There is a continued and growing interest in evaluating and capturing the patient experience of disease to provide a more robust understanding of the value of intervention and treatment benefit. While the relationship between nocturia and sleep disturbance is well-described, assessment and interpretation of the direct impact of nocturia on overall sleep quality is somewhat limited and evaluative qualitative studies to evaluate this impact even more so. The aim of this research was to fully characterize the most proximal impacts of nocturia on sleep quality from the patient perspective in order to inform clinical development programs and guide development and selection of best fit patient-reported outcome (PRO) measures.

A targeted review of the literature was conducted to gather information on concepts that patients with nocturia describe as important and to identify nocturia-related concepts that have been evaluated in clinical or observational studies. The review was conducted using PubMed and included human research articles published between February 2006 and February of 2016. Additionally, 9 of the most commonly used patient-reported outcome measures in nocturia were selected for review in light of current FDA recommendations pertaining to the use of PRO measures in support of product approval and labeling [1].

Following this review, a single visit, prospective, observational study was conducted including in-depth concept elicitation interviews with individuals meeting predefined study criteria. Briefly, these criteria included male and female adults with nocturia (defined as ≥ 2 nocturnal voids per night most nights for ≥ 6 months and ≥ 2 nocturnal voids per night all or almost all nights during the past 2 weeks as well as self-report of being awakened during the night by the need to void, not due to another cause). All patients were English-speaking and willing to participate in a 1-hour interview. Patients were excluded based on comorbidities that could confound interview results, including polydipsia (excessive fluid intake, exceeding 12 cups [3 L]/24 hours) in the past 2 weeks or enrollment in or discontinuation from a clinical trial within the past 30 days.

Following review of the citations and abstracts from the target literature review, 34 articles were selected for in-depth review. The most proximal concepts of patient-reported, sleep-related symptoms or impacts of nocturia included:
	Frequency of waking to void
	Waking to void within 2 to 3 hours of going to sleep, which interrupts restorative sleep
	Bother related to need to void at night with incremental increases in bother associated with additional nocturia episodes
	Difficulty falling asleep after waking to void
	Impaired sleep quality, sleep duration, and sleep efficiency
	Increased risk of falls and injury
	Impact on partner/caregiver sleep
Review of the concepts included in the 9 PRO measures demonstrated overlap with the concepts identified in the literature. However, none of the measures fully captured all concepts and met standards described in the FDA PRO Guidance for use of PRO measure in a clinical trial setting [1]. 

A total of 18 subjects participated in the interview study. Of these, 50% were female, and 83.3% had at least some college. Ten participants (55.6%) were employed either part- or full-time. Eleven participants (61.1%) reported being “quite a bit disturbed” by nocturia-related sleep disturbance, and seven (38.9%) reported being “moderately disturbed.” The primary impacts of nocturia were identified as awakening frequently during the night to urinate in combination with the impact on overall sleep quantity and quality caused by these awakenings. For most participants, good sleep quality was defined as achieving a deep sleep, and was related to having uninterrupted, restful, restorative sleep without awakening. Importantly, participants separated the concept of the number of voids during the night from awakenings noting these concepts as distinct (for example, more awakenings could occur compared to voids alone).

A targeted instrument and literature review and a prospective observational study fully describe the impacts of nocturia on sleep quality, demonstrating the need for capture of these impacts directly from patients in order to explore benefits of future treatments. Proximal impacts (those most closely related to the nocturia experience) focused on sleep quality and may be more easily and accurately captured via self-report, compared to other impacts more distal to the patient experience, and therefore potentially influenced by factors other than nocturia.

Nocturia impacts patient-reported sleep quality beyond number of voids per night. Improved sleep quality may be an important treatment target and benefit. Best fit, content valid measures are necessary.

Food and Drug Administration. Guidance for industry patient-reported outcome measures: use in medical product development to support labeling claims. December 2009. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory.