An adaptive randomized clinical trial in interstitial cystitis/bladder pain syndrome evaluating efficacy of ASP3652 and the relationship between disease characteristics and Hunner's lesions.

PURPOSE: The primary purpose of this study was to evaluate the effect of the fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on efficacy and safety in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). The secondary purpose was to evaluate phenotyping based on Hunner's lesions (HL). METHODS: In this randomized trial, adult female patients with moderate/severe IC/BPS received 12 weeks of treatment with an oral dose of ASP3652 (50, 150, or 300 mg twice daily) or placebo. A Bayesian model was employed using accumulating data to adjust the randomization probability and to analyze the primary efficacy variable (change from baseline to end of treatment in Mean Daily Pain [MDP; range 0-10]). Study outcomes and patient characteristics of patients with and without HL (HL+ and HL-) were compared. RESULTS: In total, 287 patients were randomized. The 300 mg dose group (n = 97) showed the largest effect, i.e., a mean change from baseline to end of treatment of -1.73 in MDP. However, the mean difference from placebo was 0.02. The probability that this dose was better than placebo was 13.5%. Adverse event incidence was low and similar between study groups. HL+ patients were older and had more severe symptoms than HL-. An association was suggested in HL+ patients between changes in micturition frequency and MDP (R = 0.41 [95% CI 0.18, 0.63]), which was not observed in HL- (R = 0.04 [95% CI -0.16, 0.29]). CONCLUSION: ASP3652 was safe and well tolerated, but did not show efficacy in IC/BPS. The observed differences between HL+ and HL- suggest that IC/BPS diagnosis and treatment may be approached differently in these two phenotypes. TRIAL REGISTRATION: EudraCT number 2011-004555-39, date of registration: 2012-05-07.

What are the additional signs and symptoms in patients with detrusor underactivity and coexisting detrusor overactivity?

AIMS: This study aimed to determine what difference the inclusion of patients with coexisting detrusor overactivity (DO) makes to the signs and symptoms of patients with detrusor underactivity (DU). METHODS: A total of 250 male and 435 female urodynamic tests were analyzed retrospectively. Signs and symptoms which showed a statistically significant difference between DU without DO and DU with DO were identified. RESULTS: Males with DO in addition to DU had higher age and number of daily micturitions, and were more likely to report urgency with or without urgency incontinence than males with DU without DO. They also had lower volumes for first desire to void, volume voided, and post void residual urine, lower abdominal pressure at Qmax and were less likely to report a history of retention or reduced bladder filling sensation than males with DU without DO. Females with DO in addition to DU had higher age and BMI, and were more likely to report urgency incontinence, higher day and night pad usage, constipation and have reduced anal tone than females with DU without DO. They also had lower volumes for first desire to void, volume voided, and post void residual urine, and lower abdominal pressure at Qmax than females who had DU without DO. CONCLUSIONS: There are differences in signs and symptoms between patients who have DU without DO, compared to patients having DU with DO. This understanding will help future studies investigating treatment options for DU patients.

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.

BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study. FINDINGS: The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66-0·90] for progression-free survival and 0·74 [0·58-0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57-0·91] for progression-free survival and 0·60 [0·45-0·79] for overall survival) and immunotherapy (HR 0·75 [0·56-1·00] and 0·64 [0·47-0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65-1·17, pinteraction=0·61] for progression-free survival and 1·03 [0·80-1·34, pinteraction=0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40-0·70]), but no associations observed in women (HR 0·85 [0·61-1·18, pinteraction=0·03]). INTERPRETATION: Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.

Signs and symptoms that distinguish detrusor underactivity from mixed detrusor underactivity and bladder outlet obstruction in male patients.

AIMS: This study aimed to identify signs and symptoms which show differences between men with detrusor underactivity (DU) compared to those with both DU and bladder outlet obstruction (BOO). METHODS: One thousand six hundred and twelve urodynamic tests on male patients were analyzed retrospectively. Signs and symptoms which showed a statistically significant difference between patients with DU alone and patients with both DU+BOO were identified. RESULTS: In the DU only group, considering only patients without a history of bladder outlet surgery, the number of daytime micturitions was lower, maximum voided volume on the bladder diary was higher, and slow stream was reported less often, whereas urinary tract infections were reported more often than for DU+BOO males. The average urine flow rate and abdominal pressure at maximum flow were greater in the DU males, compared to the DU+BOO males. CONCLUSIONS: These data suggest that by combining symptoms, medical history and signs, that could be measured without the need for invasive urodynamics, it may be possible to identify men with DU in a non-invasive way. By doing so, men with DU could be separated from men with both DU+BOO, with sufficient specificity to allow the use of any new non-surgical treatment modalities, such as new and effective medical therapy.

Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials.

AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit. METHODS: Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables. RESULTS: Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months. CONCLUSION: Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses.

Signs and Symptoms of Detrusor Underactivity: An Analysis of Clinical Presentation and Urodynamic Tests From a Large Group of Patients Undergoing Pressure Flow Studies.

BACKGROUND: The clinical diagnosis of detrusor underactivity (DU) is hampered by the need for invasive pressure flow studies (PFS) in combination with a lack of knowledge of the associated signs and symptoms. This has contributed to a lack of awareness of DU and underactive bladder, and to the assumption that symptoms are always due to bladder outlet obstruction (BOO). OBJECTIVE: To investigate the signs and symptoms recorded in a large urodynamic database of patients who met the diagnoses of DU, BOO, and normal, to identify the clinical features associated with DU. DESIGN, SETTING, AND PARTICIPANTS: From the database of 28282 adult PFS records, 1788 patients were classified into: (1) those with DU without BOO; (2) those with BOO without DU; and (3) those with normal PFS. RESULTS: Patients with DU reported a statistically significantly higher occurrence of decreased and/or interrupted urinary stream, hesitancy, feeling of incomplete bladder emptying, palpable bladder, and absent and/or decreased sensation compared with patients with normal PFS. Other differences were found between men with DU and BOO, and between women with DU and normal PFS. CONCLUSIONS: There are signs and symptoms that can distinguish DU patients from patients with normal PFS and further distinguish between DU and BOO, which is traditionally invasively diagnosed. This is a first step to better understand the clinical presentation of DU patients, is consistent with the recent underactive bladder working definition, and justifies further exploration of the signs and symptoms of DU. PATIENT SUMMARY: The clinical diagnosis of detrusor underactivity is hampered by the need for invasive urodynamics in combination with a lack of knowledge of the associated signs and symptoms. This study has shown that there are signs and symptoms that can distinguish men and women patients with DU from patients with either normal urodynamic studies or with BOO.

The efficacy and safety of mirabegron compared with solifenacin in overactive bladder patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy: results of a noninferiority, randomized, phase IIIb trial.

OBJECTIVE: To compare the efficacy and safety of mirabegron 50 mg and solifenacin 5 mg in overactive bladder (OAB) patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy. PATIENTS AND METHODS: This randomized, double-blind, phase IIIb, noninferiority study, enrolled male and female patients aged ⩾18 years old, with symptoms of OAB for ⩾3 months, who were dissatisfied with their previous antimuscarinic drug due to lack of efficacy. A total of 1887 patients were randomized to receive mirabegron 50 mg (n = 943) or solifenacin 5 mg (n = 944) daily for 12 weeks. The primary efficacy endpoint was change from baseline to end of treatment in mean number of micturitions/24 h. Noninferiority was confirmed if the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference between solifenacin and mirabegron was > -0.20. Secondary efficacy endpoints, which included change from baseline in mean number of incontinence episodes/24 h, urgency incontinence episodes/24 h, urgency episodes (grade 3 or 4)/24 h and nocturia episodes/24 h, were analyzed using analysis of covariance. RESULTS: For the primary endpoint, adjusted mean treatment difference (95% CI) in mean number of micturitions/24 h was -0.18 (-0.42, 0.06) and therefore noninferiority of mirabegron to solifenacin was not demonstrated. Both treatments demonstrated clinically meaningful reductions in efficacy variables and were well tolerated, with a lower incidence of dry mouth with mirabegron. CONCLUSIONS: Noninferiority of mirabegron compared with solifenacin for reduction in micturition frequency could not be demonstrated in this population of OAB patients who were dissatisfied with previous antimuscarinic therapy due to lack of efficacy. Both mirabegron and solifenacin improved key OAB symptoms with no statistically significant differences observed between the two treatments. Both drugs were well tolerated.

Efficacy of the ß3-adrenoceptor agonist mirabegron for the treatment of overactive bladder by severity of incontinence at baseline: a post hoc analysis of pooled data from three randomised phase 3 trials.

UNLABELLED: The ß3-adrenoceptor agonist mirabegron is approved for treatment of the symptoms of overactive bladder (OAB). Incontinence can be the most bothersome of OAB symptoms. Hence, we conducted a post hoc analysis of pooled data from three randomised, double-blind, placebo-controlled, 12-wk, phase 3 studies of mirabegron to evaluate the efficacy of mirabegron 50mg in incontinent OAB patients and in subgroups of patients stratified by severity of incontinence at baseline (an average of two or more [FAS-I ≥ 2 subgroup] or four or more [FAS-I ≥ 4 subgroup] incontinence episodes per 24h at baseline, where FAS-I is the full analysis set-incontinence population) and to determine correlations between measures of efficacy and disease severity. Mirabegron 50mg resulted in statistically significant improvements from baseline to final visit versus placebo in mean number of incontinence episodes, micturitions, and urgency episodes per 24h and mean volume voided per micturition in the pooled incontinent population and in the FAS-I ≥ 2 and FAS-I ≥ 4 subgroups. Treatment effect versus placebo for incontinence and urgency episodes increased with increasing severity of incontinence at baseline. Moderate correlations were seen between improvement in both frequency of incontinence episodes and micturitions and baseline incontinence and micturition frequency, respectively, with mirabegron 50mg and placebo. PATIENT SUMMARY: Incontinence can be the most bothersome of OAB symptoms; mirabegron 50mg once daily is effective for treatment of OAB symptoms in incontinent patients, and its effect increases with increasing severity of incontinence.

Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study.

Eliglustat tartrate is an investigational oral substrate reduction therapy for Gaucher disease type 1 that is pharmacologically distinct from intravenous enzyme replacement therapy. Eliglustat tartrate improved clinical manifestations in patients who received 50 or 100 mg twice daily for 1 year during an open-label phase 2 study (Blood. 2010;116(6):893-899). We report further improvements after 2 years of treatment in 20 patients (11 females, 9 males; mean age, 33 years) with baseline splenomegaly and thrombocytopenia and/or anemia. Statistically significant (P < .001) percentage improvements from baseline occurred in platelet count (mean ± SD, 81% ± 56%), hemoglobin level (20% ± 15%), spleen volume (-52% ± 11%), and liver volume (-24% ± 13%). Mean platelet count increased ∼ 50 000/mm(3). Mean hemoglobin level increased 2.1 g/dL overall and 3.1 g/dL in 10 patients with baseline anemia. Organ volume reductions were greatest in patients with severe baseline organomegaly. Seventeen (85%) patients met established therapeutic goals for ≥ 3 of the 4 parameters. Lumbar spine bone mineral density increased 7.8% ± 10.6% (P = .01) and T-score 0.6 ± 0.8 (P = .012), with major gains in osteoporotic and osteopenic patients. Magnetic resonance imaging assessment showed that bone marrow infiltration by Gaucher cells was decreased (8/18 patients) or stable (10/18 patients). No safety-related trends emerged during 2 years of treatment. This multisite, open-label, single-arm phase 2 study is registered at www.clinicaltrials.gov as NCT00358150.

A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1.

Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (-38.5%; 95% CI = -43.5%--33.5%), liver volume (-17.0%; 95% CI = -21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1.