Investigation of the Superiority Effect of Desmopressin to Placebo in Terms of Night Voids Reduction in Nocturia Adult Female Patients (COMFORT)

A Multi-centre, Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Demonstrate the Efficacy and Safety of Desmopressin Orally Disintegrating Tablet for the Treatment of Nocturia in Adult Females

A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to investigate the safety and efficacy of desmopressin oral melt tablets against placebo during 3 months of treatment in adult females with nocturia.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 268
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Victoria, British Columbia, Canada
      • CanMed Clinical Research Inc.
  • Ontario
    • Barrie, Ontario, Canada
      • The Male/Female Health Research Center
    • Kitchener, Ontario, Canada
      • Urology Associates/Urologic Medical Research
    • North Bay, Ontario, Canada
      • Investigational Site
• United States
  • Alabama
    • Huntsville, Alabama, United States
      • Medical Affiliated Research Center Inc.
  • Arkansas
    • Scottsdale, Arkansas, United States
      • Radiant Research Inc.
  • California
    • Foothill Ranch, California, United States
      • Family Medical Center
    • Los Angeles, California, United States
      • Axis Clinical Trials
    • Santa Rosa, California, United States
      • Radiant Research Inc.
  • Colorado
    • Denver, Colorado, United States
      • Downtown Woman's Health Care
    • Wheatridge, Colorado, United States
      • Front Range Clinical Research
  • Florida
    • Aventura, Florida, United States
      • South Florida Medical Research
    • Clearwater, Florida, United States
      • Women's Medical Research Group, LLC
    • DeLand, Florida, United States
      • Avail Clinical Research, LLC
    • Kissimmee, Florida, United States
      • FPA Clinical Research
    • Lauderdale Lakes, Florida, United States
      • Sunrise Medical Research
    • Pinellas Park, Florida, United States
      • DMI Research
  • Georgia
    • Columbus, Georgia, United States
      • Southeastern Institute
    • Columbus, Georgia, United States
      • Southeastern Medical Research Institute
  • Illinois
    • Chicago, Illinois, United States
      • Radiant Research Inc.
    • Evanston, Illinois, United States
      • Northshore University Healthsystem
    • Peoria, Illinois, United States
      • Accelovance
  • Indiana
    • South Bend, Indiana, United States
      • Accelovance
  • Massachusetts
    • Springfield, Massachusetts, United States
      • FutureCare Studies
    • Watertown, Massachusetts, United States
      • Bay State Clinical Trials, Inc.
  • Michigan
    • Paw Paw, Michigan, United States
      • Beyer Research
    • Rochester, Michigan, United States
      • Remedica, LLC
  • Minnesota
    • Edina, Minnesota, United States
      • Radiant Research, Inc.
  • Missouri
    • St. Louis, Missouri, United States
      • Radiant Research, Inc.
  • Nevada
    • Las Vegas, Nevada, United States
      • Radiant Research
  • New Jersey
    • Edison, New Jersey, United States
      • Anderson & Collins Clinical Research Inc
  • New York
    • Garden City, New York, United States
      • AccuMed Research Associates
    • Williamsville, New York, United States
      • Center for Urologic Research of WNY, LLC
  • Ohio
    • Akron, Ohio, United States
      • Radiant Research, Inc.
    • Cincinnati, Ohio, United States
      • Community Research
    • Columbus, Ohio, United States
      • Complete Healthcare For Women
    • Englewood, Ohio, United States
      • HWC Women's Research Center
  • Pennsylvania
    • Bala Cynwyd, Pennsylvania, United States
      • Urologic Consultants of SE PA
    • Philadelphia, Pennsylvania, United States
      • Philadelphia Clinical Research, LLC
  • South Carolina
    • Greer, South Carolina, United States
      • Radiant Research, Inc.
    • Myrtle Beach, South Carolina, United States
      • Carolina Urologic Research Center
  • Texas
    • Dallas, Texas, United States
      • Radiant Research Inc.
    • San Antonio, Texas, United States
      • Quality Research, Inc.
    • San Antonio, Texas, United States
      • Radiant Research, Inc.
  • West Virginia
    • Morgantown, West Virginia, United States
      • Exemplar Research Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Written informed consent prior to performance of any trial-related activity
• Female sex 18 years of age or older
• At least 2 voids every night in a consecutive 3-day period during the screening period

Exclusion Criteria:

1. Evidence of severe daytime voiding dysfunction defined as:

   • Urge urinary incontinence (more than 1 episode/day in the 3-day diary period)
   • Urgency (more than 1 episode/day in the 3-day diary period)
   • Frequency (more than 8 daytime voids/day in the 3-day diary period)
2. Interstitial cystitis
3. Urinary retention or a post void residual volume in excess of 150 mL as confirmed by bladder ultrasound performed after suspicion of urinary retention
4. Habitual or psychogenic polydipsia (fluid intake resulting in a urine production exceeding 40 mL/kg/24 hours)
5. Central or nephrogenic diabetes insipidus
6. Syndrome of inappropriate anti-diuretic hormone secretion
7. Current or a history of urologic malignancies e.g. bladder cancer
8. Genitourinary tract pathology e.g., infection or stone in the bladder and urethra causing symptoms
9. Neurogenic detrusor activity (detrusor overactivity).
10. Suspicion or evidence of cardiac failure
11. Uncontrolled hypertension
12. Uncontrolled diabetes mellitus
13. Hyponatraemia: Serum sodium level must be within normal limits
14. Renal insufficiency: Serum creatinine must be within normal limits and estimated glomerular filtration rate must be more than or equal to 50 mL/min
15. Hepatic and/or biliary diseases: Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels must not be more than twice the upper limit of normal range. Total bilirubin level must not be more than 1.5 mg/dL
16. History of obstructive sleep apnea
17. Previous desmopressin treatment for nocturia
18. Treatment with another investigational product within 3 months prior to screening
19. Concomitant treatment with any prohibited medication e.g., loop diuretics (furosemide, torsemide, ethacrynic acid) and any other investigational drug
20. Pregnancy, breastfeeding, or a plan to become pregnant during the period of the clinical trial. Subjects of reproductive age must have documentation of a reliable method of contraception. All pre-and perimenopausal subjects have to perform pregnancy tests. Amenorrhea of more than 12 months' duration based on the reported date of the last menstrual period is sufficient documentation of post-menopausal status and does not require a pregnancy test
21. Known alcohol or substance abuse
22. Work or lifestyle that may interfere with regular nighttime sleep e.g., shift workers
23. Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, or language barrier that, in the judgment of the Investigator, would impair participation in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Desmopressin 25 μg; Participants took 1 orally disintegrating tablet of desmopressin 25 μg every night approximately 1 hour before bedtime for the entire duration of the 3-month treatment period.	Drug: Desmopressin; Other Names: FE992026; Nocturin®; MINIRIN®
PLACEBO_COMPARATOR: Placebo; Participants took 1 orally disintegrating tablet of placebo every night approximately 1 hour before bedtime for the entire duration of the 3-month treatment period.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period	The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during-treatment visits (Week 1, Months 1, 2, 3) as recorded in participant diaries. The first morning void was not counted as a nocturnal void. Change from baseline values for Week 1, and Months 1, 2 and 3 are reported below. Comparison of the mean number of nocturnal voids at baseline and over a 3-month treatment period (obtained by longitudinal analysis of Week 1, and Months 1, 2 and 3) are reported in the statistical analysis. This was the first co-primary endpoint. The trial was to be declared positive only if the 25 μg desmopressin group had a statistically significant positive effect as compared to placebo on both co-primary endpoints.	Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period)
Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3	Probability of participants achieving 33% responder status during 3 months of treatment employed a longitudinal analysis assessing nocturnal void information captured in the 3-day diary. A 33% responder was defined as a participant with a decrease of at least 33% in the mean number of nocturnal voids relative to baseline. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during treatment visits (Week 1, Months 1, 2, 3) as recorded in participant diaries. The first morning void was not counted as a nocturnal void. This was the second co-primary endpoint. The trial was to be declared positive only if the 25 μg desmopressin group had a statistically significant positive effect as compared to placebo on both co-primary endpoints.	Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Number of Nocturnal Voids at Month 3	The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during-treatment visits (Month 3 for this outcome) as recorded in participant diaries. The first morning void was not counted as a nocturnal void. Secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.	Day 1 (Baseline), Month 3
Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3	Probability of participants achieving 33% responder status at Month 3 employed a longitudinal analysis assessing nocturnal void information captured in the 3-day diary. A 33% responder was defined as a participant with a decrease of at least 33% in the mean number of nocturnal voids relative to baseline. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the Month 3 visit as recorded in participant diaries. The first morning void was not counted as a nocturnal void. The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.	Day 1 (Baseline), Month 3
Change From Baseline in Mean Time to First Nocturnal Void at Month 3	The time to first void was defined as the time from going to bed with the intention of sleeping until first nocturnal void or until waking in the morning in cases where there was no nocturnal void. The time to first void was derived from the sleep and voiding diary. The mean time to first void was calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit. The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.	Day 1 (Baseline), Month 3
Change From Baseline in Nocturnal Urine Volume at Month 3	The nocturnal urine volume was derived from the 3-day urine volume diary. The nocturnal urine volume included the volume of the first morning void. Mean urine volumes were calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit. The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.	Day 1 (Baseline), Month 3
Change From Baseline in 24-Hour Urine Volume at Month 3	Twenty-four hour urine volume was derived from the 3-day urine volume diary. Mean urine volumes were calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit. The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.	Day 1 (Baseline), Month 3
Summary of Participants With Treatment-Emergent Adverse Events (TEAEs)	A TEAE was any adverse event occurring after start of treatment and within the time of residual drug effect, i.e., within 1 day of the last dose of desmopressin. An adverse drug reaction (ADR) was any AE assessed by the Investigator as possibly/probably related to study drug.	Day 1 up to 3 months
Minimum Post-Treatment Serum Sodium Levels	Serum sodium levels were monitored since hyponatremia is a potential serious adverse event associated with daily doses of desmopressin. The serum sodium level must have been within the normal reference range at the Screening Visit for the participant to be eligible for enrollment. A participant was to be withdrawn from the trial if the serum sodium level was <=125 mmol/L at any time.	Day 1 up to 3 months

Collaborators and Investigators

• Sponsor: Ferring Pharmaceuticals

Publications and helpful links

General Publications

• Sand PK, Dmochowski RR, Reddy J, van der Meulen EA. Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. J Urol. 2013 Sep;190(3):958-64. doi: 10.1016/j.juro.2013.02.037. Epub 2013 Feb 20.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (ACTUAL): November 1, 2011
• Study Completion (ACTUAL): November 1, 2011

Study Registration Dates

• First Submitted: October 18, 2010
• First Submitted That Met QC Criteria: October 18, 2010
• First Posted (ESTIMATE): October 19, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): October 15, 2015
• Last Update Submitted That Met QC Criteria: September 16, 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 CS40