乌鸦传媒

SAN DIEGO -- Two interventions, one an investigational nasal spray and the other nonpharmacologic, appear to have an impact on the severity and prevalence of adult nocturia, researchers said here.

In a phase III randomized clinical trial, a low-dose desmopressin nasal spray (SER120) reduced the number of voids per night in adults with nocturia, with a low risk of hyponatremia.

And a second study -- a cross-sectional analysis of National Health and Nutrition Examination Surveys (NHANES) 2005-2010 data -- found that exercise seemed to mitigate the excess risk of nocturia with inflammation as measured by level of C-reactive protein (CRP).

The results of both studies were presented during a press briefing at the 2016 meeting of the .

The impact of nocturia on quality of life often goes overlooked in clinical practice and clinical research, said press briefing moderator , of the University of Kansas Medical Center in Kansas City.

"Nocturia is a big issue, particularly in the geriatric population," said Griebling. "If you look at all lower urinary tract symptoms, nocturia tends to have the strongest negative impact on quality of life."

The low-dose nasal-spray formulation of desmopressin addresses perhaps the key issue that has limited the drug's success in previous clinical trials, Griebling continued.

"I'm glad to see this work continue," he said. "Prior studies have shown an effect, but the concern has always been safety. I think we're finally coming to appreciate better the mantra of geriatric medicine to 'start low and go slow' when prescribing medications. I think that's been a problem with prior trials of desmopressin. It's nice to see this kind of evidence with lower dosing."

SER120 is a low-dose desmopressin nasal spray designed to limit the antidiuretic effect of desmopressin just to the hours of sleep. It contains excipients that increase desmopressin's bioavailability and decrease its coefficient of variability for more predictable delivery of desmopressin to the systemic circulation, said , chief medical officer of the product's developer, Serenity Pharmaceuticals in Milford, Pa. These properties are intended to minimize the risk of hyponatremia.

At doses of 0.75 µg and 1.5 µg, SER120 was evaluated in a double-blind, randomized, placebo-controlled study of 782 patients 50 years and older (58% male, 42% female) for 12 weeks. Patients on antihypertensive medications except for loop diuretics could be enrolled. The treatment effect was assessed using 3-day voiding diaries at each week during screening and during the 12-week treatment period.

The co-primary endpoints were the reduction in mean nocturic voids per night and the percentage of patients with a response, defined as a ≥50% reduction in the mean nocturic voids per night.

On these endpoints, SER120 performed significantly better than placebo. In the intent-to-treat (ITT) population, the mean change from baseline in the number of nocturic episodes per night was 1.2 in the placebo group, 1.4 in the 0.75-µg SER120 arm (P=0.007 versus placebo) and 1.5 in the 1.5-µg arm (P=0.0002). Some 28.5% of patients in the placebo group met the definition of response, compared with 35.1% in the low-dose SER120 group (not significant) and 46.2% (P<0.0001) in the high-dose SER120 group.

In the responders, the absolute decrease in the mean number of nocturic voids per night exceeded two relative to baseline in both the 0.75-µg and 1.5-µg SER120 arm. In the nonresponders, the reductions were 1.0 and 0.8 in the two SER120 groups, respectively.

Quality of life was assessed using the Impact of Nighttime Urination Questionnaire (INTU), a validated instrument developed specifically for this study, administered during screening and at weeks 6 and 12 during the randomized treatment period. In the ITT analysis, the mean change from baseline in the INTU overall impact score was significantly superior in the high-dose SER120 group compared with placebo (P=0.0225), as was the nighttime domain score (P=0.0118). Among the SER120 responders, both dose groups experienced significant improvement over placebo on both the overall impact score and the nighttime domain score, representing improved quality of life.

Secondary efficacy endpoints also favored high-dose SER120 over placebo on an ITT basis, including mean time to first nocturic void (P<0.0001), change in the percentage of nights with one or fewer nocturic episodes (P=0.001), change in the percentage of nights with zero nocturic episodes (P=0.0013) and change in nocturic urine volume (P<0.0001).

There were no significant differences in benefits obtained with SER120 when stratified by age (<65 years versus ≥65 years) or gender, said Fein.

One patient in the placebo group and two in 1.5-µg SER120 arm experienced post-baseline serum sodium levels ≤125 mmol/L. Seven patients in the 1.5-µg SER120 arm and one in the 0.75-µg arm experienced post-baseline serum sodium levels between 126 and 129 mmol/L. "These results are the lowest incidences of low serum sodium and hyponatremia of any desmopressin study of which we are aware," he said. The rate of hyponatremia was evenly divided by gender.

Based on the efficacy and safety data, the 75-µg dose of SR120 would be an appropriate starting dose, he said.

Exercise Study

While studies have demonstrated both systemic and local inflammatory correlates to nocturia, new cross-sectional data on men and women older than 20 years from NHANES 2005-2010 suggest that high levels of exercise may curtail the inflammatory link between CRP and nocturia, said principal investigator , from Harvard Medical School, Boston.

In his analysis, sociodemographic and clinical variables were collected from 14,836 adults older than 20 years who participated in NHANES 2005-2010. Two-thirds of the cohort were older than 40 years and one-fifth of the cohort had metabolic syndrome. Physical activity was ascertained by self-report.

CRP and metabolic syndrome were each positively associated with nocturia, but these two variables were closely correlated. Exercise was found to inversely correlate with nocturia in a multivariate model. CRP was highly correlated with nocturia in lower (P<0.001) and middle (P<0.001) tertile exercisers but not in highest tertile exercisers (P=0.06). "Something about these highest exercisers broke down this relationship between CRP and nocturia," said Dagenais.

With aging, an increased amount of serum inflammation together with "a second hit" such as metabolic syndrome can tip the scale toward a dysfunctional bladder, he said, but the influence of inflammation seems to be mitigated in the presence of exercise.