Efficacy and Safety of Desmopressin Melt for the Treatment of Nocturia

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy and safety of several doses of the melt formulation of desmopressin in a broad population of adult patients with nocturia.

Official Title
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A Randomized, Double Blind, Placebo Controlled, Parallel Group, Multi-Center Study With a Double Blind Extension Investigating the Efficacy and Safety of a Fast- Dissolving (Melt) Formulation of Desmopressin for the Treatment of Nocturia in Adults

Conditions
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Nocturia

Intervention / Treatment
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* Drug: desmopressin acetate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Written informed consent prior to the performance of any study-related activity. Patients 18 years and older with an average of ≥ 2 nocturnal voids per night as determined by a 3 day frequency-volume chart during the screening period. Exclusion Criteria: Males: Clinical suspicion of bladder outlet obstruction and/or urine flow < 5 ml/s. If medical history and/or physical examination suggest bladder outlet obstruction, uroflowmetry should be performed to confirm the diagnosis Surgical treatment for bladder outlet obstruction/benign prostatic hyperplasia performed within the past 6 months Females: Pregnancy. Females of reproductive age must have documentation of a reliable method of contraception. Use of pessary for pelvic prolapse. Unexplained pelvic mass. Males and Females: Clinical suspicion of urinary retention and/or post void residual volume > 150 ml. If medical history and/or physical examination suggest urinary retention, bladder ultrasound or catheterization should be performed to confirm the diagnosis. Current or past urologic malignancy (e.g., bladder cancer, prostate cancer). Clinical evidence of current genitourinary tract pathology that could interfere with voiding. History of neurogenic detrusor activity (previously known as detrusor hyperreflexia). Suspicion or evidence of cardiac failure. Uncontrolled hypertension. Uncontrolled diabetes mellitus. Renal insufficiency. Serum creatinine must be within normal limits and estimated glomerular filtration rate (eGFR) >=60 mL/min. Active hepatic and/or biliary disease. Aspartate transaminase (AST) or alanine transaminase (ALT) should not be >2 times the upper limit of normal. Total bilirubin should not be > 1.5 mg/dL. Hyponatremia. Serum sodium level must be within normal limits Syndrome of Inappropriate antidiuretic hormone secretion (SIADH). Diabetes insipidus (urine output > 40 ml/kg over 24 hours) as determined by the 3-day voiding diary. Psychogenic or habitual polydipsia Obstructive sleep apnea Other Known alcohol or substance abuse Work or lifestyle potentially interfering with regular nighttime sleep (e.g., shift workers) Previous desmopressin treatment for nocturia. Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity or language barrier that, in the judgment of the investigator, could impair patient participation in the trial. Use of loop diuretics (furosemide, torsemide, ethacrynic acid). Other classes of diuretics (thiazides, triamterene, chlorthalidone, amiloride, indapamide) were permitted, either as monotherapy or combination therapy. Subjects using a diuretic were to be encouraged to take it in the morning, if medically feasible. Use of any other investigational drug within 30 days of screening. Concomitant Medications The following medications are permitted provided that the subject has been on a stable dose for the 3 months prior to the screening date (i.e. treatment has not been initiated or discontinued and there has been no change in dose): Alpha-blockers: Cardura (doxazosin); Flomax (tamsulosin); Hytrin (terazosin); Uroxatral (alfuzosin) 5 alpha-reductase inhibitors: Avodart (dutasteride); Proscar (finasteride) Antispasmodic, anticholinergic, antimuscarinic therapy for overactive bladder: Detrol, Detrol LA (tolterodine); Ditropan, Ditropan XL (oxybutynin); Enablex (darifenacin); Levsin(hyoscyamine); Oxytrol transdermal (oxybutynin); Sanctura (trospium); Vesicare (solifenacin) Sedative/hypnotic medications for sleep disorders Selective serotonin and mixed norepinephrine/serotonin reuptake inhibitors: Celexa (citalopram); Cymbalta (duloxetine); Effexor (venlafaxine); Lexapro (escitalopram); Paxil(paroxetine); Prozac (fluoxetine); Zoloft (sertraline) Chronic use of nonsteroidal anti-inflammatory agents Diabinese (chlorpropamide) Carbamazepine (carbatrol/tegretol) Amiodarone

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants took a placebo 'melt' for 28 days to complete part 1 of the study. In part 2, placebo patients were randomized to one of the other 4 treatment arms based on assignments predetermined at the initial randomization, to receive active desmopressin melt for between 1 and 6 months (until the database for part 1 was locked and treatment was unblinded). | Drug: Placebo<br>* Oral placebo placed under the participant's tongue, without water, once daily approximately 1 hour before bedtime.<br>|
| Experimental: desmopressin melt 10 μg<br>Participants took desmopressin melt 10 μg for 28 days to complete part 1 of the study. Participants continued on this dose in part 2 of the study for between 1 and 6 months (until the database for part 1 was locked and treatment was unblinded). | Drug: desmopressin acetate<br>* Oral lyophilisate of desmopressin acetate placed under the participant's tongue, without water, once daily approximately 1 hour before bedtime in the assigned dosage: 10, 25, 50 or 100 μg<br>* Other names: FE992026;|
| Experimental: desmopressin melt 25 μg<br>Participants took desmopressin melt 25 μg for 28 days to complete part 1 of the study. Participants continued on this dose in part 2 of the study for between 1 and 6 months (until the database for part 1 was locked and treatment was unblinded). | Drug: desmopressin acetate<br>* Oral lyophilisate of desmopressin acetate placed under the participant's tongue, without water, once daily approximately 1 hour before bedtime in the assigned dosage: 10, 25, 50 or 100 μg<br>* Other names: FE992026;|
| Experimental: desmopressin melt 50 μg<br>Participants took desmopressin melt 50 μg for 28 days to complete part 1 of the study. Participants continued on this dose in part 2 of the study for between 1 and 6 months (until the database for part 1 was locked and treatment was unblinded). | Drug: desmopressin acetate<br>* Oral lyophilisate of desmopressin acetate placed under the participant's tongue, without water, once daily approximately 1 hour before bedtime in the assigned dosage: 10, 25, 50 or 100 μg<br>* Other names: FE992026;|
| Experimental: desmopressin melt 100 μg<br>Participants will take desmopressin melt 100 μg for 28 days to complete part 1 of the study. Participants will continue on this dose in part 2 of the study for between 1-6 months (until the database for part 1 is locked and treatment is unblinded). | Drug: desmopressin acetate<br>* Oral lyophilisate of desmopressin acetate placed under the participant's tongue, without water, once daily approximately 1 hour before bedtime in the assigned dosage: 10, 25, 50 or 100 μg<br>* Other names: FE992026;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Change From Baseline in Mean Number of Nocturnal Voids at Week 4 | The number of nocturnal voids was the average over 3 consecutive 24-hours periods prior to Day 1 and prior to the week 4 visit as recorded in participant diaries. This was the first co-primary outcome. | - Week 3 to Day 1 (Baseline), Week 4 (end of Part I) | 
| Part I: Percentage of Participants With Greater Than 33 Percent Reduction From Baseline in Mean Number of Nocturnal Voids at Week 4 | Percentage of participants in each treatment arm that had a greater than 33% reduction from baseline to the end of Part I (week 4) in mean number of nocturnal voids. Nocturnal void data were recorded in participant diaries. This was the second co-primary outcome. | - Week 3 to Day 1 (Baseline), Week 4 (end of Part I) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part II: Change From Baseline in Mean Number of Nocturnal Voids to Days 29, 57, 113 and 169 | Part II outcomes tested the durability of the effect observed in Part I. The number of nocturnal voids was the average over 3 consecutive 24-hours periods prior to Part I baseline and prior to the Part II visit as recorded in participant diaries. | - Week 3 to Day 1 (Baseline), Days 29, 57, 113 and 169 | 
| Part II: Percentage of Participants With Greater Than 33 Percent Reduction From Baseline in Mean Number of Nocturnal Voids to Days 29, 57, 113 and 169 | Part II outcomes tested the durability of the effect observed in Part I. Percentage of participants in each treatment arm that had a greater than 33% reduction from baseline to Days 29, 57, 113 and 169 in mean number of nocturnal voids. Nocturnal void data were recorded in participant diaries. | - Week 3 to Day 1 (Baseline), Days 29, 57, 113 and 169 | 
| Part I: Change From Baseline in Total Reported Sleep Time at Week 4 | Total sleep time was recorded by participants in study diaries. | - Week 3 to Day 1 (Baseline), Week 4 (end of Part I) | 
| Part I: Change From Baseline in Initial Period of Undisturbed Sleep at Week 4 | Initial period of undisturbed sleep was the time elapsed from first falling asleep until either first void or morning arising. Data were captured in patient diaries. | - Week 3 to Day 1 (Baseline), Week 4 (end of Part I) | 
| Part I: Change From Baseline in Quality of Life Assessed by The International Consultation on Incontinence Modular Questionnaire - Nocturia (ICIQ-N) at Week 4 | The ICIQ-N is a self-administered questionnaire designed to assess the frequency and bother of daytime and nighttime urination. Subjects were asked to rate the degree of bother of daytime urination and nighttime urination on a scale ranging from 0 (not at all) to 10 (a great deal). Higher numbers indicate lower quality of life. | - Week 3 to Day 1 (Baseline), Week 4 (end of Part I) | 
| Part I: Change From Baseline in the Two Domain Scores of the Nocturia Quality of Life (NQoL) Questionnaire at Week 4 | The NQoL questionnaire is a self-administered questionnaire designed to assess the impact of nocturia on quality of life. It contains a sleep/energy domain (6 questions), a bother/concern domain (6 questions), and 1 global QoL question. The twelve core questions are scored on a 0 to 4 scale with higher numbers indicating a better quality of life. Domain summary scores were calculated by transforming the raw score into a 0-100 scale with higher numbers indicating a better quality of life. | - Week 3 to Day 1 (Baseline), Week 4 (end of Part I) | 
| Part I: Change From Baseline in Quality of Sleep as Assessed by the Global Score of the Pittsburgh Sleep Quality Index (PSQI) at Week 4 | The PSQI is a self-administered 19-item questionnaire designed to assess sleep quality and disturbances. The global score ranges from 0 (better sleep quality) to 21 (worse sleep quality). Higher numbers indicate lower quality of life. | - Week 3 to Day 1 (Baseline), Week 4 (end of Part I) | 
| Part I: Change From Baseline in the Mental Health Summary and the Physical Health Summary of the Short Form-12 Version 2 (SF-12v2) at Week 4 | The SF-12v2 was used to measure the impact of nocturia and lack of sleep on general quality of life. The SF-12 consists of 12 questions. Data were analyzed using norm-based scoring and summarized along 2 dimensions: Physical Health Summary and Mental Health Summary. Each summary has a range from 0 (poor health) to 100 (highest level of health). Higher numbers indicate better quality of life. | - Week 3 to Day 1 (Baseline), Week 4 (end of Part I) | 
| Part I: Participants With Treatment-Emergent Adverse Events (AEs) During Study Part I | A treatment-emergent adverse event (AE) was any AE occurring during the treatment period or a pretreatment AE that worsened in intensity during the treatment period. The treatment period was the period during which a subject received investigational medicinal product. If a subject discontinued the investigational medicinal product, the date of last dose was the last day of the treatment period. | Day 1 up to Week 4 (end of Part I) | 
| Part II: Participants With Treatment-Emergent Adverse Events (AEs) During Study Part II | A treatment-emergent adverse event (AE) was any AE occurring during the treatment period or a pretreatment AE that worsened in intensity during the treatment period. The treatment period was the period during which a subject received investigational medicinal product. If a subject discontinued the investigational medicinal product, the date of last dose was the last day of the treatment period. | Week 5 up to Day 169 |