“The clinical benefit of the active medication relative to the substantial improvements seen in the placebo arm was relatively small,” said panelist Dr. Brendan Everett, director of the general cardiology inpatient service at Brigham and Women’s Hospital, Boston, who voted against approval. “The sponsor is on to something with respect to the time to the first nocturnal void being longer” among those on the drug, an exploratory endpoint that he recommended should be studied further. The company’s plan to address the outliers with substantial drops in sodium that are considered more dangerous was “reasonable,” he said, but added that he shared the concern of other committee members “that implementing that risk-mitigation strategy in the real world after approval would be difficult.”
The company developed lower doses to minimize the risk of hyponatremia and conducted two pivotal phase III confirmatory randomized, placebo-controlled studies of 268 women and almost 400 men with at least two voids per night (an average of 2.9 episodes), evaluating a 25-mcg dose in women and 50 mcg and 75 mcg in men over 3 months. Exclusion criteria included treatable causes of nocturia, such as diabetes insipidus and cardiac failure, and medical conditions that increased risk, such as hyponatremia and psychogenic polydipsia. (The company is not pursuing approval of the 75-mcg dose in men.)
Among the women, the number of voids per night over 3 months dropped by a mean of 1.46 among those on desmopressin vs. 1.24 among those on placebo, a 0.22 difference that was statistically significant, despite the large placebo effect. In the study of men, the number of voids per night dropped by a mean of 1.25 among those on the 50-mcg dose, vs. 0.88 among those on placebo, a difference of 0.37 that was also statistically significant.
In both studies, patients on desmopressin were almost twice as likely to achieve at least a 33% reduction in voids, the second primary endpoint. The large placebo effect in both studies, particularly among the women, is typically observed in studies of lower urinary tract dysfunction treatment, according to the company and several panelists.
An increase in the time to the first nocturnal void, a secondary endpoint, was increased by a mean of 49 minutes in women and by 39 minutes in men over placebo, which were both statistically significant differences.
There were two cases (1%) of hyponatremia among the women and three cases (3%) among the men on the 50-mcg dose; no patients on these two doses developed a serum sodium below 125 mmol/L (severe hyponatremia).