S ( p < 0.05), two of six Diary items, and three of four Event Log items; a one-grade change in PGI-S was considered a meaningful difference with mean change scores on all Diary items −0.13 to −0.86 [standard deviation (SD) 0.79–1.39]. Similarly, for patients who reported being ‘slightly improved’ (considered a clinically meaningful difference) on the PGI-C, mean change scores on Diary items ranged from −0.45 to −1.55 (SD 0.69–1.39). All estimates of clinically important change for each item and all summary scores were small and should be considered preliminary. These results are aligned with the previous standalone psychometric study regarding reliability and validity tests. Conclusions: These analyses provide evidence of the psychometric properties of the IBS-D Daily Symptom Diary and Event Log in a clinical trial population.

Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUC ave ]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate.

Background Best practice to establish dosage regimens for “first-in-pediatric” clinical trials requires knowledge of efficacious and safe exposures in adults. Methods Pediatric equivalent doses were predicted for patients aged 6 months and Results As shown in the figure, an isavuconazonium sulfate dose of 10 mg/kg is expected to result in AUCss within the target range for the majority of patients >1 year old, in agreement with that predicted by allometry for patients aged 2–17 years. For patients aged 6 months to 1 year, a dose of 6 mg/kg predicts comparable exposures. Conclusion A proposed isavuconazonium sulfate dose of 10 mg/kg administered every 8 hours for the first 2 days and once daily thereafter is predicted to result in safe and efficacious steady state exposures in patients aged 1–17 years, similar to predictions from allometric scaling for patients aged 2–17 years. For subjects aged 6 months to 1 year, a dose of 6 mg/kg is predicted to achieve similar exposures. These doses should be tested in clinical trials to confirm. Disclosures A. Desai, Astellas Pharma, Inc.: Employee, Salary. L. Kovanda, Astellas Pharma, Inc.: Employee, Salary. C. Lademacher, Astellas Pharma, Inc.: Employee, Salary. W. Hope, F2G: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Astellas: Grant Investigator and Investigator, Grant recipient and Research grant. Pfizer: Grant Investigator, Research support. Gilead: Consultant and Scientific Advisor, Consulting fee. P. Bonate, Astellas Pharma, Inc.: Employee, Salary. A. Edginton, Astellas Pharma Global Development, Inc.: Independent Contractor, Consulting fee.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Hyperuricaemia and gout frequently coexist with cardiovascular disorders such as hypertension and heart failure. The use of diuretics has been re-established as a first-line treatment for patients with hypertension and the effects of diuretics on serum uric acid may diminish the urate-lowering effects of febuxostat, a novel, potent, non-purine selective inhibitor of xanthine oxidase. WHAT THIS STUDY ADDS • Co-administration of febuxostat 80 mg and hydrochlorothiazide 50 mg had no effect on the pharmacokinetics and did not have a clinically significant effect on the pharmacodynamics of febuxostat. Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide. AIM This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat. METHODS Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed. RESULTS Mean febuxostat Cmax, AUC(0–t), AUC(0–∞), t1/2,z, CL/F and Vss/F values for regimens co-administration/febuxostat alone were 2.9/2.9 µg ml−1, 9.3/9.1 µg ml−1 h, 9.6/9.3 µg ml−1 h, 6.5/6.1 h, 8.8/9.3 l h−1 and 45/44 l, respectively. Geometric mean ratios (co-administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma Cmax, AUC(0–t), and AUC(0–∞) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid Cmean,24h, Cmean,48h and CLR for both regimens co-administration/febuxostat alone were 216/203 µmol l−1, 218/202 µmol l−1 and 9.1/10.1 ml min−1, respectively. Although serum uric acid Cmean,24h and Cmean,48h values were higher and CLR values lower after co-administration compared with dosing of febuxostat alone, with the differences being statistically significant (P < 0.003), none of the differences (6.5%–9.5%) was considered clinically significant. CONCLUSION Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.

This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration‐time curves (AUC0–∞) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (Cmax) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cmax of mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism.

This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein‐1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion‐transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P‐glycoprotein (P‐gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P‐gp substrate), digoxin (0.5 mg; P‐gp substrate), metformin (850 mg; OCT1, OCT2, and MATE1 substrate), or methotrexate (7.5 mg; BCRP, OAT1, and OAT3 substrate) in the presence and absence of clinical doses of isavuconazole (200 mg 3 times a day for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased mean area under the plasma concentration‐time curves (90% confidence interval) of atorvastatin, digoxin, and metformin to 137% (129, 145), 125% (117, 134), and 152% (138, 168) and increased mean maximum plasma concentrations to 103% (88, 121), 133% (119, 149), and 123% (109, 140), respectively. Methotrexate parameters were unaffected by isavuconazole. There were no serious adverse events. These findings indicate that isavuconazole is a weak inhibitor of P‐gp, as well as OCT1, OCT2, MATE1, or a combination thereof but not of BCRP, OATP1B1, OAT1, or OAT3.

This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration‐time curves from time 0 to infinity of S‐ and R‐warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S‐ and R‐warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment‐emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.

This phase 1, open‐label study evaluated the pharmacokinetic effects of coadministration of the antifungal agent, isavuconazole (administered as its water‐soluble prodrug isavuconazonium sulfate), with the antiretroviral agent lopinavir/ritonavir in healthy adults. In part 1, 13 subjects were randomized to 2 arms to receive multiple doses of oral isavuconazole 100 mg either alone or with lopinavir/ritonavir 400/100 mg. In part 2, a different group of 55 subjects were randomized to 3 arms to receive multiple doses of oral isavuconazole 200 mg, either alone or with lopinavir/ritonavir 400/100 mg, or to receive oral lopinavir/ritonavir 400/100 mg alone. Mean area under the concentration‐time curve (AUC) following the last dose (AUCτ) and Cmax of isavuconazole increased by 113% and 96% in part 1 and by 96% and 74% in part 2 in the presence vs absence of lopinavir/ritonavir, respectively. Mean AUCτ and Cmax of lopinavir were 27% and 23% lower, and mean AUCτ and Cmax of ritonavir were 31% and 33% lower in the presence vs absence of isavuconazole, respectively. Mild to moderate gastrointestinal disorders were the most common adverse events experienced. These findings indicate that coadministration of lopinavir/ritonavir with isavuconazole can decrease the exposure of lopinavir/ritonavir and increase the exposure of isavuconazole. Patients should be monitored for reduced antiviral efficacy if these agents are coadministered.

Background: Available stool form scales do not optimally capture the continuum of stool consistency experienced by patients with irritable bowel syndrome with diarrhea (IBS-D). This paper describes the development of a new measure to assess stool form and consistency for IBS-D. Methods: Descriptors for a new scale were selected by comparing spontaneous descriptions of stools from patients with IBS-D (Rome III) with spontaneous patient descriptions of images in the Bristol Stool Form Scale (BSFS) and an adapted BSFS. New images were prepared by an artist based on the final descriptors and literature images. The new Astellas Stool Form Scale (ASFS) was assessed in cognitive interviews. Results: Spontaneous reports of stool descriptors from 50 patients with IBS-D were broadly grouped based on conceptual equivalence. From these, 8 final stool descriptors were selected, ranging from “like marbles or hard rocks” to “just liquid,” and an image was created for each descriptor. In 20 cognitive interviews, 75% of patients with IBS-D indicated that descriptors matched the appropriate images, 95% of patients indicated that there were enough images to depict each stool type, and 70% of patients indicated that all images were clear. Conclusion: The ASFS, developed using spontaneous patient reports and rigorous qualitative methods, was well understood by patients with IBS-D and was relevant to their experience of stool form and consistency with IBS-D. Further evaluation is ongoing to confirm its utility in clinical research and in the clinical setting as a tool to monitor change in patients with IBS-D and to assess treatments.

Hyperuricaemia and gout frequently coexist with cardiovascular disorders such as hypertension and heart failure. The use of diuretics has been re-established as a first-line treatment for patients with hypertension and the effects of diuretics on serum uric acid may diminish the urate-lowering effects of febuxostat, a novel, potent, non-purine selective inhibitor of xanthine oxidase.Co-administration of febuxostat 80 mg and hydrochlorothiazide 50 mg had no effect on the pharmacokinetics and did not have a clinically significant effect on the pharmacodynamics of febuxostat. Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat.Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed.Mean febuxostat C(max), AUC((0-t)), AUC((0-infinity)), t(1/2,z), CL/F and V(ss)/F values for regimens co-administration/febuxostat alone were 2.9/2.9 microg ml(-1), 9.3/9.1 microg ml(-1) h, 9.6/9.3 microg ml(-1) h, 6.5/6.1 h, 8.8/9.3 l h(-1) and 45/44 l, respectively. Geometric mean ratios (co-administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma C(max), AUC((0-t)), and AUC((0-infinity)) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid C(mean,24h), C(mean,48h) and CL(R) for both regimens co-administration/febuxostat alone were 216/203 micromol l(-1), 218/202 micromol l(-1) and 9.1/10.1 ml min(-1), respectively. Although serum uric acid C(mean,24h) and C(mean,48h) values were higher and CL(R) values lower after co-administration compared with dosing of febuxostat alone, with the differences being statistically significant (P0.003), none of the differences (6.5%-9.5%) was considered clinically significant.Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.

Objective.To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with febuxostat or allopurinol in subjects with gout.Methods.Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and < 6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance.Results.After 1 month initial treatment, > 80% of subjects receiving either febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA < 6.0 mg/dl. After ULT reassignment, > 80% of all remaining subjects maintained the primary efficacy endpoint of SUA < 6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA < 6.0 mg/dl compared with subjects receiving febuxostat. Maintenance of SUA < 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater febuxostat than allopurinol exposure, did not differ significantly among treatment groups.Conclusion.Durable maintenance of goal range SUA level with either dose of febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time. Registered as NCT00175019.

Objective To compare the urate-lowering efficacy and safety of febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function. Methods Subjects (n = 1,072) with hyperuricemia (serum urate level ≥8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to ≤2.0 mg/dl) renal function were randomized to receive once-daily febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks. Results Significantly (P ≤ 0.05) higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels

OBJECTIVES: Despite a documented clinical need, no patient reported outcome (PRO) symptom measure meeting current regulatory requirements for clinically relevant end points is available for the evaluation of treatment benefit in diarrhea-predominant IBS (IBS-D). METHODS: Patients (N=113) with IBS-D participated in five study phases: (1) eight concept elicitation focus groups (N=34), from which a 17-item IBS-D Daily Symptom Diary and four-item IBS-D Symptom Event Log (Diary and Event Log) were developed; (2) one-on-one cognitive interviews (N=11) to assess the instrument's comprehensiveness, understandability, appropriateness, and readability; (3) four data triangulation focus groups (N=32) to confirm the concepts elicited; (4) two hybrid (concept elicitation and cognitive interview) focus groups (N=16); and (5) two iterative sets of one-on-one cognitive interviews (N=20) to further clarify the symptoms of IBS-D and debrief a revised seven-item Diary and four-item Event Log. RESULTS: Of thirty-six concepts initially identified, 22 were excluded because they were not saturated, not clinically relevant, not critical symptoms of IBS-D, considered upper GI symptoms, or too broad or vaguely defined. The remaining concepts were diarrhea, immediate need (urgency), bloating/pressure, frequency of bowel movements, cramps, abdominal/stomach pain, gas, completely emptied bowels/incomplete evacuation, accidents, bubbling in intestines (bowel sounds), rectal burning, stool consistency, rectal spasm, and pain while wiping. The final instrument included a daily diary with separate items for abdominal and stomach pain and an event log with four items completed after each bowel movement as follows: (1) a record of the bowel movement/event and an assessment of (2) severity of immediacy of need/bowel urgency, (3) incomplete evacuation, and (4) stool consistency (evaluated using the newly developed Astellas Stool Form Scale). Based on rounds of interviews and clinical input, items considered secondary or nonspecific to IBS-D (rectal burning, bubbling in intestines, spasms, and pain while wiping) were excluded. CONCLUSIONS: The IBS-D Symptom Diary and Event Log represent a rigorously developed PRO instrument for the measurement of the IBS-D symptom experience from the perspective of the patient. Its content validity has been supported, and future work should evaluate the instrument's psychometric properties.

BACKGROUND: Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. METHODS: Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. RESULTS: Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. CONCLUSIONS: This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. CLINICAL TRIALS REGISTRATION: NCT00413218. ispartof: CLINICAL INFECTIOUS DISEASES vol:68 issue:12 pages:1981-1989 ispartof: location:United States status: published

Introduction The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial. Methods Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA