Study Investigating the Impact Burden of Nocturia Using the Nocturia Impact Diary (IMPACT)

A Double-blind, Randomized, Placebo-controlled Study Investigating the Impact Burden of Nocturia Using the Nocturia Impact Diary

The purpose of this study is to assess psychometric properties (reliability and validity) of the Nocturia Impact (NI) diary.

To assess the association between reduction of number of nocturnal voids and the mean changes in NI scores (sensitivity of the NI total score to change in nocturia).

To assess which NI diary items account for the main difference in change in total NI score in treatment versus placebo.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Florida
    • Aventura, Florida, United States
      • South Florida Medical Research
    • DeLand, Florida, United States
      • Avail Clinical Research, LLC
  • Illinois
    • Peoria, Illinois, United States
      • Accelovance
  • Massachusetts
    • Springfield, Massachusetts, United States
      • DM Clinical Research
  • Michigan
    • Kalamazoo, Michigan, United States
      • Beyer Research
    • Rochester, Michigan, United States
      • Remedica LLC
  • New York
    • Garden City, New York, United States
      • AccuMed Research Associates
  • South Carolina
    • Greer, South Carolina, United States
      • Radiant Research, Inc.
  • Texas
    • San Antonio, Texas, United States
      • Quality Research, Inc.
    • San Antonio, Texas, United States
      • Radiant 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: All

Description

Inclusion Criteria:

1. Written informed consent prior to performance of any study-related activity
2. 18 years of age (at the time of written consent) or older
3. Previous participation in FE992026 CS40 or FE992026 CS41 with a completion ≥ 30 days prior to Screening. The subject should have responded to active treatment during FE992026 CS40 or FE992026 CS41 or if he/she received placebo during these two studies he/she should have been a non-responder.
4. At least two nocturnal voids every night in two consecutive 3-day periods during the screening period (as determined by the two night-time voiding diaries dispensed at Visit 1 and collected at Visit 2)

Exclusion Criteria:

1. Chronic prostatitis (males)/chronic pelvic pain syndrome (CPPS)
2. Suspicion of bladder outlet obstruction (BOO) or a urine flow of < 5 mL/s as confirmed by uroflowmetry performed after suspicion of BOO
3. Surgical treatment, including transurethral resection, for BOO or benign prostatic hyperplasia (males) within the past six months
4. Urinary retention or a post void residual volume > 150 mL for females and > 250 mL for males as confirmed by bladder ultrasound performed after suspicion of urinary retention
5. Central or nephrogenic diabetes insipidus
6. Syndrome of inappropriate antidiuretic hormone
7. Current or a history of urologic malignancies e.g. bladder cancer
8. Genito-urinary 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. Chronic prostatitis (males)/chronic pelvic pain syndrome (CPPS)
12. Uncontrolled hypertension
13. Uncontrolled diabetes mellitus
14. Hyponatraemia: serum sodium level must be within normal limits
15. Renal insufficiency: Serum creatinine must be within normal limits and estimated glomerular filtration rate must be ≥ 50 mL/min
16. 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 > 1.5 mg/dL
17. History of obstructive sleep apnea
18. Treatment with another investigational product (except desmopressin) within three months prior to screening and throughout the study
19. Concomitant treatment with loop diuretics (furosemide, torsemide, ethacrynic acid)
20. Pregnancy, breastfeeding, or an intention of becoming pregnant during the period of the clinical study. Female subjects of reproductive age must have documentation of a reliable method of contraception. All pre-and perimenopausal female subjects have to perform pregnancy tests. Amenorrhea of > 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 night-time sleep e.g. shiftworkers 23. Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, or language barrier which, in the judgment of the Investigator, would impair participation in the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Female - Desmopressin 25 μg; Female participants took 1 tablet of 25 μg every night, approximately 1 hour prior to bedtime (with the intention to sleep), for a period of 1 month.	Drug: Desmopressin; Desmopressin orally disintegrating tablets. Female participants took a 25 μg tablet and male participants took a 75 μg tablet one hour prior to bedtime for one month.; Other Names: FE992026; Nocturin®; MINIRIN®
Placebo Comparator: Female - Placebo; Female participants took 1 tablet of placebo every night, approximately 1 hour prior to bedtime (with the intention to sleep), for a period of 1 month.	Drug: Placebo; Placebo to match the 25 μg tablet of active drug taken by female participants or the 75 μg tablet taken by males. One placebo tablet taken one hour prior to bedtime for one month.
Experimental: Male - Desmopressin 75 μg; Male participants took 1 tablet 75 μg every night, approximately 1 hour prior to bedtime (with the intention to sleep), for a period of 1 month.	Drug: Desmopressin; Desmopressin orally disintegrating tablets. Female participants took a 25 μg tablet and male participants took a 75 μg tablet one hour prior to bedtime for one month.; Other Names: FE992026; Nocturin®; MINIRIN®
Placebo Comparator: Male - Placebo; Male participants took 1 tablet of placebo every night, approximately 1 hour prior to bedtime (with the intention to sleep), for a period of 1 month.	Drug: Placebo; Placebo to match the 25 μg tablet of active drug taken by female participants or the 75 μg tablet taken by males. One placebo tablet taken one hour prior to bedtime for one month.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Pearson Correlation Coefficient Between Change From Baseline to Month 1 in Number of Nocturnal Voids and Change From Baseline to Month 1 in Nocturia Impact (NI) Diary Total Score	This outcome is a measure of sensitivity of the NI Diary to change in nocturia. The NI Diary is a 12-item instrument consisting of 11 core items and an overall impact question (Q12). Responses are scored from 0 (no impact) to 4 (highest impact); a lowering of score equals a decrease in impact caused by nocturia. The NI total score is the sum of the 11 core items scores. The NI total score was analyzable only if all 11 items (Q1-Q11) had non-missing responses. Otherwise, it was defined as missing. Missing values were not imputed. The average over the 3-day diary period prior to baseline (Day 1) and Month 1 was used for the overall impact score. The correlation was estimated using Fisher's z transformation, i.e. the NI total score was based on a standardized scale from 0 (lowest impact) to 100 (highest impact). Corresponding adjusted partial correlation coefficients were based on adjustments for mean number of Baseline voids, Baseline NI total score, age, and gender.	Day 1 (Baseline), Month 1
Difference in Mean Change From Baseline to Month 1 in Nocturia Impact (NI) Total Scores and Overall Impact Question for Responders and Non-Responders	This outcome is a measure of sensitivity of the NI Diary to change in nocturia. The NI Diary is a 12-item instrument consisting of 11 core items and an overall impact question (Q12). The NI total score is defined as the sum of the 11 core items scores. The overall impact question (Q12) and the NI total score were transformed using Fisher's z transformation, i.e. the scores were based on a standardized scale from 0 (lowest impact) to 100 (highest impact). The difference in mean change in NI total score for subjects who experienced a reduction from baseline of <33% in nocturnal voids at the Month 1 visit (non-responders) versus those with a reduction in nocturnal voids from Baseline of ≥33% (responders) was estimated.	Day 1 (Baseline), Month 1
Cohen's D Effect Size in Responsiveness in the Nocturia Impact (NI) Total Scores and Overall Impact Question as Measured From Baseline (Day 1) to Month 1	The responsiveness of the NI Diary was measured with Cohen's D effect size. The effect size was calculated for active treatment versus placebo, based on change from Baseline to Month 1. The effect size was evaluated as "small," "medium," or "large" if D was <=0.35, >0.35 - 0.65, or >0.65, respectively. Mean values are the Cohen's D effect size. Standard deviation is the pooled standard deviation.	Day 1 (Baseline), Month 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Internal Consistency of the Nocturia Impact (NI) Total Score for Each Day NI Diaries Were Completed Assessed as Cronbach's Alpha Values	Cronbach's alpha (CA) is a measure of the internal consistency of the Nocturia Impact (NI) Total scores. Higher scores indicate a more reliable (precise) instrument. A value of 0.70 set as the benchmark for declaring the scale as internally consistent. Cronbach's alpha was assessed for each of the three consecutive days NI diaries were completed during screening (Day -20 to Day -18), baseline (Day -2 to Day 1) and Month 1 (Day 28 to Day 30).	Screening (Day -20 to Day -18), Baseline (Day -2 to Day 1) and Treatment (Day 28 to Day 30)
Construct Validity For the Nocturia Impact (NI) Total Scores and Overall Impact Question (Q12) for Participants With High/Low Number of Nocturnal Voids	The known group validity was assessed by comparing participants who experienced ≥3 nocturnal voids to those who experienced <3 nocturnal voids, using the average over 3 days for the Screening and Baseline diaries. Results are reported for the NI Total Scores and the Overall Impact Question (Q12). The NI Diary is a 12-item instrument consisting of 11 core items and an overall impact question (Q12). The NI total score is defined as the sum of the 11 core items scores. The overall impact question (Q12) and the NI total score were transformed using Fisher's z transformation, i.e. the scores were based on a standardized scale from 0 (lowest impact) to 100 (highest impact).	Screening (Day -20), Baseline (Day 1)
Change From Baseline to Month 1 on Nocturia Impact (NI) Total Score	The NI Diary is a 12-item instrument consisting of 11 core items and an overall impact question (Q12). Responses are scored from 0 (no impact) to 4 (highest impact); the NI total score is the sum of the 11 core items scores (range of 0-44) which is then transformed to a 0-100 scale (high score indicates high impact). The NI total score was analyzable only if all 11 items (Q1-Q11) had non-missing responses. Otherwise, it was defined as missing. Missing values were not imputed. The average over the 3-day diary period prior to baseline (Day 1) and Month 1 was used for the overall impact score. Negative change from baseline scores indicate a decrease in impact caused by nocturia.	Baseline (Day -2 to Day 1), Treatment (Day 28-30)
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. 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 1 month
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 one day of the last dose of desmopressin.	Day 1 up to 1 month

Collaborators and Investigators

• Sponsor: Ferring Pharmaceuticals

Publications and helpful links

General Publications

• Holm-Larsen T, Andersson F, van der Meulen E, Yankov V, Rosen RC, Norgaard JP. The Nocturia Impact Diary: a self-reported impact measure to complement the voiding diary. Value Health. 2014 Sep;17(6):696-706. doi: 10.1016/j.jval.2014.06.007. Epub 2014 Aug 20.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: March 5, 2012
• First Submitted That Met QC Criteria: March 9, 2012
• First Posted (Estimate): March 13, 2012

Study Record Updates

• Last Update Posted (Actual): July 11, 2017
• Last Update Submitted That Met QC Criteria: June 15, 2017
• Last Verified: June 1, 2017

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: 000034