Zuranolone Concentrations in the Breast Milk of Healthy, Lactating Individuals: Results From a Phase 1 Open-Label Study.

PURPOSE/BACKGROUND: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the United States. This study assessed zuranolone transfer into breast milk. METHODS/PROCEDURES: Healthy, nonpregnant, lactating adult female participants received once-daily 30 mg zuranolone from day (D)1 through D5 in this phase 1 open-label study. The relative infant dose (RID; weight-adjusted proportion of the maternal dose in breast milk over 24 hours) for 30 mg zuranolone was assessed at D5. An RID for 50 mg zuranolone was estimated using a simulation approach across a range of infant ages and weights. FINDINGS/RESULTS: Of 15 enrolled participants (mean age, 30.1 years), 14 completed the study. The mean RID for 30 mg zuranolone at D5 was 0.357%; the mean steady-state milk volume over D3 to D5 decreased from baseline by 8.3%. Overall unbound zuranolone in plasma was low (≤0.49%). Plasma concentrations peaked at D5 before decreasing in a biexponential manner. There was strong concordance between the temporal profiles of zuranolone concentrations in plasma and breast milk. The estimated mean RID for 50 mg zuranolone based on a milk intake of 200 mL/kg per day was 0.984%. All treatment-emergent adverse events reported by participants were mild, the most common being dizziness (n = 3). IMPLICATIONS/CONCLUSIONS: Zuranolone transfer into the breast milk of healthy, nonpregnant, lactating adult female participants was low; the estimated RID for 50 mg zuranolone was <1%, well below the <10% threshold generally considered compatible with breastfeeding.

Zuranolone in Major Depressive Disorder: Results From MOUNTAIN-A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

Objective: To evaluate the efficacy and safety of zuranolone, an investigational neuroactive steroid and GABAA receptor positive allosteric modulator, in major depressive disorder (MDD).Methods: The phase 3, double-blind, randomized, placebo-controlled MOUNTAIN study enrolled adult outpatients with DSM-5-diagnosed MDD, 17-item Hamilton Depression Rating Scale total score (HDRS-17) ≥ 22, and Montgomery-Asberg Depression Rating Scale total score ≥ 32. Patients were randomized to treatment with zuranolone 20 mg, zuranolone 30 mg, or placebo for 14 days, followed by an observation period (days 15-42) and an extended follow-up (days 43-182). The primary endpoint was change from baseline (CFB) in HDRS-17 at day 15.Results: 581 patients were randomized to receive zuranolone (20 mg, n = 194; 30 mg, n = 194) or placebo (n = 193). Day 15 HDRS-17 least-squares mean (LSM) CFB was -12.5 (zuranolone 30 mg) vs -11.1 (placebo; P = .116). Improvement vs placebo was significant at days 3, 8, and 12 (all P < .05). LSM CFB (zuranolone 20 mg vs placebo) was not significant at any measured time point. Post hoc analyses of zuranolone 30 mg in patients with measurable plasma zuranolone concentration and/or severe disease (baseline HDRS-17 ≥ 24) showed significant improvement vs placebo at days 3, 8, 12, and 15 (all P < .05). Incidence of treatment-emergent adverse events was similar between zuranolone and placebo groups; the most common (≥ 5%) were fatigue, somnolence, headache, dizziness, diarrhea, sedation, and nausea.Conclusions: MOUNTAIN did not meet its primary endpoint. Significant rapid improvements in depressive symptoms were observed with zuranolone 30 mg at days 3, 8, and 12. Zuranolone was generally well tolerated in patients with MDD.Trial Registration: ClinicalTrials.gov identifier: NCT03672175.

Olipudase alfa for treatment of acid sphingomyelinase deficiency (ASMD): safety and efficacy in adults treated for 30 months.

Olipudase alfa, a recombinant human acid sphingomyelinase (ASM), is an enzyme replacement therapy for the treatment of nonneurologic manifestations of acid sphingomyelinase deficiency (ASMD). This ongoing, open-label, long-term study (NCT02004704) assessed safety and efficacy of olipudase alfa following 30 months of treatment in five adult patients with ASMD. There were no deaths, serious or severe events, or discontinuations during 30 months of treatment. The majority of adverse events were mild and included headache, nausea, and abdominal pain. No patient developed anti-drug antibodies and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Statistically significant reductions in liver (31%) and spleen (39%) volumes were maintained through 30 months of treatment. There was a mean increase in lung diffusing capacity of 35%, and clinically relevant improvements in infiltrative lung disease parameters. Lipid profiles improved in all patients. Improvements in bone mineral density of the spine were observed in some patients. Chitotriosidase in serum and lyso-sphingomyelin in dried blood spots decreased with olipudase alfa treatment, suggesting utility as biomarkers for monitoring treatment efficacy. Olipudase alfa is the first etiology-specific treatment in development for ASMD. This study demonstrates that treatment with olipudase alfa for 30 months is well-tolerated and associated with life-transforming sustained improvements in relevant disease clinical measures.

Predictors of pathological progression among men with localized prostate cancer undergoing active surveillance: a sub-analysis of the REDEEM study.

PURPOSE: We identify risk factors for pathological progression among men on active surveillance in the REDEEM (REduction by Dutasteride of clinical progression Events in Expectant Management trial). MATERIALS AND METHODS: REDEEM was a 3-year, randomized, double-blind study of patients in 65 North American academic centers. Eligible men were 48 to 82 years old, with low risk prostate cancer (T1c-T2a), Gleason score 6 or less, 3 or fewer cores positive, tumor less than 50% of any 1 core, serum prostate specific antigen 11 ng/ml or less, life expectancy greater than 5 years and undergoing active surveillance. Entry biopsies (10 cores or more) were required. The analysis included 276 patients with 1 biopsy or more after the start of study treatment. Patients received dutasteride 0.5 mg per day or placebo for 3 years. Time to pathological progression (volume [4 or more cores positive or 50% or greater of 1 core] or grade progression [Gleason score 7 or greater]) in a post-baseline biopsy (not preceded by therapeutic intervention), and baseline variables were analyzed using a Cox proportional hazard model. RESULTS: In total 94 of 276 patients with a post-baseline biopsy (34.1%) had pathological progression, 54 (19.6%) had volume progression only, 19 (6.9%) had grade progression only and 21 (7.6%) had both types of progression. Older age (HR 1.05, 95% CI 1.01-1.08, p=0.009) and higher prostate specific antigen density (HR 1.06, 95% CI 1.04-1.09, p<0.001) were associated with pathological progression. Post-baseline prostate specific antigen identified grade, but not volume progression in patients treated with placebo and dutasteride. CONCLUSIONS: Older age and higher prostate specific antigen density were independent predictors of pathological progression. Post-baseline measurements as predictors of pathological progression could not be established. Further studies are needed to evaluate the role of dutasteride and establish better markers of pathological progression in active surveillance.

Dutasteride treatment over 2 years delays prostate-specific antigen progression in patients with biochemical failure after radical therapy for prostate cancer: results from the randomised, placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS).

BACKGROUND: Rising prostate-specific antigen (PSA) levels after radical therapy are indicative of recurrent or residual prostate cancer (PCa). This biochemical recurrence typically predates clinically detectable metastatic disease by several years. Management of patients with biochemical recurrence is controversial. OBJECTIVE: To assess the effect of dutasteride on progression of PCa in patients with biochemical failure after radical therapy. DESIGN, SETTING, AND PARTICIPANTS: Randomised, double-blind, placebo-controlled trial in 294 men from 64 centres across 9 European countries. INTERVENTION: The 5α-reductase inhibitor, dutasteride. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was time to PSA doubling from start of randomised treatment, analysed by log-rank test stratified by previous therapy and investigative-site cluster. Secondary end points included time to disease progression and the proportion of subjects with disease progression. RESULTS AND LIMITATIONS: Of the 294 subjects randomised (147 in each treatment group), 187 (64%) completed 24 mo of treatment and 107 discontinued treatment prematurely (71 [48%] of the placebo group, 36 [24%] of the dutasteride group). Dutasteride significantly delayed the time to PSA doubling compared with placebo after 24 mo of treatment (p<0.001); the relative risk (RR) reduction was 66.1% (95% confidence interval [CI], 50.35-76.90) for the overall study period. Dutasteride also significantly delayed disease progression (which included PSA- and non-PSA-related outcomes) compared with placebo (p<0.001); the overall RR reduction in favour of dutasteride was 59% (95% CI, 32.53-75.09). The incidence of adverse events (AEs), serious AEs, and AEs leading to study withdrawal were similar between the treatment groups. A limitation was that investigators were not blinded to PSA levels during the study. CONCLUSIONS: Dutasteride delayed the biochemical progression of PCa in patients with biochemical failure after radical therapy for clinically localised disease. The safety and tolerability of dutasteride were generally consistent with previous experience. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT00558363.

Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial.

BACKGROUND: We aimed to investigate the safety and efficacy of dutasteride, a 5α-reductase inhibitor, on prostate cancer progression in men with low-risk disease who chose to be followed up with active surveillance. METHODS: In our 3 year, randomised, double-blind, placebo-controlled study, undertaken at 65 academic medical centres or outpatient clinics in North America, we enrolled men aged 48-82 years who had low-volume, Gleason score 5-6 prostate cancer and had chosen to be followed up with active surveillance. We randomly allocated participants in a one-to-one ratio, stratified by site and in block sizes of four, to receive once-daily dutasteride 0·5 mg or matching placebo. Participants were followed up for 3 years, with 12-core prostate biopsy samples obtained after 18 months and 3 years. The primary endpoint was time to prostate cancer progression, defined as the number of days between the start of study treatment and the earlier of either pathological progression (in patients with ≥1 biopsy assessment after baseline) or therapeutic progression (start of medical therapy). This trial is registered with ClinicalTrials.gov, number NCT00363311. FINDINGS: Between Aug 10, 2006, and March 26, 2007, we randomly allocated 302 participants, of whom 289 (96%) had at least one biopsy procedure after baseline and were included in the primary analysis. By 3 years, 54 (38%) of 144 men in the dutasteride group and 70 (48%) of 145 controls had prostate cancer progression (pathological or therapeutic; hazard ratio 0·62, 95% CI 0·43-0·89; p=0·009). Incidence of adverse events was much the same between treatment groups. 35 (24%) men in the dutasteride group and 23 (15%) controls had sexual adverse events or breast enlargement or tenderness. Eight (5%) men in the dutasteride group and seven (5%) controls had cardiovascular adverse events, but there were no prostate cancer-related deaths or instances of metastatic disease. INTERPRETATION: Dutasteride could provide a beneficial adjunct to active surveillance for men with low-risk prostate cancer. FUNDING: GlaxoSmithKline.

The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study.

BACKGROUND: Combination therapy with dutasteride and tamsulosin provides significantly greater benefit than either monotherapy for various patient-reported outcomes in men with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and prostatic enlargement. OBJECTIVE: To investigate whether combination therapy is more effective than either monotherapy in reducing the relative risk for acute urinary retention (AUR), BPH-related surgery, and BPH clinical progression over 4 yr in men at increased risk of progression. DESIGN, SETTING, AND PARTICIPANTS: The Combination of Avodart and Tamsulosin (CombAT) study was a 4-yr, multicenter, randomised, double-blind, parallel-group study in 4844 men > or =50 yr of age with a clinical diagnosis of BPH, International Prostate Symptom Score > or =12, prostate volume > or =30 cm(3), prostate-specific antigen 1.5-10 ng/ml, and maximum urinary flow rate (Q(max)) >5 and < or =15 ml/s with minimum voided volume > or =125 ml. INTERVENTION: Oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. MEASUREMENTS: The 4-yr primary end point was time to first AUR or BPH-related surgery. Secondary end points included BPH clinical progression, symptoms, Q(max), prostate volume, safety, and tolerability. RESULTS AND LIMITATIONS: Combination therapy was significantly superior to tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery. Combination therapy was also significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression. Combination therapy provided significantly greater symptom benefit than either monotherapy at 4 yr. Safety and tolerability of combination therapy was consistent with previous experience with dutasteride and tamsulosin monotherapies, with the exception of an imbalance in the composite term of cardiac failure among the three study arms. The lack of placebo control is a study limitation. CONCLUSIONS: The 4-yr CombAT data provide support for the long-term use of dutasteride and tamsulosin combination therapy in men with moderate-to-severe LUTS due to BPH and prostatic enlargement. CLINICALTRIALS.GOV IDENTIFIER: NCT00090103 (http://www.clinicaltrials.gov/ct2/show/NCT00090103).

Solifenacin for overactive bladder: patient-reported outcomes from a large placebo-controlled trial.

OBJECTIVE: Overactive bladder (OAB) is a prevalent, chronic condition that can negatively affect health-related quality of life (HRQL). Treatment goals are to improve symptoms and HRQL. We assessed the efficacy of solifenacin in OAB patients using several patient-reported outcome (PRO) measures, with a focus on urgency severity. Results for the primary endpoint, reductions in daily urgency episodes, and other bladder-diary variables have been recently reported. MATERIALS AND METHODS: In this 12-week multicenter trial, 739 patients (aged >or= 18 years) were randomized to flexibly dosed solifenacin (5/10 mg) or placebo. Prespecified secondary PRO measures included the Indevus Urgency Severity Scale (IUSS), Urgency Perception Scale (UPS), Patient Perception of Bladder Condition (PPBC), and Overactive Bladder Questionnaire (OAB-q). Appropriate statistical tests compared treatment-group differences in continuous and categorical data. RESULTS: In the full analysis set, patients who received solifenacin (n = 357) versus placebo (n = 350) showed significant improvements on the IUSS and UPS; treatment-group differences were 0.4 (P < 0.0001) and 0.2 (P = 0.0018), respectively. On the PPBC, significantly more patients taking solifenacin (66%) than placebo (48%) perceived fewer bladder-related problems (P < 0.0001) by week 12. On the OAB-q, solifenacin was superior to placebo for the Symptom Bother and total HRQL scales and for 3 of the 4 HRQL domains at study end (P

Can dutasteride delay or prevent the progression of prostate cancer in patients with biochemical failure after radical therapy? Rationale and design of the Avodart after Radical Therapy for Prostate Cancer Study.

OBJECTIVE: To describe the Avodart after Radical Therapy for prostate cancer Study (ARTS), investigating the use of dutasteride (a dual 5alpha-reductase inhibitor that suppresses intraprostatic dihydrotestosterone, reduces tumour volume and improves other markers of tumour regression in prostate cancer) to prevent or delay disease progression in patients with biochemical recurrence after therapy with curative intent. PATIENTS AND METHODS: An increasing serum prostate-specific antigen (PSA) level after radical prostatectomy (RP) or radiotherapy (RT) is indicative of recurrent prostate cancer and typically pre-dates clinically detectable metastatic disease by several years. ARTS is an ongoing European multicentre trial in which patients are stratified by previous therapy (RP with or without salvage RT vs primary RT) and randomized to double-blind treatment with dutasteride 0.5 mg or placebo once daily for 2 years. Eligible patients will have a PSA doubling time (DT) of 3-24 months. Biochemical recurrence is defined as three increases in PSA level from the nadir, with each increase > or =4 weeks apart and each PSA level > or =0.2 ng/mL, and a final PSA level of > or =0.4 ng/mL (after RP) or > or =2 ng/mL (after primary RT). Study endpoints include time to PSA doubling, time to disease progression, treatment response (PSA decrease or an increase of < or =15% from baseline), changes in PSA and PSADT, and changes in anxiety (Memorial Anxiety Scale for Prostate Cancer). CONCLUSIONS ARTS: will be the first study to evaluate the effects of dutasteride on PSADT, disease progression and treatment response in patients with biochemical failure after RP or RT, and should help to elucidate the potential role of dual 5alpha-reductase inhibition in prostate cancer.

Efficacy of solifenacin in patients previously treated with tolterodine extended release 4 mg: results of a 12-week, multicenter, open-label, flexible-dose study.

OBJECTIVE: This study evaluated the use of solifenacin in patients experiencing residual urgency symptoms during treatment with tolterodine extended release (ER) 4 mg for overactive bladder (OAB). METHODS: This was a 12-week, multicenter, openlabel, flexible-dose study of the efficacy, tolerability, and effects on health-related quality of life (HRQL) of solifenacin in patients aged >or=18 years who had symptoms of OAB for >or=3 months, had been treated with tolterodine ER 4 mg for >or=4 weeks, and wished to switch therapy because of a lack of sufficient subjective improvement in urgency. At baseline (before washout of tolterodine), patients had to have >or=3 urgency episodes/24 hours. After >or=14 days' washout of tolterodine, all patients received oral solifenacin 5 mg/d, with the option of a dose increase to 10 mg at weeks 4 and 8. On 3 consecutive days before the prewashout, postwashout (no drug treatment for OAB), and week 4, 8, and 12 visits (during and at the end of treatment with solifenacin), patients used a bladder diary to document daily symptoms of urgency, urge incontinence, frequency, nocturia, and nocturnal voids. Changes in these measures at study end were compared with prewashout and postwashout values. The Patient Perception of Bladder Condition (PPBC) and Overactive Bladder Questionnaire (OAB-q) were used to assess patient-reported outcomes at prewashout, postwashout, and week 12. Tolerability was evaluated based on the nature, frequency, and severity of observed or reported adverse events (AEs). RESULTS: Of 606 patients screened, 441 received study medication (mean [SD] age, 61.4 [13.8] years; 88.9% white; 88.2% female). Diary-documented urgency changed from a mean of 6.0 episodes/24 hours at prewashout to 2.6 episodes/24 hours at study end, a mean decrease of 3.4 episodes/24 hours (95% CI, -3.8 to -3.0; P < 0.001). The frequency of all other diary variables was also significantly reduced from prewashout to study end (P < 0.001). The mean PPBC score changed from 4.2 points at prewashout to 3.0 points at study end, a mean improvement of 1.2 points (95% CI, -1.3 to -1.1; P < 0.001). Changes in all OAB-q scales and domains (symptom bother, coping, concern, sleep, social interaction, and total HRQL) from prewashout and postwashout to study end were also statistically significant (P < 0.001). Treatment-emergent AEs were mainly mild or moderate (237/261 [90.8%]) and led to few discontinuations (16/441 [3.6%]). Treatment-emergent AEs included anticholinergic AEs such as dry mouth (77 [17.5%]), constipation (51 [11.6%]), and blurred vision (10 [2.3%]). CONCLUSIONS: Among these patients with residual urgency after treatment with tolterodine ER 4 mg, solifenacin was associated with significant improvements in urgency and other diary-documented symptoms of OAB. Patients receiving solifenacin also had significant improvements in HRQL and the perceived bother of OAB.