How Well and Safely Does Lemborexant Work for People Who Wake up at Night to Urinate (LENS)

Nocturia, defined by the International Continence Society (ICS) as the complaint of waking up one or more times per night to void, with each void typically preceded and followed by sleep (4,5). Nocturia is not only described as one of the most bothersome of all urinary symptoms, but also as one of the most prevalent, with devastating impacts on quality of life (QOL)(5,6). Although nocturia is relatively infrequent among young adults, especially young women (compared to young men), its prevalence tends to increase with age. In individuals aged 60 years or older, reported rates can reach as high as 70%, with over 36% reporting the need to wake up 2 or more times per night to void (7). A recently published meta-analysis reported associations between nocturia and risk of falls, fractures, and early mortality (8).

The causes of nocturia are complex and multifactorial, including nocturnal polyuria (NP - defined as excessive urine production during sleep), sleep disorders (such as insomnia, sleep apnea), metabolic conditions (such as diabetes, uncontrolled hypertension), bladder dysfunctions (OAB or BPE), lifestyle factors (fluid or alcohol intake), or a combination of these conditions (7,9,10).

In Canada, the increasing proportion of older adults, projected to constitute approximately 25% of the population by 2041, poses a notable public health concern owing to the association between nocturia and aging and the potential public health costs of managing the condition (11,12). Bothersome nocturia, defined clinically as two or more nightly voids, is more than just an inconvenience. It has notable clinical implications, including impaired cognitive function during the day, fatigue, falls, depression, and a considerable decrease in health-related quality of life (HRQOL), highlighting the need for new treatment approaches.

Rationale for the study:

The results of a recent study conducted with 32 insomnia patients with nocturia who typically awoke two or more times per night to void demonstrated that 4 weeks of once-daily 5mg Lemborexant significantly improved multiple clinical parameters related to sleep quality and nocturia (13). Nocturia frequency was significantly reduced from a mean of 3.4 episodes per night to 2.3 episodes (p<0.001). Additionally, measures from the frequency-volume chart showed a significant increase in mean single voided urine volume at night from 182.5ml to 222.3 ml (p<0.001). The mean duration of undisturbed sleep also increased from 105.3 minutes to 174.8 minutes (p < 0.001), approaching the three-hour period of deep sleep vital for older adults. Participant quality of life, assessed by the Nocturia Quality of Life Questionnaire (N-QOL), significantly improved from 49.6% to 64.8% (p<0.001).

This recent study, however, was a single-arm, uncontrolled, prospective study conducted at two centers in Japan. Its key limitations include the absence of a placebo control group, relatively small sample size (n=32), and a population limited to patients with comorbid insomnia (Athens Insomnia Scale ≥6).

The present study addresses some of these methodological gaps by employing a randomized, double-blind, placebo-controlled, crossover design with bothersome nocturia confirmed using a validated bother instrument (ICIQ-N), following a standardized period of conservative treatment. Conservative treatment will consist of individualized, physician-recommended measures, including fluid intake, leg elevation, sodium restriction, medication review, and the use of mild compression stockings where relevant.

Primary Objective:

The primary objective of this study is to assess the efficacy of Lemborexant (versus placebo) in reducing nocturia episodes in older men and women (≥65) with bothersome nocturia. Efficacy will be assessed as a change in mean nocturia episodes per 24 hours, measured using a 7-night bladder diary, between baseline and the end of study (EoS).

Inclusion criteria

• Age ≥65 years
• Has nocturia as determined by ICS criteria (ICIQ-N)
• Has Nocturia, after 4 weeks of conservative treatment (fluid advice, leg elevation, sodium restriction, medication review, mild compression stockings where relevant), indicates a score of ≥4 on question 4b of the validated ICIQ Nocturia module [https://iciq.net/iciq-n] - (indication of bother rating of 4-10)
• Participants with prior treatment for concomitant OAB should have been on stable doses of therapy for 12 weeks prior to inclusion.

Exclusion criteria

• Participant has a 24h polyuria (>3L), measured by a 7-day bladder diary

• Participant has a post-void residual (>250mL), measured by ultrasound following void from a comfortably full bladder
• Participant has an acute symptomatic UTI (can be treated and rescreened for inclusion)
• The participant has known untreated sleep apnoea, or highly likely OSA according to the validated STOP-BANG questionnaire (score 5-8)
• The participant has significant heart failure (NYHA C/D)
• The participant has severe renal impairment (eGFR <30mL/min), severe hepatic impairment (Child-Pugh class 3)
• The participant is taking hypnotics
• The participant is taking strong CYP3A inducers such as rifampin, carbamazepine, St. John's wort
• The participant has a known drug allergy to Lemborexant or its constituents
• The participant has cognitive impairment of a degree which, in the opinion of the investigator, is likely to impair the ability to adhere to trial requirements
• The participant is unwilling to abstain from alcohol consumption for the period of the study
• Other condition(s) which would preclude inclusion.