Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria.

BACKGROUND: Clinical benefit has not been evaluated much in patients with nocturia. OBJECTIVE: To assess the clinical benefit of desmopressin orally disintegrating tablet (ODT) in women (25µg) and men (50µg) with nocturia due to nocturnal polyuria (NP). DESIGN, SETTING, AND PATIENTS: Patients with NP from two randomised, placebo-controlled trials in men (CS41) and women (CS40) with two or more nocturnal voids per night were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Change from baseline in nocturnal voids, 33% and 50% responder status (average reduction of ≤33% and ≤50%, respectively, in the mean number of nocturnal voids vs baseline), and percentage of nights with at most one void or no voids (ie, complete response) during 3-mo treatment period were assessed for clinical benefit. Two-sided test (5% significance level) was used for all endpoints. RESULTS AND LIMITATIONS: Demographics and baseline characteristics of patients in CS41 (N=230) and CS40 (N=232) were similar. A greater reduction in the mean number of nocturnal voids was seen with desmopressin ODT in men (treatment difference [TD]: -0.37 voids) compared with women (TD: -0.29 voids). For 33% and 50% responder status, TD with ODT versus placebo were 21% and 12%, respectively, in men, and 12% and 17%, respectively, in women. For the number of nights with at most one void, TDs were 11% and 13% (p<0.009 for both) for men and women, respectively. For complete response, TD was significant in men (TD: 9%, p<0.001). Limitations inherent in this analysis were evident as the data for cotreatments (baseline) and quality of life were not collected. CONCLUSIONS: A stronger treatment effect with desmopressin ODT versus placebo and the magnitude of differences are indicative of clinical benefit in patients with NP. PATIENT SUMMARY: We looked at the clinical benefit of desmopressin ODT in patients with nocturnal polyuria. We conclude that clinical benefit was observed with desmopressin ODT in these patients.

Rationale and Design of an Adaptive Phase 2b/3 Clinical Trial of Selepressin for Adults in Septic Shock. Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial.

Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V1a receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation Programme for Sepsis-induced Shock-Adaptive Clinical Trial) is a blinded, randomized, placebo-controlled, two-part, adaptive phase 2b/3 trial, evaluating up to four selepressin dosing strategies. The primary outcome is pressor- and ventilator-free days, with a value of zero assigned for death within 30 days. We calculate Bayesian probabilities of final trial success to guide interim decision-making. Part 1 (dose-finding) has an adaptive sample size based on response-adaptive randomization and prespecified rules to determine stopping for futility or selection of the best dosing regimen for Part 2. Part 2 (confirmation) randomizes a minimum of 1,000 patients equally to the selected dosing regimen or placebo. The final estimate of treatment effect compares all selepressin-treated patients with all placebo-treated patients. The sample size of 1,800 provides 91% power to detect an increase of 1.5 pressor- and ventilator-free days with a reduction in mortality of 1.5%. The trial received a Special Protocol Assessment agreement from the U.S. Food and Drug Administration Center for Drug Evaluation and Research and is underway in Europe and the United States. SEPSIS-ACT is an innovative trial that addresses both optimal dose and confirmation of benefit, accelerating the evaluation of selepressin while mitigating risks to patients and sponsor through use of response-adaptive randomization, a novel registration endpoint, prespecified futility stopping rules, and a large sample size. Clinical Trial registered with www.clinicaltrials.gov (NCT02508649).

Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia.

OBJECTIVE: To explore risk factors for desmopressin-induced hyponatraemia and evaluate the impact of a serum sodium monitoring plan. SUBJECTS AND METHODS: This was a meta-analysis of data from three clinical trials of desmopressin in nocturia. Patients received placebo or desmopressin orally disintegrating tablet (ODT; 10-100 µg). The incidence of serum sodium <130 mmol/L was recorded by age, sex and dose. Potential predictors of clinically significant hyponatraemia were identified using multivariate analysis in a Cox proportional hazards model. RESULTS: Dose, age, baseline serum sodium level and kidney function, according to estimated GFR clearance, were significant risk factors for hyponatraemia in both sexes; similar to the known risk factors associated with hyponatraemia in the general population. In men, arthritis and use of drugs for bone disease were also predictive of hyponatraemia, while in women, raised monocytes and absence of lipid-modifying drugs increased the risk of hyponatraemia. Use of the proposed monitoring scheme and the minimum effective dose would have omitted all patients with clinically significant hyponatraemia from further treatment. CONCLUSIONS: The incidence of hyponatraemia can be reduced by using minimum effective gender-specific dosing with the ODT formulation of desmopressin (25 µg in women, 50 µg in men). A sodium monitoring plan is proposed whereby baseline sodium must be ≥135 mmol/L (especially important in the elderly), with additional monitoring at week 1 and month 1 for those at elevated risk because they are aged ≥65 years or receiving concomitant medication associated with hyponatraemia. This monitoring plan would help to prevent some at-risk patients developing hyponatraemia; retrospective application of the monitoring plan showed that, once at-risk patients were appropriately screened out, only mild, non-clinically significant hyponatraemia was observed, within ranges of other drugs associated with hyponatraemia and similar to the background prevalence in the treatment population.

Delaying time to first nocturnal void may have beneficial effects on reducing blood glucose levels.

Experimental studies disrupting sleep and epidemiologic studies of short sleep durations indicate the importance of deeper and longer sleep for cardiometabolic health. We examined the potential beneficial effects of lengthening the first uninterrupted sleep period (FUSP) on blood glucose. Long-term data (≥3 months of treatment) were derived from three clinical trials, testing low-dose (10-100 µg) melt formulations of desmopressin in 841 male and female nocturia patients (90 % of which had nocturnal polyuria). We performed post hoc multiple regression with non-fasting blood glucose as dependent variable and the following potential covariates/factors: time-averaged change of FUSP since baseline, age, gender, race, ethnicity, baseline glucose, baseline weight, change in weight, patient metabolic status (normal, metabolic syndrome, type II diabetes), dose, follow-up interval, and time of random glucose sampling. Increases in FUSP resulted in statistically significant reductions in blood glucose (p = 0.0131), even after controlling for all remaining covariates. Per hour increase in time to first void was associated with glucose decreases of 1.6 mg/dL. This association was more pronounced in patients with increased baseline glucose levels (test of baseline glucose by FUSP change interaction: p < 0.0001). Next to FUSP change, other statistically significant confounding factors/covariates also associated with glucose changes were gender, ethnicity, metabolic subgroup, and baseline glucose. These analyses indicate that delaying time to first void may have beneficial effects on reducing blood glucose in nocturia patients. These data are among the first to suggest that improving sleep may have salutary effects on a cardiometabolic measure.

Delay of first voiding episode is associated with longer reported sleep duration.

OBJECTIVES: Time to first void is a common outcome in nocturia clinical trials, but its relationship to other conventional self-reported sleep measures is uncertain. We examined associations between change in time to first void and change in sleep duration over the course of such a trial. METHODS: Secondary data analyses were based on a previously published study of a medication treating nocturia in 757 adult patients studied for periods up to 5 months. We used repeated-measures logistic regression models with generalized estimating equations (GEE) to examine the odds ratios (ORs) for achieving 6.0, 6.5, or 7.0 hours of total sleep duration based on increases of time to first void of 1, 2, or 3 hours. RESULTS: Increases in time to first void were associated with longer sleep durations from beginning to end of study. A 1-hour increment in time to first void was associated with a higher likelihood of obtaining a total sleep duration of e6 (OR = 1.43; 95% confidence interval [CI], 1.19-1.73), e6.5 (OR = 1.30; 95% CI, 1.16-1.47), or e7 (OR = 1.24; 95% CI, 1.12-1.37) hours, after controlling for baseline time to first void, baseline sleep duration, time, and age (all Ps < .0001). Similar results were seen for 2- and 3-hour increments in time to first void. CONCLUSIONS: Time to first void may be an important supplementary variable about which to inquire in population-based studies.

The Nocturia Impact Diary: a self-reported impact measure to complement the voiding diary.

BACKGROUND: Nocturia is a chronic, fluctuating disease that disrupts sleep and has a wide-ranging impact on quality of life. Valid tools to measure the patient-reported impact of nocturia are essential for evaluating the value of treatment, but the available tools are suboptimal. OBJECTIVES: This study reports the development and validation of the Nocturia Impact Diary-an augmented form of the Nocturia Quality of Life questionnaire designed to be completed in conjunction with the widely used 3-day voiding diary. METHODS: The process comprised three steps: Step 1: Development of a concept pool using the Nocturia Quality of Life questionnaire and data from relevant studies; Step 2: Content validity study; Step 3: Psychometric testing of construct validity, reliability, and sensitivity of the diary in a randomized, placebo-controlled study in patients with nocturia. RESULTS: Step 1: Fourteen items and 4 domains were included in the first draft of the diary. Step 2: Twenty-three patients with nocturia participated in the cognitive debriefing study. Items were adjusted accordingly, and the content validity was high. Step 3: Fifty-six patients were randomized to desmopressin orally disintegrating tablet or placebo. The diary demonstrated high construct validity, with good sensitivity and a good fit to Rasch model, as well as high internal consistency, discriminatory ability, and acceptable sensitivity to change. Results indicated that the diary was unidimensional. CONCLUSIONS: The Nocturia Impact Diary is a convenient, validated patient-reported outcome measure. It should be used in conjunction with a voiding diary to capture the real-life consequences of nocturia and its treatment.

Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study.

PURPOSE: We investigated the efficacy and safety of 50 and 75 µg desmopressin orally disintegrating tablets in men with nocturia (2 or more nocturnal voids). MATERIALS AND METHODS: In this 3-month, randomized, double-blind, parallel study 50 and 75 µg desmopressin were compared with placebo. The co-primary efficacy end points were changes from baseline in mean number of nocturnal voids and proportions of patients achieving at least a 33% reduction from baseline in nocturnal voids (33% responders) during a 3-month treatment period. RESULTS: The full analysis set comprised 385 men (age range 20 to 87 years). The 50 and 75 µg doses significantly reduced the number of nocturnal voids (-0.37, p <0.0001 and -0.41, p = 0.0003, respectively) and increased the odds of a 33% or greater response (OR 1.98, p = 0.0009 and OR 2.04, p = 0.0004, respectively) compared with placebo during 3 months. Desmopressin 50 and 75 µg increased the time to first void from baseline by approximately 40 minutes compared to placebo (p = 0.006 and p = 0.003, respectively). The response to desmopressin was seen by 1 week of treatment and was sustained. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated as only 2 subjects (age 74 and 79 years) on 50 µg had a serum sodium level of less than 130 mmol/L (vs 9 subjects on 75 µg). CONCLUSIONS: Desmopressin (orally disintegrating tablet) is an effective and well tolerated treatment for men with nocturia. Treatment with 50 µg desmopressin, the minimum effective dose, provided sustained improvement of nocturia throughout the study and meaningful benefits to patients with an improved safety profile.

Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study.

PURPOSE: Previous studies suggest a lower dose of desmopressin orally disintegrating tablet may be effective in females compared to males with nocturia. We confirm the efficacy and safety of 25 µg desmopressin orally disintegrating tablet compared to placebo in female patients. MATERIALS AND METHODS: In this 3-month, randomized, double-blind, parallel group study 25 µg desmopressin once daily was compared to placebo in women with nocturia (2 or more nocturnal voids). The co-primary efficacy end points were change from baseline in mean number of nocturnal voids and proportion of patients achieving at least a 33% reduction from baseline in the mean number of nocturnal voids (33% responders). RESULTS: The full analysis set comprised 261 patients (age range 19 to 87 years). Desmopressin significantly reduced the mean number of nocturnal voids and increased the odds of a 33% or greater response compared to placebo during 3 months, assessed by longitudinal analysis (-0.22, p = 0.028 and OR 1.85, p = 0.006, respectively). Desmopressin increased the mean time to first nocturnal void by 49 minutes compared to placebo at 3 months (p = 0.003). The response to desmopressin was seen by week 1 of treatment and was sustained throughout the trial. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated. Serum sodium levels remained greater than 125 mmol/L throughout the trial and 3 transient decreases to less than 130 mmol/L were recorded. CONCLUSIONS: At a dose of 25 µg, desmopressin orally disintegrating tablet is an effective and well tolerated treatment for women with nocturia. Treatment provides rapid and sustained improvement in nocturia and quality of life.

Degarelix versus goserelin (+ antiandrogen flare protection) in the relief of lower urinary tract symptoms secondary to prostate cancer: results from a phase IIIb study (NCT00831233).

INTRODUCTION: No studies to date have assessed the efficacy/tolerability of degarelix in the relief of lower urinary tract symptoms (LUTS) secondary to prostate cancer (PrCa). METHODS: Patients were randomised to degarelix 240/80 mg or goserelin 3.6 mg + bicalutamide flare protection (G+B); both treatments were administered for 3 months. The primary endpoint was change in International Prostate Symptom Score (IPSS) at week 12 compared with baseline. RESULTS: This study was stopped early due to recruitment difficulties. 40 patients received treatment (degarelix n = 27; G+B n = 13); most had locally advanced disease and were highly symptomatic. Degarelix was non-inferior to G+B in reducing IPSS at week 12 in the full analysis set (p = 0.20); the significantly larger IPSS reduction in the per-protocol analysis (p = 0.04) was suggestive of superior reductions with degarelix. Significantly more degarelix patients had improved quality of life (IPSS question) at week 12 (85 vs. 46%; p = 0.01). Mean prostate size reductions at week 12 were 42 versus 25% for patients receiving degarelix versus G+B, respectively (p = 0.04; post hoc analysis). Most adverse events were mild/moderate; more degarelix patients experienced injection site reactions whereas more G+B patients had urinary tract infections/cystitis. CONCLUSION: In 40 men with predominantly locally advanced PrCa and highly symptomatic LUTS, degarelix was at least non-inferior to G+B in reducing IPSS at week 12.

The effect of baseline testosterone on the efficacy of degarelix and leuprolide: further insights from a 12-month, comparative, phase III study in prostate cancer patients.

OBJECTIVE: To investigate the effects of baseline testosterone on testosterone control and prostate-specific antigen (PSA) suppression using data from a phase III trial (CS21) comparing degarelix and leuprolide in prostate cancer. METHODS: In CS21, patients with histologically confirmed prostate cancer (all stages) were randomized to degarelix 240 mg for 1 month followed by monthly maintenance doses of 80 or 160 mg, or leuprolide 7.5 mg/month. Patients receiving leuprolide could receive antiandrogens for flare protection. Treatment effects on testosterone and PSA reduction, testosterone surge, and microsurges were investigated in 3 baseline testosterone subgroups: <3.5, 3.5-5.0, and >5.0 ng/mL. Data are presented for the groups receiving degarelix 240/80 mg (the approved dose) and leuprolide 7.5 mg. RESULTS: Higher baseline testosterone delayed castration with both treatments. However, castrate testosterone levels and PSA suppression occurred more rapidly with degarelix irrespective of baseline testosterone. With leuprolide, the magnitude of testosterone surge and microsurges increased with increasing baseline testosterone. There was no overall correlation between baseline testosterone and initial PSA decrease in either treatment group, although PSA suppression tended to be slowest with leuprolide and fastest with degarelix in the high baseline testosterone subgroup. CONCLUSION: Patients with high baseline testosterone may have greater risk of tumor stimulation (clinical flare) and mini-flares during gonadotrophin-releasing hormone agonist treatment and so the need for flare protection with antiandrogens in these patients is obvious, especially in metastatic disease. Although higher baseline testosterone delays castration, castrate testosterone and PSA suppression occur more rapidly with degarelix, irrespective of baseline testosterone, without the need for flare protection.