Nocturia
Conditions
Brief summary
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.
Interventions
DRUGDesmopressin
DRUGPlacebo
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment 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. |
| Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3 | Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Time to First Nocturnal Void at Month 3 | Day 1 (Baseline), 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. |
| Change From Baseline in Nocturnal Urine Volume at Month 3 | Day 1 (Baseline), 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. |
| Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | Day 1 (Baseline), 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. |
| Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Day 1 up to 3 months | 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. |
| Minimum Post-Treatment Serum Sodium Levels | Day 1 up to 3 months | 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. |
| Change From Baseline in 24-Hour Urine Volume at Month 3 | Day 1 (Baseline), 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. |
| Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3 | Day 1 (Baseline), 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. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Randomization was stratified by age (\<65 years, \>= 65 years).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 128 |
| 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. | 133 |
| Total | 261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Other | 4 | 1 |
| Overall Study | Protocol Violation | 8 | 7 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Placebo | Desmopressin 25 μg | Total |
|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 14.1 | 59.5 years STANDARD_DEVIATION 14.3 | 59.8 years STANDARD_DEVIATION 14.2 |
| Age, Customized < 65 years | 65 participants | 71 participants | 136 participants |
| Age, Customized >=65 years | 63 participants | 62 participants | 125 participants |
| Body Mass Index | 29.1 kg/m^2 STANDARD_DEVIATION 6.58 | 31.4 kg/m^2 STANDARD_DEVIATION 7.03 | 30.3 kg/m^2 STANDARD_DEVIATION 6.9 |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black/African American | 22 participants | 23 participants | 45 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 17 participants | 26 participants | 43 participants |
| Race/Ethnicity, Customized Native Hawaiian/other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 111 participants | 107 participants | 218 participants |
| Race/Ethnicity, Customized White | 104 participants | 109 participants | 213 participants |
| Sex: Female, Male Female | 128 Participants | 133 Participants | 261 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 126 | 12 / 135 |
| serious Total, serious adverse events | 2 / 126 | 0 / 135 |
Outcome results
Primary
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.
Time frame: Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period)
Population: Full analysis set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3 | 0.64 probability |
| Desmopressin 25 μg | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3 | 0.76 probability |
Comparison: 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 outcomes.p-value: 0.006195% CI: [1.19, 2.86]Generalized Estimating Equation (GEE)
Primary
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.
Time frame: Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period)
Population: Full analysis set (FAS).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Week 1 (n=124, 128) | -1 nocturnal voids | Standard Deviation 0.94 |
| Placebo | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 1 (n=121, 126) | -1.25 nocturnal voids | Standard Deviation 1.12 |
| Placebo | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 2 (n=116, 121) | -1.36 nocturnal voids | Standard Deviation 1.12 |
| Placebo | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 3 (n=107, 113) | -1.38 nocturnal voids | Standard Deviation 1.13 |
| Desmopressin 25 μg | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 3 (n=107, 113) | -1.69 nocturnal voids | Standard Deviation 0.978 |
| Desmopressin 25 μg | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Week 1 (n=124, 128) | -1.21 nocturnal voids | Standard Deviation 0.957 |
| Desmopressin 25 μg | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 2 (n=116, 121) | -1.57 nocturnal voids | Standard Deviation 1.03 |
| Desmopressin 25 μg | Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period | Month 1 (n=121, 126) | -1.47 nocturnal voids | Standard Deviation 1 |
Comparison: 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 outcomes.~A summary of mean change in nocturnal voids, assessed longitudinally during 3 months of treatment, is presented below for the FAS using LOCF.p-value: 0.02895% CI: [-0.42, -0.02]ANCOVA
Secondary
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.
Time frame: Day 1 (Baseline), Month 3
Population: Full Analysis Set (FAS), including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3 | 0.69 probability |
| Desmopressin 25 μg | Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3 | 0.79 probability |
p-value: 0.058695% CI: [0.98, 3.05]Regression, Logistic
Secondary
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.
Time frame: Day 1 (Baseline), Month 3
Population: Full Analysis Set (FAS), including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 24-Hour Urine Volume at Month 3 | -152 mL | Standard Deviation 497 |
| Desmopressin 25 μg | Change From Baseline in 24-Hour Urine Volume at Month 3 | -255 mL | Standard Deviation 522 |
p-value: 0.182995% CI: [-180.42, 34.6]ANCOVA
Secondary
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.
Time frame: Day 1 (Baseline), Month 3
Population: Full Analysis Set (FAS), including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | -1.38 nocturnal voids | Standard Deviation 1.13 |
| Desmopressin 25 μg | Change From Baseline in Mean Number of Nocturnal Voids at Month 3 | -1.69 nocturnal voids | Standard Deviation 0.978 |
Comparison: Change from baseline in the adjusted mean number of nocturnal voids in the FAS using LOCF.p-value: 0.010495% CI: [-0.54, -0.07]ANCOVA
Secondary
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.
Time frame: Day 1 (Baseline), Month 3
Population: Full Analysis Set (FAS), including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Time to First Nocturnal Void at Month 3 | 115 minutes | Standard Deviation 139 |
| Desmopressin 25 μg | Change From Baseline in Mean Time to First Nocturnal Void at Month 3 | 168 minutes | Standard Deviation 138 |
p-value: 0.003495% CI: [16.35, 81.7]ANCOVA
Secondary
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.
Time frame: Day 1 (Baseline), Month 3
Population: Full Analysis Set (FAS), including participants with complete data supporting this outcome in the participant diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Nocturnal Urine Volume at Month 3 | -151 mL | Standard Deviation 262 |
| Desmopressin 25 μg | Change From Baseline in Nocturnal Urine Volume at Month 3 | -242 mL | Standard Deviation 283 |
p-value: 0.003195% CI: [-138.74, -28.38]ANCOVA
Secondary
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.
Time frame: Day 1 up to 3 months
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Minimum Post-Treatment Serum Sodium Levels | <=125 mmol/L | 0 participants |
| Placebo | Minimum Post-Treatment Serum Sodium Levels | 130-134 mmol/L | 2 participants |
| Placebo | Minimum Post-Treatment Serum Sodium Levels | 126-129 mmol/L | 0 participants |
| Placebo | Minimum Post-Treatment Serum Sodium Levels | >=135 mmol/L | 124 participants |
| Desmopressin 25 μg | Minimum Post-Treatment Serum Sodium Levels | >=135 mmol/L | 121 participants |
| Desmopressin 25 μg | Minimum Post-Treatment Serum Sodium Levels | <=125 mmol/L | 0 participants |
| Desmopressin 25 μg | Minimum Post-Treatment Serum Sodium Levels | 126-129 mmol/L | 3 participants |
| Desmopressin 25 μg | Minimum Post-Treatment Serum Sodium Levels | 130-134 mmol/L | 11 participants |
Secondary
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.
Time frame: Day 1 up to 3 months
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | All adverse events (AEs) | 57 participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | ADRs leading to discontinuation | 0 participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Adverse drug reactions (ADRs) | 15 participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious AEs | 2 participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Severe AEs | 3 participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Deaths | 0 participants |
| Placebo | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | AEs leading to discontinuation | 1 participants |
| Desmopressin 25 μg | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Deaths | 0 participants |
| Desmopressin 25 μg | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | All adverse events (AEs) | 60 participants |
| Desmopressin 25 μg | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Severe AEs | 1 participants |
| Desmopressin 25 μg | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Adverse drug reactions (ADRs) | 26 participants |
| Desmopressin 25 μg | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | AEs leading to discontinuation | 4 participants |
| Desmopressin 25 μg | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | ADRs leading to discontinuation | 3 participants |
| Desmopressin 25 μg | Summary of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious AEs | 0 participants |