Efficacy and Safety of Desmopressin Melt for the Treatment of Nocturia

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

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.

Study Overview

• Status: Completed
• Conditions: Nocturia
• Intervention / Treatment: Drug: Placebo; Drug: desmopressin acetate

• Study Type: Interventional
• Enrollment (Actual): 799
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y-2H4
      • Southern Interior Medical Center
    • Victoria, British Columbia, Canada, V8T 5G1
      • Can-Med Clinical Research Inc.
    • Victoria, British Columbia, Canada, V8V 3N1
      • Investigational site - Clinical Research
  • New Brunswick
    • Fredericton, New Brunswick, Canada, E3B 5B8
      • Investigational site - Professional Corporation
  • Ontario
    • Barrie, Ontario, Canada, L4M 7G1
      • The Male/Female Health and Reserach
    • Brantford, Ontario, Canada, N3R 4N3
      • Brantford Urology Research
    • Guelph, Ontario, Canada, N1H 5J1
      • Guelph Urology Associates
    • North Bay, Ontario, Canada, P1B 4Z2
      • Investigational Site
    • Oakville, Ontario, Canada, L6H 3P1
      • The Fe/Male Health Centres
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Radiant Research
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Radiant Research
  • Arkansas
    • Little Rock, Arkansas, United States, 72204
      • Arkansas Primary Care Clinic
  • California
    • Anaheim, California, United States, 92801
      • Advanced Urology Medical Center
    • Beverly Hills, California, United States, 90211
      • Impact Clinical Trials
    • Long Beach, California, United States, 90806
      • Atlantic Urology Medical Group
    • Newport Beach, California, United States, 92660
      • California Professional Research
    • San Diego, California, United States, 92103
      • San Diego Uro-Research
    • Santa Rosa, California, United States, 95404
      • Radiant Research
    • Tarzana, California, United States, 91356
      • West Coast Clinical Research
    • Torrance, California, United States, 90505
      • Western Clinical Research
  • Colorado
    • Denver, Colorado, United States, 80218
      • Downtown Women's Health Care
    • Denver, Colorado, United States, 80220
      • Genitourinary Surgical Consultants
    • Denver, Colorado, United States, 80210
      • Urology Associates PC
  • Connecticut
    • Middlebury, Connecticut, United States, 06762
      • Connecticut Clinical Research Center, LLC
  • Florida
    • Aventura, Florida, United States, 33180
      • South Florida Medical Research
    • Clearwater, Florida, United States, 33759
      • Women's Medical Research Group, LLC
    • Miami, Florida, United States, 33145
      • Medsearch Professional Group
    • Plantation, Florida, United States, 33324
      • Sunrise Medical Research
    • Stuart, Florida, United States, 34996
      • Radiant Research
    • Tallahassee, Florida, United States, 32308
      • Southeastern Research Group, Inc.
    • Tampa, Florida, United States, 33607
      • Tampa Bay Urology
    • West Palm Beach, Florida, United States, 33407
      • Radiant Research
  • Georgia
    • Columbus, Georgia, United States, 31904
      • Southeastern Medical Research Institute
    • Dunwoody, Georgia, United States, 30338
      • Investigational site - PC
  • Illinois
    • Peoria, Illinois, United States, 61602
      • Accelovance
  • Kansas
    • Overland park, Kansas, United States, 66202
      • Radiant Research, Kansas City
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Benchmark Research
    • Shreveport, Louisiana, United States, 71106
      • Regional Urology, LLC
    • Shreveport, Louisiana, United States, 71111
      • Pierremont Women's Clinic
  • Massachusetts
    • Springfield, Massachusetts, United States, 01103
      • FutureCare Studies, Inc.
  • Missouri
    • St. Louis, Missouri, United States, 63141
      • Radiant Research Inc.
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Women's Clinic of Lincoln, P.C
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Investigational Site
  • New Jersey
    • Lawrenceville, New Jersey, United States, 08648
      • Lawrenceville Urology
    • Lawrenceville, New Jersey, United States, 08648
      • AdvanceMed Research
    • Morristown, New Jersey, United States, 07960
      • Morristown Urology
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Urology Group of New Mexico, PC
  • New York
    • Albany, New York, United States, 12206
      • Upstate Urology
    • Carmel, New York, United States, 10512
      • Investigational site - Adult & Pediatric Urology
    • Garden City, New York, United States, 11530
      • AccuMed Research Associates
    • New York, New York, United States, 10016
      • University Urology Associates
    • Suffern, New York, United States, 10901
      • Ferring Pharmaceutical Inc
  • North Carolina
    • Concord, North Carolina, United States, 28025
      • Northeast Urology Research
    • Greensboro, North Carolina, United States, 27401
      • PharmQuest
    • Wilmington, North Carolina, United States, 28401
      • New Hanover Medical Research
    • Winston-Salem, North Carolina, United States, 27103
      • Piedmont Medical Research Associates
  • Ohio
    • Cincinnati, Ohio, United States, 45249
      • Radiant Research
    • Mogadore, Ohio, United States, 44260
      • Radiant Research - Akron
  • Pennsylvania
    • Bala Cynwyd, Pennsylvania, United States, 19004
      • Urologic Consultants of SE PA
    • Philadelphia, Pennsylvania, United States, 19115
      • Radiant Research
    • Philadelphia, Pennsylvania, United States, 19114
      • Philadelphia Clinical Research, LLC
    • Reading, Pennsylvania, United States, 19611
      • Advanced Clinical Concepts
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • University Medical Group
    • Greer, South Carolina, United States, 29651
      • Radiant Research, Greer
    • Mt. Pleasant, South Carolina, United States, 29464
      • Palmetto Medical Research
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Holston Medical Group
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Corpus Christi, Texas, United States, 78414
      • Advanced Research Associates
    • Dallas, Texas, United States, 75231
      • Health Central Women's Care
    • Houston, Texas, United States, 77024
      • Accelovance
    • Humble, Texas, United States, 77338
      • Regional Medical Center and Diagnostic
    • San Antonio, Texas, United States, 78229
      • Urology San Antonio Research, PA
    • San Antonio, Texas, United States, 78228
      • Radiant Research San Antonio
  • Virginia
    • Richmond, Virginia, United States, 23235
      • Virginia Urology Center
    • Virginia Beach, Virginia, United States, 23454
      • Urology of Virginia PC
  • Washington
    • Seattle, Washington, United States, 98105
      • Women's Clinical Research Center
    • Seattle, Washington, United States, 98166
      • Seattle Urology Research Center
    • Seattle, Washington, United States, 98166
      • Investigational site - Medical Professional

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Written informed consent prior to the performance of any study-related activity.
2. 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:

1. 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

2. Surgical treatment for bladder outlet obstruction/benign prostatic hyperplasia performed within the past 6 months

   Females:

3. Pregnancy. Females of reproductive age must have documentation of a reliable method of contraception.
4. Use of pessary for pelvic prolapse.

5. Unexplained pelvic mass.

   Males and Females:

6. 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.
7. Current or past urologic malignancy (e.g., bladder cancer, prostate cancer).
8. Clinical evidence of current genitourinary tract pathology that could interfere with voiding.
9. History of neurogenic detrusor activity (previously known as detrusor hyperreflexia).
10. Suspicion or evidence of cardiac failure.
11. Uncontrolled hypertension.
12. Uncontrolled diabetes mellitus.
13. Renal insufficiency. Serum creatinine must be within normal limits and estimated glomerular filtration rate (eGFR) >=60 mL/min.
14. 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.
15. Hyponatremia. Serum sodium level must be within normal limits
16. Syndrome of Inappropriate antidiuretic hormone secretion (SIADH).
17. Diabetes insipidus (urine output > 40 ml/kg over 24 hours) as determined by the 3-day voiding diary.
18. Psychogenic or habitual polydipsia

19. Obstructive sleep apnea

    Other

20. Known alcohol or substance abuse
21. Work or lifestyle potentially interfering with regular nighttime sleep (e.g., shift workers)
22. Previous desmopressin treatment for nocturia.
23. 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.
24. 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.
25. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 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; Oral placebo placed under the participant's tongue, without water, once daily approximately 1 hour before bedtime.
Experimental: desmopressin melt 10 μg; 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; 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; Other Names: FE992026; Nocturin®; Minirin® Melt
Experimental: desmopressin melt 25 μg; 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; 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; Other Names: FE992026; Nocturin®; Minirin® Melt
Experimental: desmopressin melt 50 μg; 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; 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; Other Names: FE992026; Nocturin®; Minirin® Melt
Experimental: desmopressin melt 100 μg; 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; 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; Other Names: FE992026; Nocturin®; Minirin® Melt

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ferring Pharmaceuticals

Publications and helpful links

General Publications

• Juul KV, Klein BM, Norgaard JP. Long-term durability of the response to desmopressin in female and male nocturia patients. Neurourol Urodyn. 2013 Apr;32(4):363-70. doi: 10.1002/nau.22306. Epub 2012 Sep 12.
• Weiss JP, Zinner NR, Klein BM, Norgaard JP. Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial. Neurourol Urodyn. 2012 Apr;31(4):441-7. doi: 10.1002/nau.22243. Epub 2012 Mar 22.
• Juul KV, Malmberg A, van der Meulen E, Walle JV, Norgaard JP. Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia. BJU Int. 2017 May;119(5):776-784. doi: 10.1111/bju.13718. Epub 2016 Dec 10.
• Bliwise DL, Holm-Larsen T, Goble S. Increases in duration of first uninterrupted sleep period are associated with improvements in PSQI-measured sleep quality. Sleep Med. 2014 Oct;15(10):1276-8. doi: 10.1016/j.sleep.2014.05.013. Epub 2014 Jun 13.
• Juul KV, Klein BM, Sandstrom R, Erichsen L, Norgaard JP. Gender difference in antidiuretic response to desmopressin. Am J Physiol Renal Physiol. 2011 May;300(5):F1116-22. doi: 10.1152/ajprenal.00741.2010. Epub 2011 Mar 2.

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): February 1, 2008

Study Registration Dates

• First Submitted: May 22, 2007
• First Submitted That Met QC Criteria: May 22, 2007
• First Posted (Estimate): May 23, 2007

Study Record Updates

• Last Update Posted (Estimate): November 1, 2015
• Last Update Submitted That Met QC Criteria: September 29, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Lower Urinary Tract Symptoms; Urological Manifestations; Nocturia; Physiological Effects of Drugs; Natriuretic Agents; Hemostatics; Coagulants; Antidiuretic Agents; Deamino Arginine Vasopressin
• Other Study ID Numbers: FE992026 CS29