Overactive Bladder
Conditions
Brief summary
The purpose of the trial is to investigate the efficacy of combining tolterodine and desmopressin compared with tolterodine monotherapy in the treatment of women with overactive bladder with nocturia in terms of reduction of nocturnal voids during 3 months of treatment
Interventions
DRUGTolterodine tartrate extended release capsules
DRUGDesmopressin orally disintegrating tablets
DRUGPlacebo orally disintegrating tablets
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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, at least 18 years of age (at the time of written consent) * Nocturia and overactive bladder symptoms present for ≥6 months prior to trial entry (patient-reported) * At least 2 nocturnal voids each night as documented in 2 diary periods during the screening. A mean of at least 8 daytime voids per day over 3 days with a minimum of at least 6 daytime voids each day as documented in 2 diary periods during the screening. At least 1 urgency episode each 24 hours as documented in 2 diary periods during the screening. Each diary period consists of 3 consecutive days, with at least 14 days between each period.
Exclusion criteria
* Evidence of severe voiding dysfunction defined as: More than 10 nocturnal voids per 24 hours as documented on any of the days in both diary periods during screening. More than 20 daytime voids per 24 hours as documented on any of the days in both diary periods during screening. * Genito-urinary tract pathology that can in the investigator's opinion be responsible for urgency or urinary incontinence e.g., symptomatic or recurrent urinary tract infections, interstitial cystitis, bladder related pain, or stone in the bladder and urethra causing symptoms * Current or a history within 5 years of lower urologic malignancies (e.g., bladder cancer), lower urinary tract surgery, previous pelvic irradiation, or severe neurological disease affecting bladder function or muscle strength (e.g., multiple sclerosis, Parkinson's disease, spinal cord injury, spina bifida) * Symptoms of severe stress urinary incontinence in the opinion of the investigator * Urinary retention or a post void residual volume in excess of 150 mL as confirmed by bladder ultrasound performed after suspicion of urinary retention * Habitual or psychogenic polydipsia (fluid intake resulting in a urine production exceeding 40 mL/kg/24 hours) or a mean volume voided per void of 350 mL or more during one or more 24-hour periods as assessed by the screening diaries * Central or nephrogenic diabetes insipidus * Syndrome of inappropriate antidiuretic hormone (SIADH) * Gastric retention * Myasthenia gravis * Uncontrolled narrow-angle glaucoma * Suspicion or evidence of cardiac failure * Uncontrolled and clinically relevant (in the judgement of the investigator) hypertension or diabetes mellitus * History and/or current treatment of obstructive sleep apnoea * Hyponatraemia:Serum sodium level must not be below 135 mmol/L * Evidence of potential renal impairment:Serum creatinine must be within normal laboratory reference intervals AND estimated glomerular filtration rate must be more than or equal to 50 mL/min * Hepatic and/or biliary diseases: Aspartate aminotransferase and/or alanine aminotransferase 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 * Pregnancy, breastfeeding, or a plan to become pregnant during the period of the trial. Women of reproductive age must have documentation of a reliable method of contraception. All pre- and perimenopausal women 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 * Known alcohol or substance abuse; work or lifestyle that may interfere with regular night-time sleep e.g., shift workers; or any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, illiteracy or language barrier which, in the judgement of the investigator, would impair participation in the trial * Known or suspected hypersensitivity to any active ingredient or excipients in the investigational medicinal products used in the trial * Previous participation in any desmopressin trial within the last 5 years * Use of any prohibited therapy, as defined in the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Number of Nocturnal Voids From Baseline | Baseline to 3 months of treatment | A nocturnal void was defined as a void occurring at least 5 minutes after going to bed, but before getting up the next morning. The mean estimate was the average over 3 consecutive 24-hour periods prior to the respective visit as captured in the voiding and sleep diary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Impact on Sleep as Measured by the Sleep Rating Scales From Baseline | Baseline to 3 months of treatment | An electronic diary was used in the trial to document the impact on sleep quality (sleep rating scales). The sleep rating scales included three questions that ranged from 0 (poor) to 10 (good). The average of each question for each visit was summarised and the change from baseline was analysed longitudinally during the three months of treatment. |
| Change in Mean Time to First Nocturnal Void From Baseline | Baseline to 3 months of treatment | The time to first nocturnal 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 the case there is no nocturnal void. The time to first void was calculated as the average over three consecutive 24-hour periods prior to the respective visits. |
| Change in Mean Nocturnal Urine Volume From Baseline | Baseline to 3 months of treatment | The mean nocturnal urine volume was derived from the three-day urine volume diary. The nocturnal volume was defined as the sum of the volumes for all nocturnal voids including the volume of the first morning void within 30 min of waking up in the morning. |
| Responder Status | Baseline to 3 months of treatment | Responder status was defined as ≥33% decrease in the mean number of nocturnal void and at least one night with no voids out of the 3-day diary period. |
| Onset of Effect as Seen in Change in Mean Number of Nocturnal Voids From Baseline for Each Visit During Three Months of Treatment | Baseline to 3 months of treatment | A nocturnal void was defined as a void occurring at least 5 minutes after going to bed, but before getting up the next morning. The mean estimate was the average over 3 consecutive 24-hour periods prior to the respective visit as captured in the voiding and sleep diary. |
Countries
United States
Participant flow
Recruitment details
This was a multi-centre trial conducted in the US. A total of 33 sites were initiated in this trial, and of these eligible patients from 20 sites were randomised to a treatment. The first patient first visit was on 28 January 2013. The last patient last visit was on 19 November 2014.
Pre-assignment details
The trial was initiated with a screening period of 3-4 weeks between Visits 1 and 2a, where no investigational medicinal product was taken. Patients who were on a prohibited medication and needed a wash-out period of 1-2 weeks initiated the trial at Visit 0. Eligible patients were randomised to one of the two treatment groups at Visit 2a.
Participants by arm
| Arm | Count |
|---|---|
| Combination Tolterodine tartrate extended release capsules (4 mg) + Desmopressin orally disintegrating tablets (25 µg)
Tolterodine tartrate extended release capsules
Desmopressin orally disintegrating tablets | 45 |
| Tolterodine Tolterodine tartrate extended release capsules (4 mg)+ Placebo orally disintegrating tablets
Tolterodine tartrate extended release capsules
Placebo orally disintegrating tablets | 52 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Other reason | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Combination | Tolterodine | Total |
|---|---|---|---|
| Age, Continuous | 55.3 Years STANDARD_DEVIATION 12.6 | 51.8 Years STANDARD_DEVIATION 10.3 | 53.4 Years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 10 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 42 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mean Nocturnal Urine Volume | 546 mL STANDARD_DEVIATION 281 | 537 mL STANDARD_DEVIATION 278 | 541 mL STANDARD_DEVIATION 278 |
| Mean Number of Day time Voids | 9.69 Voids STANDARD_DEVIATION 1.35 | 10.1 Voids STANDARD_DEVIATION 1.97 | 9.91 Voids STANDARD_DEVIATION 1.71 |
| Mean Number of Nocturnal Voids | 3.38 Voids STANDARD_DEVIATION 0.97 | 3.11 Voids STANDARD_DEVIATION 1.06 | 3.24 Voids STANDARD_DEVIATION 1.02 |
| Mean Time to First Nocturnal Void | 125 Minutes STANDARD_DEVIATION 44.6 | 143 Minutes STANDARD_DEVIATION 56.1 | 135 Minutes STANDARD_DEVIATION 51.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 14 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 35 Participants | 38 Participants | 73 Participants |
| Sex: Female, Male Female | 45 Participants | 52 Participants | 97 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 | 0 / 48 | 0 / 55 |
| other Total, other adverse events | 3 / 48 | 9 / 55 |
| serious Total, serious adverse events | 0 / 48 | 0 / 55 |
Outcome results
Primary
Change in Mean Number of Nocturnal Voids From Baseline
A nocturnal void was defined as a void occurring at least 5 minutes after going to bed, but before getting up the next morning. The mean estimate was the average over 3 consecutive 24-hour periods prior to the respective visit as captured in the voiding and sleep diary.
Time frame: Baseline to 3 months of treatment
Population: The FAS comprised of all randomised and exposed subjects with at least one efficacy assessment after treatment initiation. The FAS comprised of 97 subjects (45 in the combination group and 52 in the tolterodine group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Change in Mean Number of Nocturnal Voids From Baseline | -1.63 Voids |
| Tolterodine | Change in Mean Number of Nocturnal Voids From Baseline | -1.29 Voids |
Comparison: Combination versus tolterodine (i.e. effect in combination group minus effect in tolterodine group) is presented. The trial was to be declared positive if a statistically significant (two-sided, p \< 0.05) positive effect for combining tolterodine and desmopressin compared to tolterodine monotherapy on the primary endpoint had been demonstrated.p-value: 0.11295% CI: [-0.77, 0.08]ANCOVA
Secondary
Change in Mean Nocturnal Urine Volume From Baseline
The mean nocturnal urine volume was derived from the three-day urine volume diary. The nocturnal volume was defined as the sum of the volumes for all nocturnal voids including the volume of the first morning void within 30 min of waking up in the morning.
Time frame: Baseline to 3 months of treatment
Population: The FAS comprised of all randomised and exposed subjects with at least one efficacy assessment after treatment initiation. The FAS comprised of 97 subjects (45 in the combination group and 52 in the tolterodine group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Change in Mean Nocturnal Urine Volume From Baseline | -156.6 mL |
| Tolterodine | Change in Mean Nocturnal Urine Volume From Baseline | -92.46 mL |
Comparison: Combination versus tolterodine (i.e. effect in combination group minus effect in tolterodine group) is presentedp-value: 0.10395% CI: [-141.46, 13.14]ANCOVA
Secondary
Change in Mean Time to First Nocturnal Void From Baseline
The time to first nocturnal 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 the case there is no nocturnal void. The time to first void was calculated as the average over three consecutive 24-hour periods prior to the respective visits.
Time frame: Baseline to 3 months of treatment
Population: The FAS comprised of all randomised and exposed subjects with at least one efficacy assessment after treatment initiation. The FAS comprised of 97 subjects (45 in the combination group and 52 in the tolterodine group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Combination | Change in Mean Time to First Nocturnal Void From Baseline | 118.19 Minutes |
| Tolterodine | Change in Mean Time to First Nocturnal Void From Baseline | 100.19 Minutes |
Comparison: Combination versus tolterodine (i.e. effect in combination group minus effect in tolterodine group) is presented.p-value: 0.38595% CI: [-22.96, 58.96]ANCOVA
Secondary
Change in the Impact on Sleep as Measured by the Sleep Rating Scales From Baseline
An electronic diary was used in the trial to document the impact on sleep quality (sleep rating scales). The sleep rating scales included three questions that ranged from 0 (poor) to 10 (good). The average of each question for each visit was summarised and the change from baseline was analysed longitudinally during the three months of treatment.
Time frame: Baseline to 3 months of treatment
Population: The FAS comprised of all randomised and exposed subjects with at least one efficacy assessment after treatment initiation. The FAS comprised of 97 subjects (45 in the combination group and 52 in the tolterodine group).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Combination | Change in the Impact on Sleep as Measured by the Sleep Rating Scales From Baseline | From very tired to wide awake, how do you feel now | 1.76 Score on scale |
| Combination | Change in the Impact on Sleep as Measured by the Sleep Rating Scales From Baseline | Rate how refreshed you feel now | 1.81 Score on scale |
| Combination | Change in the Impact on Sleep as Measured by the Sleep Rating Scales From Baseline | Rate the quality of your sleep last night | 1.95 Score on scale |
| Tolterodine | Change in the Impact on Sleep as Measured by the Sleep Rating Scales From Baseline | From very tired to wide awake, how do you feel now | 1.33 Score on scale |
| Tolterodine | Change in the Impact on Sleep as Measured by the Sleep Rating Scales From Baseline | Rate how refreshed you feel now | 1.46 Score on scale |
| Tolterodine | Change in the Impact on Sleep as Measured by the Sleep Rating Scales From Baseline | Rate the quality of your sleep last night | 1.67 Score on scale |
Comparison: Combination versus tolterodine (i.e. score on scale in combination group versus score on scale in tolterodine group) is presented.Statistical analysis for from very tired to wide awake, how do you feel nowp-value: 0.17895% CI: [-0.2, 1.05]ANCOVA
Comparison: Combination versus tolterodine (i.e. score on scale in combination group versus score on scale in tolterodine group) is presented. Statistical analysis for Rate how refreshed you feel nowp-value: 0.25795% CI: [-0.26, 0.94]ANCOVA
Comparison: Combination versus tolterodine (i.e. score on scale in combination group versus score on scale in tolterodine group) is presented. Statistical analysis for Rate the quality of your sleep last nightp-value: 0.3695% CI: [-0.32, 0.88]ANCOVA
Secondary
Onset of Effect as Seen in Change in Mean Number of Nocturnal Voids From Baseline for Each Visit During Three Months of Treatment
A nocturnal void was defined as a void occurring at least 5 minutes after going to bed, but before getting up the next morning. The mean estimate was the average over 3 consecutive 24-hour periods prior to the respective visit as captured in the voiding and sleep diary.
Time frame: Baseline to 3 months of treatment
Population: The FAS comprised of all randomised and exposed subjects with at least one efficacy assessment after treatment initiation. The FAS comprised of 97 subjects (45 in the combination group and 52 in the tolterodine group).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Combination | Onset of Effect as Seen in Change in Mean Number of Nocturnal Voids From Baseline for Each Visit During Three Months of Treatment | Month 1 | -0.19 Voids |
| Combination | Onset of Effect as Seen in Change in Mean Number of Nocturnal Voids From Baseline for Each Visit During Three Months of Treatment | Month 2 | -0.44 Voids |
| Combination | Onset of Effect as Seen in Change in Mean Number of Nocturnal Voids From Baseline for Each Visit During Three Months of Treatment | Month 3 | -0.43 Voids |
| Combination | Onset of Effect as Seen in Change in Mean Number of Nocturnal Voids From Baseline for Each Visit During Three Months of Treatment | Overall (during the three months) | -0.35 Voids |
Comparison: Treatment difference (Combination-tolterodine) at Month 1p-value: 0.443ANCOVA
Comparison: Treatment difference (Combination-tolterodine) at Month 2p-value: 0.086ANCOVA
Comparison: Treatment difference (Combination-tolterodine) at Month 3p-value: 0.055ANCOVA
Comparison: Treatment difference (Combination-tolterodine) for the duration of 3 monthsp-value: 0.106ANCOVA
Secondary
Responder Status
Responder status was defined as ≥33% decrease in the mean number of nocturnal void and at least one night with no voids out of the 3-day diary period.
Time frame: Baseline to 3 months of treatment
Population: The FAS comprised of all randomised and exposed subjects with at least one efficacy assessment after treatment initiation. The FAS comprised of 97 subjects (45 in the combination group and 52 in the tolterodine group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination | Responder Status | 0.40 Proportion of responders |
| Tolterodine | Responder Status | 0.29 Proportion of responders |
Comparison: Combination versus tolterodine (i.e. odds of being responder in combination group versus odds of being responder in tolterodine group) is presented. The proportion of responders during three months of treatment was analysed (i.e. the odds ratio of the odds of being a responder) longitudinally using Generalised Estimating Equation (GEE) for a repeated logistic regression.p-value: 0.35295% CI: [0.71, 2.62]Generalized Estimating Equation