Cystitis, Interstitial
Conditions
Keywords
Interstitial, Cystitis, Bladder, Pain
Brief summary
A Randomized, Double-blind, Placebo Controlled Trial of Certolizumab Pegol in Women with Refractory Interstitial Cystitis/Bladder Pain Syndrome
Detailed description
Interstitial cystitis (IC) is a chronic disabling bladder syndrome characterized by urinary frequency, nocturia, urinary urgency, and pain or discomfort with bladder filling. There is no cure for IC and the treatment options are suboptimal. Patients with IC report significant negative effects on their physical and mental quality of life. The etiology of IC is unknown. Certain aspects of IC suggest that autoimmunity may play a role in initiating or sustaining the chronic inflammatory response. Bladder biopsies of patients with IC demonstrate an increase number of mast cells. Mast cell activation with the release of tumor necrosis factor (TNF) may mediate this bladder inflammation. Cimzia (certolizumab pegol) is a medication that blocks the effect of TNF. Cimzia (certolizumab pegol) is FDA approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn's disease. These diseases are similar to IC. In this study, the hypothesis being tested is that Cimzia (certolizumab pegol) will show efficacy in improving the symptoms of patients with IC.
Interventions
BIOLOGICALCertolizumab pegol
400 mg
DRUGPlacebo
Normal saline
Sponsors
UCB Pharma
ICStudy, LLC
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 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. A diagnosis of IC/BPS defined based on AUA guidelines as the following: an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than 6 months duration, in the absence of infection or identifiable causes, documented history or patient reported. 2. Only those patients with moderate to severe IC/BPS will be included in the study. 3. Able to provide informed consent to participate in the study and comply with study requirements 4. Able to provide written authorization for use and release of health and research study information 5. Written documentation of being provided California's Experimental Subject's Bill of Rights 6. Females ≥18 and ≤ 65 years of age previously diagnosed with interstitial cystitis/ bladder pain syndrome (IC/BPS) for a duration of greater than 6 months 7. Female patients of child-bearing potential must have a negative serum pregnancy test at Screening and use birth control while in the study. 8. O'Leary-Sant Interstitial Cystitis Symptom and Problem Indexes (OSPI) score ≥ 18 9. No history of any cancer. 10. No bacterial cystitis in previous 1 month 11. No active herpes in previous 3 months 12. Never treated with cyclophosphamide 13. No neurogenic bladder dysfunction (due to a spinal cord injury, stroke, Parkinson's disease, multiple sclerosis, spina bifida or diabetic cystopathy) 14. Absence of bladder, ureteral or urethral calculi for previous 3 months
Exclusion criteria
1. Symptoms are relieved at one month reevaluation visit after receiving IC/BPS behavior modification advice at screening visit. 2. Symptoms are relieved by antimicrobials, antibiotics, or other medications for IC/BPS 3. Pregnant women, lactating mothers, nursing mothers, women suspected of being pregnant and woman who plan to be pregnant during the course of the clinical trial 4. Males 5. Patients with inadequate renal, hepatic, or cardiac function 6. Patients with history of gross hematuria within 2 years. 7. Patients with the following medical history: Lower urinary tract anatomical anomaly, pelvic radiotherapy, or active genital herpes 8. Patients with a history of tuberculosis (TB), recent exposure to TB, or recent travel to TB endemic regions. Patients should have a recent negative PPD (or negative CXR) prior to receiving treatment. 9. Patients who have undergone cystoscopy under anesthesia with bladder biopsy, hydrodistension, or fulguration of Hunner's ulcer within 3 months 10. Patients taking the following treatments for interstitial cystitis at Screening: Intravesical BCG, corticosteroid therapy, cyclosporine, or TNF-alpha inhibitors. 11. Patients with a history of receiving live vaccine including Flumist® influenza vaccine in the past 3 months. 12. Patients with a history of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG-fusion protein. 13. Patients with a history of alcohol, analgesic or drug abuse within 2 years of Screening. 14. Patients with a history of any cancer. 15. Patients with a history of active Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) infection, or who are known carriers (Hepatitis B). 16. Patients with a history of invasive fungal infections, recent travel to regions endemic for the following invasive fungal infections: San Joaquin Fever, aspergillosis, histoplasmosis, candidiasis, coccidiodomycosis, blastomycosis, and pneumocystosis. 17. Patients with a history of diabetes mellitus. 18. Patients with a history of a neurologic disease included but not limited to central demyelinating diseases, including multiple sclerosis; and a history of peripheral demyelinating disease, including Guillain-Barre syndrome. 19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | Week 2 | Patient-reported global response assessment (GRA) such as Compared to when you began this trial, how would you rate your IC symptoms now? Study subjects reported their response to treatment of their pain, urgency, and overall status compared to their condition at trial start with a symmetric scale global response assessment (GRA) 28 at weeks 2, 4, 10, and 18. Possible responses were markedly worse (100% worse), moderately worse (50% worse), slightly worse (25% worse), no change (0% improvement), slightly improved (25% improvement), moderately improved (50% improvement), and markedly improved (100% improved). Treatment responders were defined by rating the GRA as moderately improved or markedly improved. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | Week 4, 10, 18 | Patient-reported global response assessment (GRA) such as Compared to when you began this trial, how would you rate your IC symptoms now? Study subjects reported their response to treatment of their pain, urgency, and overall status compared to their condition at trial start with a symmetric scale global response assessment (GRA) 28 at weeks 2, 4, 10, and 18. Possible responses were markedly worse (100% worse), moderately worse (50% worse), slightly worse (25% worse), no change (0% improvement), slightly improved (25% improvement), moderately improved (50% improvement), and markedly improved (100% improved). Treatment responders were defined by rating the GRA as moderately improved or markedly improved. |
| IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Value at Weeks 2, 4, 10 and 18 minus Baseline | The Interstitial Cystitis Symptom Index is one of the two O'Leary-Sant Interstitial Cystitis Symptom and Problem Indexes. This scale has a 0 if the patient has no symptoms and a maximum of 19 with severe symptoms. Lubeck et al. validated ICSI as a valid measure of change in treatment outcome studies. A change of -4.03 in the ICSI score was the same as a 2 point improvement in GRA. Propert et al. validated the ICSI as responsive to change in IC/BPS symptoms and was recommended as secondary endpoints in clinical trials. A change of -2.4 in the ICSI score was the same as a 2 point improvement in GRA. |
| IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Value of Weeks 2, 4, 10, and 18 minus baseline | The Interstitial Cystitis Symptom Index (ICPI) is one of the two O'Leary-Sant Interstitial Cystitis Symptom and Problem Indexes. This scale has a 0 if the patient has no symptoms and a maximum of 16 with severe symptoms. |
| Pain Scale | Value at Weeks 2, 4, 10, and 18 minus baseline | an 11-point pain intensity numerical rating scale. Subjects rated their average pain, pressure, or discomfort associated with their bladder using an 11-point pain intensity numerical rating scale of 0-no pain to 10-worse ever pain at baseline, and at weeks 2, 4, 10, and 18. Meaningful, clinically important pain relief is a reduction in pain of approximately 30% from baseline. |
| Urgency Scale | Value of Weeks 2, 4, 10, and 18 minus baseline | Subjects rated their average urinary urgency or need to urinate using an 11-point numerical rating scale of 0-no urgency to 10-worse ever urgency |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from my practice, web site, and Urology clinic at UCSD from December 10, 2015 through March 1, 2017.
Pre-assignment details
There were 3 patients who did not meet screening criteria. Twenty-four patients had sufficient improvement in their IC/BPS symptoms and did not continue with the drug versus placebo phase of the study.
Participants by arm
| Arm | Count |
|---|---|
| Certolizumab Pegol Experimental drug certolizumab pegol 400mg. | 28 |
| Placebo Normal saline | 14 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Moved out of area | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Certolizumab Pegol | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 46.9 years STANDARD_DEVIATION 12.7 | 49.9 years STANDARD_DEVIATION 10.7 | 47.9 years STANDARD_DEVIATION 10.8 |
| O'Leary Sant Symptom and Problem Index | 26.8 units on a scale STANDARD_DEVIATION 5.2 | 26.7 units on a scale STANDARD_DEVIATION 4.8 | 26.8 units on a scale STANDARD_DEVIATION 5.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 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 | 24 Participants | 13 Participants | 37 Participants |
| Region of Enrollment United States | 28 Count of participants | 14 Count of participants | 42 Count of participants |
| Sex: Female, Male Female | 28 Participants | 14 Participants | 42 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 / 28 | 0 / 14 |
| other Total, other adverse events | 7 / 28 | 4 / 14 |
| serious Total, serious adverse events | 0 / 28 | 0 / 14 |
Outcome results
Primary
IC/BPS Symptoms Change With Overall Global Response Assessment (GRA)
Patient-reported global response assessment (GRA) such as Compared to when you began this trial, how would you rate your IC symptoms now? Study subjects reported their response to treatment of their pain, urgency, and overall status compared to their condition at trial start with a symmetric scale global response assessment (GRA) 28 at weeks 2, 4, 10, and 18. Possible responses were markedly worse (100% worse), moderately worse (50% worse), slightly worse (25% worse), no change (0% improvement), slightly improved (25% improvement), moderately improved (50% improvement), and markedly improved (100% improved). Treatment responders were defined by rating the GRA as moderately improved or markedly improved.
Time frame: Week 2
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: Experimental | IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | 2 Participants |
| Group 2: Placebo Comparator | IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | 1 Participants |
Secondary
IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI)
The Interstitial Cystitis Symptom Index (ICPI) is one of the two O'Leary-Sant Interstitial Cystitis Symptom and Problem Indexes. This scale has a 0 if the patient has no symptoms and a maximum of 16 with severe symptoms.
Time frame: Value of Weeks 2, 4, 10, and 18 minus baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: Experimental | IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Week 2 | -1.4 units on a scale | Standard Deviation 2.4 |
| Group 1: Experimental | IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Week 4 | -2.3 units on a scale | Standard Deviation 3.4 |
| Group 1: Experimental | IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Week 10 | -4.1 units on a scale | Standard Deviation 4.4 |
| Group 1: Experimental | IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Week 18 | -4.8 units on a scale | Standard Deviation 4.8 |
| Group 2: Placebo Comparator | IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Week 18 | -1.8 units on a scale | Standard Deviation 3.9 |
| Group 2: Placebo Comparator | IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Week 2 | -1.4 units on a scale | Standard Deviation 2 |
| Group 2: Placebo Comparator | IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Week 10 | -2.3 units on a scale | Standard Deviation 3.2 |
| Group 2: Placebo Comparator | IC/BPS Symptoms Assessment With the Interstitial Cystitis Problem Index (ICPI) | Week 4 | -2.3 units on a scale | Standard Deviation 4 |
Secondary
IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index
The Interstitial Cystitis Symptom Index is one of the two O'Leary-Sant Interstitial Cystitis Symptom and Problem Indexes. This scale has a 0 if the patient has no symptoms and a maximum of 19 with severe symptoms. Lubeck et al. validated ICSI as a valid measure of change in treatment outcome studies. A change of -4.03 in the ICSI score was the same as a 2 point improvement in GRA. Propert et al. validated the ICSI as responsive to change in IC/BPS symptoms and was recommended as secondary endpoints in clinical trials. A change of -2.4 in the ICSI score was the same as a 2 point improvement in GRA.
Time frame: Value at Weeks 2, 4, 10 and 18 minus Baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: Experimental | IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Week 2 | -1.9 units on a scale | Standard Deviation 2.7 |
| Group 1: Experimental | IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Week 4 | -3.3 units on a scale | Standard Deviation 3.4 |
| Group 1: Experimental | IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Week 10 | -4.1 units on a scale | Standard Deviation 4.8 |
| Group 1: Experimental | IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Week 18 | -5.1 units on a scale | Standard Deviation 4.9 |
| Group 2: Placebo Comparator | IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Week 18 | -1.5 units on a scale | Standard Deviation 4.6 |
| Group 2: Placebo Comparator | IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Week 2 | -0.6 units on a scale | Standard Deviation 2.4 |
| Group 2: Placebo Comparator | IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Week 10 | -2.8 units on a scale | Standard Deviation 3.2 |
| Group 2: Placebo Comparator | IC/BPS Symptoms Assessment With the Interstitial Cystitis Symptom Index | Week 4 | -1.5 units on a scale | Standard Deviation 3 |
Secondary
IC/BPS Symptoms Change With Overall Global Response Assessment (GRA)
Patient-reported global response assessment (GRA) such as Compared to when you began this trial, how would you rate your IC symptoms now? Study subjects reported their response to treatment of their pain, urgency, and overall status compared to their condition at trial start with a symmetric scale global response assessment (GRA) 28 at weeks 2, 4, 10, and 18. Possible responses were markedly worse (100% worse), moderately worse (50% worse), slightly worse (25% worse), no change (0% improvement), slightly improved (25% improvement), moderately improved (50% improvement), and markedly improved (100% improved). Treatment responders were defined by rating the GRA as moderately improved or markedly improved.
Time frame: Week 4, 10, 18
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Experimental | IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | Week 4 | 8 Participants |
| Group 1: Experimental | IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | Week 10 | 12 Participants |
| Group 1: Experimental | IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | Week 18 | 15 Participants |
| Group 2: Placebo Comparator | IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | Week 4 | 3 Participants |
| Group 2: Placebo Comparator | IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | Week 10 | 3 Participants |
| Group 2: Placebo Comparator | IC/BPS Symptoms Change With Overall Global Response Assessment (GRA) | Week 18 | 1 Participants |
Secondary
Pain Scale
an 11-point pain intensity numerical rating scale. Subjects rated their average pain, pressure, or discomfort associated with their bladder using an 11-point pain intensity numerical rating scale of 0-no pain to 10-worse ever pain at baseline, and at weeks 2, 4, 10, and 18. Meaningful, clinically important pain relief is a reduction in pain of approximately 30% from baseline.
Time frame: Value at Weeks 2, 4, 10, and 18 minus baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: Experimental | Pain Scale | Week 2 | -0.9 units on a scale | Standard Deviation 1.7 |
| Group 1: Experimental | Pain Scale | Week 4 | -1.1 units on a scale | Standard Deviation 1.9 |
| Group 1: Experimental | Pain Scale | Week 10 | -2.0 units on a scale | Standard Deviation 2.8 |
| Group 1: Experimental | Pain Scale | Week 18 | -2.4 units on a scale | Standard Deviation 2.9 |
| Group 2: Placebo Comparator | Pain Scale | Week 18 | -0.4 units on a scale | Standard Deviation 2.2 |
| Group 2: Placebo Comparator | Pain Scale | Week 2 | -0.8 units on a scale | Standard Deviation 1.8 |
| Group 2: Placebo Comparator | Pain Scale | Week 10 | -0.6 units on a scale | Standard Deviation 2.1 |
| Group 2: Placebo Comparator | Pain Scale | Week 4 | -0.1 units on a scale | Standard Deviation 1.4 |
Secondary
Urgency Scale
Subjects rated their average urinary urgency or need to urinate using an 11-point numerical rating scale of 0-no urgency to 10-worse ever urgency
Time frame: Value of Weeks 2, 4, 10, and 18 minus baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1: Experimental | Urgency Scale | Week 2 | -0.8 units on a scale | Standard Deviation 1.7 |
| Group 1: Experimental | Urgency Scale | Week 4 | -1.0 units on a scale | Standard Deviation 2.1 |
| Group 1: Experimental | Urgency Scale | Week 10 | -1.6 units on a scale | Standard Deviation 3 |
| Group 1: Experimental | Urgency Scale | Week 18 | -2.6 units on a scale | Standard Deviation 2.9 |
| Group 2: Placebo Comparator | Urgency Scale | Week 18 | -0.8 units on a scale | Standard Deviation 1.6 |
| Group 2: Placebo Comparator | Urgency Scale | Week 2 | -0.6 units on a scale | Standard Deviation 1.4 |
| Group 2: Placebo Comparator | Urgency Scale | Week 10 | -1.1 units on a scale | Standard Deviation 2.4 |
| Group 2: Placebo Comparator | Urgency Scale | Week 4 | -0.6 units on a scale | Standard Deviation 2.1 |