Bladder Diseases, Interstitial Cystitis
Conditions
Keywords
painful bladder syndrome, interstitial cystitis, newly diagnosed
Brief summary
This is a randomized clinical trial study to test the efficacy and safety of amitriptyline in the treatment of patients newly diagnosed with painful bladder syndrome (PBS). PBS is defined by symptoms--frequent urination day and night and increasing pain as the bladder fills--according to the International Continence Society. The syndrome includes interstitial cystitis (IC), which has been estimated to affect as many as 700,000 people, mostly women. Estimates for PBS vary widely, but as many as 10 million people may suffer from this condition. Although amitriptyline is a Food and Drug Administration (FDA)-approved medication used for depression, the way it works makes it useful for treating the pain of fibromyalgia, multiple sclerosis, and other chronic pain syndromes. Prior small studies in interstitial cystitis (IC) suggested the drug may be a wise choice for this syndrome as well, because it blocks nerve signals that trigger pain and may also decrease muscle spasms in the bladder, helping to relieve the symptoms of pain and frequent urination.
Detailed description
The current trial is recruiting newly diagnosed adults who have not yet received treatment. Approximately 270 participants will be randomly assigned to take up to 75 milligrams of amitriptyline or a placebo each day for 14 to 26 weeks. All participants will be given techniques to practice suppressing the urge to urinate for increasingly longer stretches until they can wait 3 or 4 hours before going to the bathroom. Participants will also regulate when and how much they drink and avoid bladder irritants such as alcohol, acidic foods and carbonated or caffeinated drinks. Staff and patients will find out who received the amitriptyline when the study is finished. Medications and tests are free to participants. Ten medical centers in the United States and Canada are recruiting adults newly diagnosed with either painful bladder syndrome (PBS) or interstitial cystitis (IC).The centers make up the Interstitial Cystitis Clinical Research Network, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at NIH.
Interventions
DRUGAmitriptyline
Amitriptyline will be titrated over a 6-week period as tolerated, to a maximum dose of 75mg. During the 6-week titration period, the patient who cannot tolerate a scheduled increased dose may adjust the medication dose for tolerance by tapering down one 25mg tablet.
OTHERPlacebo
Placebo will be dosed exactly as active arm.
Sponsors
University of Pennsylvania
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Participant must report bladder pain/discomfort score of 3 or greater on a 0-10 Likert scale over the previous 4 weeks. * Participant must report a symptom score of abnormal urinary frequency of 3 or greater on a 0-10 Likert scale over the previous 4 weeks. * Symptoms of abnormal urinary frequency and bladder pain/discomfort must have been present for at least six weeks prior to screening visit.
Exclusion criteria
* Known allergy or intolerance to amitriptyline or any of its components. * Currently receives treatment with amitriptyline or other tricyclic antidepressant, selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI), or monoamine oxidase (MAO) inhibitor antidepressants. * Previous treatment with amitriptyline or other tricyclics, hydroxyzine or other antihistamines for bladder symptoms; pentosanpolysulfate; DMSO or any other intravesical therapy, biofeedback or pelvic floor physical therapy for PBS symptoms
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Response Assessment (GRA) | 12 Weeks | The primary efficacy analysis was based on intent to treat, comparing the proportion of responders between treatment arms on a patient reported GRA recorded at 12 weeks or study withdrawal. The 7-point GRA queried, As compared to when you started the current study, how would you rate your overall symptoms now? The 7 response options were markedly worse, moderately worse, slightly worse, the same, slightly improved, moderately improved and markedly improved. Participants who indicated that they were markedly or moderately improved were considered responders. Subjects who withdrew from the study for any reason and did not provide data on the primary outcome were considered treatment failures, and were included in the denominator for calculation of response rates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Quality of Life Measures From Baseline to 12 Weeks | Baseline and 12 Weeks | A number of secondary outcomes \[as detailed in the Baseline Measures section\] were assessed throughout the study. These outcomes include pain, urgency and frequency on 0 to 10-point Likert scales, a 24-hour voiding diary, the Health Status Questionnaire for Quality of Life (SF-36), the Hospital Anxiety and Depression Scale, and the Female Sexual Function Index or International Index of Erectile Function. When applicable, additional analyses of the symptom outcomes may include evaluation of secondary response rates defined by specific changes in symptoms. Associations between changes from baseline in secondary outcomes and GRA will be used to supplement the primary endpoint analysis, and to evaluate the validity of the symptom scales for assessing change. |
| Change in Urinary Symptoms Measures | Baseline and 12 weeks | The O'Leary-Sant Interstitial Cystitis Symptom and Problem Indices, and the University of Wisconsin Interstitial Cystitis Symptom Inventory The IC Symptom Index is a 4-question survey w/ a severity scale from min.0(not at all) to max.5(always). The IC Problem Index is a 4-question survey with a severity scale ranging from min.0 (no problem) to max.4 (big problem). Higher subscale responses for each index indicate more severe symptoms. A sub-set of the University of Wisconsin Symptom Survey is designated as the Interstitial Cystitis Symptom Inventory w/ questions ranging from 0(not at all) to 6(a lot). Pts. reported symptoms the day of assessment. Scores ranged from 0 to 42. A higher score indicates more severe symptoms. Symptoms include: bladder pain; bladder discomfort; getting up at night to go to the bathroom; going to the bathroom frequently during the day; urgency to urinate; difficulty sleeping because of bladder problems; and burning sensation in the bladder. |
| Adherence to Study Drug and Urinary Educational/Behavioral Program (EBMP Educational/Behavioral Modification Program) | 12 weeks | Adherence to protocol treatment, to study drug and EBMP, at 6 weeks was assessed in 4 categories of 1) symptom management, 2) fluid management, 3) diet modification and 4) bladder training. For each of these EBMP categories adherence was defined as the overall percentage of participants who reported adhering to each component of the EBMP at each telephone contact or clinic visit. Subjects were classified into 3 groups based on the maximum dose obtained at 6 and 12 weeks as shown in the Outcome Measure Data Table below. |
| Change in Nighttime Voiding From Baseline to 12 Weeks | Baseline and 12 weeks | Baseline nighttime \[sleep period\] voiding frequency was collected by participant report on a Voiding Diary with entries for each void in a 24-hour period. Each void entry included the question: Did this void occur during your intended sleep period? Responses: 1=Yes, 0=No. The sum was totaled for Yes entries in response to this question. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1 - Active Comparator Amitryptiline, increased during a 6-week period from 10 mg up to 75 mg, taken once daily.
Amitriptyline: Amitriptyline will be titrated over a 6-week period as tolerated, to a maximum dose of 75mg. During the 6-week titration period, the patient who cannot tolerate a scheduled increased dose may adjust the medication dose for tolerance by tapering down one 25mg tablet. | 135 |
| 2 - Placebo Comparator Placebo will be dosed exactly as the active arm and taken once daily.
Placebo: Placebo will be dosed exactly as active arm. | 136 |
| Total | 271 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal lab result | 0 | 1 |
| Overall Study | Adverse Event | 7 | 2 |
| Overall Study | Lack of Efficacy | 3 | 6 |
| Overall Study | Lost to Follow-up | 10 | 6 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Personal constraints | 0 | 2 |
| Overall Study | Use of unacceptable medication | 1 | 0 |
Baseline characteristics
| Characteristic | 2 - Placebo Comparator | 1 - Active Comparator | Total |
|---|---|---|---|
| 24-Hr voiding frequency | 13.7 Voiding events STANDARD_DEVIATION 5.7 | 13.9 Voiding events STANDARD_DEVIATION 5.2 | 13.8 Voiding events STANDARD_DEVIATION 5.5 |
| Age, Continuous | 39.9 years STANDARD_DEVIATION 14 | 38.0 years STANDARD_DEVIATION 13.8 | 39.0 years STANDARD_DEVIATION 13.9 |
| Frequency score | 6.8 units on a scale STANDARD_DEVIATION 1.8 | 6.8 units on a scale STANDARD_DEVIATION 1.7 | 6.8 units on a scale STANDARD_DEVIATION 1.8 |
| Interstitial Cystitis Problem Index | 11.2 units on a scale STANDARD_DEVIATION 3 | 11.1 units on a scale STANDARD_DEVIATION 2.8 | 11.2 units on a scale STANDARD_DEVIATION 2.9 |
| Interstitial Cystitis Symptom Index | 12.0 units on a scale STANDARD_DEVIATION 3.6 | 12.2 units on a scale STANDARD_DEVIATION 3.1 | 12.1 units on a scale STANDARD_DEVIATION 3.4 |
| Nighttime voiding frequency | 3.0 Voiding events STANDARD_DEVIATION 2.8 | 2.4 Voiding events STANDARD_DEVIATION 1.8 | 2.7 Voiding events STANDARD_DEVIATION 2.3 |
| Pain score | 6.0 units on a scale STANDARD_DEVIATION 1.8 | 5.8 units on a scale STANDARD_DEVIATION 1.5 | 5.9 units on a scale STANDARD_DEVIATION 1.7 |
| Participants ever diagnosed with IC/PBS | 75 Participants | 62 Participants | 137 Participants |
| 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 | 15 Participants | 18 Participants | 33 Participants |
| Race (NIH/OMB) More than one race | 17 Participants | 21 Participants | 38 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 | 104 Participants | 96 Participants | 200 Participants |
| Sex: Female, Male Female | 111 Participants | 115 Participants | 226 Participants |
| Sex: Female, Male Male | 25 Participants | 20 Participants | 45 Participants |
| University of Wisconsin Symptom Inventory | 26.7 units on a scale STANDARD_DEVIATION 8.3 | 25.9 units on a scale STANDARD_DEVIATION 8.6 | 26.3 units on a scale STANDARD_DEVIATION 8.5 |
| Urgency score | 6.4 units on a scale STANDARD_DEVIATION 1.8 | 6.4 units on a scale STANDARD_DEVIATION 1.8 | 6.4 units on a scale STANDARD_DEVIATION 1.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 135 | 0 / 136 |
| other Total, other adverse events | 119 / 135 | 98 / 136 |
| serious Total, serious adverse events | 2 / 135 | 3 / 136 |
Outcome results
Primary
Global Response Assessment (GRA)
The primary efficacy analysis was based on intent to treat, comparing the proportion of responders between treatment arms on a patient reported GRA recorded at 12 weeks or study withdrawal. The 7-point GRA queried, As compared to when you started the current study, how would you rate your overall symptoms now? The 7 response options were markedly worse, moderately worse, slightly worse, the same, slightly improved, moderately improved and markedly improved. Participants who indicated that they were markedly or moderately improved were considered responders. Subjects who withdrew from the study for any reason and did not provide data on the primary outcome were considered treatment failures, and were included in the denominator for calculation of response rates.
Time frame: 12 Weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 1 - Active Comparator | Global Response Assessment (GRA) | Marked/moderate improvement | 74 Participants |
| 1 - Active Comparator | Global Response Assessment (GRA) | Slight improvement, same or worse | 61 Participants |
| 2 - Placebo Comparator | Global Response Assessment (GRA) | Marked/moderate improvement | 61 Participants |
| 2 - Placebo Comparator | Global Response Assessment (GRA) | Slight improvement, same or worse | 75 Participants |
Secondary
Adherence to Study Drug and Urinary Educational/Behavioral Program (EBMP Educational/Behavioral Modification Program)
Adherence to protocol treatment, to study drug and EBMP, at 6 weeks was assessed in 4 categories of 1) symptom management, 2) fluid management, 3) diet modification and 4) bladder training. For each of these EBMP categories adherence was defined as the overall percentage of participants who reported adhering to each component of the EBMP at each telephone contact or clinic visit. Subjects were classified into 3 groups based on the maximum dose obtained at 6 and 12 weeks as shown in the Outcome Measure Data Table below.
Time frame: 12 weeks
Population: Consistent with intent to treat analytic strategies participants who did not provide data at 12 weeks, including 24 (18%) on amitriptyline and 17 (13%) on placebo, were considered treatment non-responders.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 1 - Active Comparator | Adherence to Study Drug and Urinary Educational/Behavioral Program (EBMP Educational/Behavioral Modification Program) | 50 mg or > achieved/maintained @ 12 wks | 62 Participants |
| 1 - Active Comparator | Adherence to Study Drug and Urinary Educational/Behavioral Program (EBMP Educational/Behavioral Modification Program) | 50 mg or > achieved, reduced < 50 by 12 wks | 27 Participants |
| 1 - Active Comparator | Adherence to Study Drug and Urinary Educational/Behavioral Program (EBMP Educational/Behavioral Modification Program) | 50 mg or greater not achieved | 46 Participants |
| 2 - Placebo Comparator | Adherence to Study Drug and Urinary Educational/Behavioral Program (EBMP Educational/Behavioral Modification Program) | 50 mg or > achieved/maintained @ 12 wks | 98 Participants |
| 2 - Placebo Comparator | Adherence to Study Drug and Urinary Educational/Behavioral Program (EBMP Educational/Behavioral Modification Program) | 50 mg or > achieved, reduced < 50 by 12 wks | 20 Participants |
| 2 - Placebo Comparator | Adherence to Study Drug and Urinary Educational/Behavioral Program (EBMP Educational/Behavioral Modification Program) | 50 mg or greater not achieved | 18 Participants |
Secondary
Change in Nighttime Voiding From Baseline to 12 Weeks
Baseline nighttime \[sleep period\] voiding frequency was collected by participant report on a Voiding Diary with entries for each void in a 24-hour period. Each void entry included the question: Did this void occur during your intended sleep period? Responses: 1=Yes, 0=No. The sum was totaled for Yes entries in response to this question.
Time frame: Baseline and 12 weeks
Population: Changes in nighttime voids from baseline to 12 weeks were reported by treatment arm for those with available data at those points. Nighttime \[sleep period\] voiding frequency was collected by participant report on a Voiding Diary with entries for each void in a 24-hour period. Each void entry included the question: Did this void occur during your intended sleep period? Responses: 1=Yes, 0=No. The sum was totaled for Yes entries in response to this question.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 - Active Comparator | Change in Nighttime Voiding From Baseline to 12 Weeks | -0.9 Change in voiding events | Standard Deviation 2.4 |
| 2 - Placebo Comparator | Change in Nighttime Voiding From Baseline to 12 Weeks | -0.9 Change in voiding events | Standard Deviation 2.4 |
Secondary
Change in Urinary Symptoms Measures
The O'Leary-Sant Interstitial Cystitis Symptom and Problem Indices, and the University of Wisconsin Interstitial Cystitis Symptom Inventory The IC Symptom Index is a 4-question survey w/ a severity scale from min.0(not at all) to max.5(always). The IC Problem Index is a 4-question survey with a severity scale ranging from min.0 (no problem) to max.4 (big problem). Higher subscale responses for each index indicate more severe symptoms. A sub-set of the University of Wisconsin Symptom Survey is designated as the Interstitial Cystitis Symptom Inventory w/ questions ranging from 0(not at all) to 6(a lot). Pts. reported symptoms the day of assessment. Scores ranged from 0 to 42. A higher score indicates more severe symptoms. Symptoms include: bladder pain; bladder discomfort; getting up at night to go to the bathroom; going to the bathroom frequently during the day; urgency to urinate; difficulty sleeping because of bladder problems; and burning sensation in the bladder.
Time frame: Baseline and 12 weeks
Population: Change between the Baseline and 12-week time points is reported for each measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1 - Active Comparator | Change in Urinary Symptoms Measures | IC Symptom Index | -4.8 Change in score baseline to 12 weeks | Standard Deviation 3.7 |
| 1 - Active Comparator | Change in Urinary Symptoms Measures | IC Problem Index | -5.2 Change in score baseline to 12 weeks | Standard Deviation 3.9 |
| 1 - Active Comparator | Change in Urinary Symptoms Measures | Wisconsin Symptom Survey | -13.1 Change in score baseline to 12 weeks | Standard Deviation 10.2 |
| 2 - Placebo Comparator | Change in Urinary Symptoms Measures | IC Symptom Index | -3.3 Change in score baseline to 12 weeks | Standard Deviation 3.9 |
| 2 - Placebo Comparator | Change in Urinary Symptoms Measures | IC Problem Index | -3.9 Change in score baseline to 12 weeks | Standard Deviation 4 |
| 2 - Placebo Comparator | Change in Urinary Symptoms Measures | Wisconsin Symptom Survey | -9.3 Change in score baseline to 12 weeks | Standard Deviation 9.3 |
Comparison: IC Symptom Index - change from baseline to 12 weeks95% CI: [-2.5, -0.5]
Comparison: IC Problem Index - change from baseline to 12 weeks95% CI: [-2.3, -0.2]
Comparison: Wisconsin Symptom Survey - change from baseline to 12 weeks95% CI: [-6.3, -1.3]
Secondary
Changes in Quality of Life Measures From Baseline to 12 Weeks
A number of secondary outcomes \[as detailed in the Baseline Measures section\] were assessed throughout the study. These outcomes include pain, urgency and frequency on 0 to 10-point Likert scales, a 24-hour voiding diary, the Health Status Questionnaire for Quality of Life (SF-36), the Hospital Anxiety and Depression Scale, and the Female Sexual Function Index or International Index of Erectile Function. When applicable, additional analyses of the symptom outcomes may include evaluation of secondary response rates defined by specific changes in symptoms. Associations between changes from baseline in secondary outcomes and GRA will be used to supplement the primary endpoint analysis, and to evaluate the validity of the symptom scales for assessing change.
Time frame: Baseline and 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1 - Active Comparator | Changes in Quality of Life Measures From Baseline to 12 Weeks | Pain score | -2.6 Change in score baseline to 12 weeks | Standard Deviation 2.5 |
| 1 - Active Comparator | Changes in Quality of Life Measures From Baseline to 12 Weeks | Urgency | -3.0 Change in score baseline to 12 weeks | Standard Deviation 2.5 |
| 1 - Active Comparator | Changes in Quality of Life Measures From Baseline to 12 Weeks | Frequency | -3.5 Change in score baseline to 12 weeks | Standard Deviation 2.3 |
| 1 - Active Comparator | Changes in Quality of Life Measures From Baseline to 12 Weeks | 24-Hr voiding frequency | -4.4 Change in score baseline to 12 weeks | Standard Deviation 5.4 |
| 2 - Placebo Comparator | Changes in Quality of Life Measures From Baseline to 12 Weeks | 24-Hr voiding frequency | -2.0 Change in score baseline to 12 weeks | Standard Deviation 3.9 |
| 2 - Placebo Comparator | Changes in Quality of Life Measures From Baseline to 12 Weeks | Pain score | -2.3 Change in score baseline to 12 weeks | Standard Deviation 2.4 |
| 2 - Placebo Comparator | Changes in Quality of Life Measures From Baseline to 12 Weeks | Frequency | -2.6 Change in score baseline to 12 weeks | Standard Deviation 2.5 |
| 2 - Placebo Comparator | Changes in Quality of Life Measures From Baseline to 12 Weeks | Urgency | -2.5 Change in score baseline to 12 weeks | Standard Deviation 2.6 |