Pilot Study Evaluating the Efficacy of Certolizumab Pegol for Interstitial Cystitis
Phase: PHASE3
Conditions: Cystitis, Interstitial
Sponsor: ICStudy, LLC

1 
 
 
 
STUDY PROTOCOL 
 
IC-201 
Protocol Number 
FDA IND Number: 127083 
 
Pilot Study Evaluating the Efficacy of Certolizumab Pegol for Interstitial Cystitis  
Protocol Title 
 
Date   
November 5, 2015 
 
Philip C. Bosch, MD, Urologist 
Principal Investigator 
Email: pboschmd@gmail.com 
pbosch@ucsd.edu 
Cell phone: (760) 518-2421 
 
IC Study, LLC 
Official Name 
651 E. Pennsylvania Ave. Ste. 201 
Escondido, CA 92025 
(760) 743-0532 
Email: icbpsstudy@gmail.com 
Web site: ICStudy.net 
 
Philip C. Bosch, MD  
Recruitment and Study Sites 
651 E. Pennsylvania Ave. Ste. 201 
Escondido, CA 92025 
(760) 743-3135 
 
Department of Urology 
University of California, San Diego Medical Center 
200 West Arbor Drive 
San Diego, CA USA 92103 
 
Laboratory                                                    
Quest Diagnostics 
8410 Fallbrook Ave. 

2 
 
West Hills, CA  91304 
800 287-4309  
Institutional Review Board 
Aspire IRB   
Protocol: IC-201 
Approval: 7/24/2015 
11491 Woodside Ave. 
Santee, CA 92071 
619 469-0108 
 
Purpose and Study Background 
Interstitial cystitis/ bladder pain syndrome (IC/BPS) is a chronic, debilitating bladder disease 
characterized by suprapubic pressure or pain accompanied by urinary frequency and urgency, in 
the absence of an identifiable cause.1-3 Population based studies have demonstrated a prevalence 
rate of 3 to 12 percent among women4-6 and 2 to 4 percent for men.4 The symptoms of IC/BPS 
result in a poor quality of life with sleep dysfunction, sexual dysfunction, depression, anxiety, 
and stress.7-9  
 
The pathogenesis of IC/BPS is undefined. Treatments of IC/BPS have been empirical and 
inadequate.10-12 Narcotics are the most commonly prescribed medication.13 The direct cost of 
medical care for IC/BPS patients is > $11,000 per year.14 There are also the indirect costs to 
society including work absenteeism and decreased productivity. Investigation of novel therapies 
is needed. 
 
IC/BPS has been postulated to be one of the autoimmune diseases. Like autoimmune 
diseases, IC/BPS affects more women than men. Infection and stress worsen both conditions.  
Pregnancy improves symptoms for both IC/BPS and autoimmune diseases. There is a clinical 
concordance of IC/BPS with other established autoimmune diseases.15 IC/BPS as an autoimmune 
disease is not a new theory. In 1938 Fister recognized the clinical and histopathologic similarities 
between IC/BPS and lupus erythematosus.16 In the 1980 review article, Oravisto viewed IC/BPS 
as an autoimmune disease due to the very chronic course of the disease, the absence of infection, 
the pathological findings, the common occurrence of antinuclear antibodies, and the response to 
certain modalities of treatment.17 Immunosuppressive drugs including methotrexate, prednisone, 
and cyclosporine A, routinely used to treat autoimmune diseases, have shown efficacy in 
selected IC/BPS patients.18-20 There are more than 80 different documented autoimmune diseases 
affecting every organ and tissue in the body. IC/BPS may be the autoimmune disease of the 
bladder. 

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Selective release of tumor necrosis factor-alpha (TNFα) by mast cells (MC) plays a 
central role in the pathogenesis and pathophysiology of IC/BPS. Bladder biopsies of patients 
with IC demonstrate increase numbers of MC.21-23 A selective release or degranulation of 
vasoactive and proinflammatory mediators by MC, a process called "activation", may explain 
IC/BPS pathogenesis.24,25 MC activation elicits an inflammatory response in urothelial cell 
IC/BPS models with secreted product TNFα playing a central role.26,27 Inflammation in 
experimental IC/BPS was mediated by TNFα.26,28-30 Drugs that inhibited TNFα decreased this 
experimental IC/BPS bladder inflammation. Interruption of mast cell activation, with a decrease 
expression of TNFα, inhibited bladder inflammation in an autoimmune cystitis model.31   
Elevated levels of TNFα in urine, serum, and tissue were found in patients with IC/BPS. 
TNFα, a proinflammatory cytokine released by immune cells, is central to the acute and chronic 
inflammation in autoimmune diseases.32,33 Patients with clinically diagnosed IC/BPS, but no 
glomerulations observed with cystoscopy under anesthesia after hydrodistention, had elevated 
levels of TNFα in urine or bladder wash fluid.34 However, patients with clinically diagnosed 
IC/BPS, but did have glomerulations observed with cystoscopy under anesthesia after 
hydrodistention, did not have elevated levels of TNFα in urine or bladder wash fluid compared to 
controls. Interestingly, cystoscopic findings were not felt to identify distinct subgroups of 
patients with IC/BPS symptoms.35 TNFα was upregulated in urine of patients with overactive 
bladder36, a syndrome that has been considered a milder form of IC/BPS.37 Serum levels of 
TNFα were significantly higher in patients with IC/BPS.38 Tissue levels of TNFα were 
significantly elevated in women with vulvar vestibulitis.39 Vulvar vestibulitis, also known as 
vulvodynia is part of the symptom complex in women with IC/BPS.40 TNFα is highly expressed 
in bladder urothelium tissue of patients with ulcerative IC/BPS and was suggested to be the 
causative etiology of IC/BPS.41   
 
I recently completed a study (ClinicalTrials.gov Identifier NCT01295814) "A 
Randomized, Double-Blind, Placebo Controlled Trial of Adalimumab in the Treatment of 
Interstitial Cystitis/Bladder Pain Syndrome".42 Adalimumab is one of several biological agents 
that are known as TNFα antagonists or TNFα blocking agents. Adalimumab is a recombinant, 
fully human, monoclonal antibody that neutralizes human TNFα. In this study adalimumab 
treatment demonstrated a statistically significant improvement in outcome measures compared to 
baseline in patients with moderate to severe IC/BPS. However, adalimumab failed to 
demonstrate positive proof of concept compared to placebo due to a significant placebo effect. 
This confounding result was evaluated and analyzed in my paper “Examination of the Significant 
Placebo Effect in the Treatment of Interstitial Cystitis/ Bladder Pain Syndrome”.43  The 

4 
 
conclusions of this paper were that this greater "placebo effect" represented the benefits of 
advice, support, education, and behavior modification programs. The recommendation was that 
physicians should review standard advice with all IC/BPS patients before starting medical 
therapy or clinical trials. Future studies should include a washout period after subjects receive 
standard IC/BPS advice. Only those patients who do not improve with standard IC advice and 
therapy would be participants in clinical trials. 
Current understanding of the TNFα blocking agents recognizes differences in each of 
their mechanism of action and clinical experience. Adalimumab may not theoretically be the best 
TNFα blocking agent for the treatment of IC/BPS. Adalimumab mediates complement-
dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Adalimumab 
increases the proportion of cells undergoing apoptosis and the level of granulocyte 
degranulation.44 This may not be therapeutically beneficial  as IC/BPS histologically 
demonstrates a pancystitis with mast cell infiltration.45 A total degranulation of these 
inflammatory cells with the release of histamine, cytokines, and proteolytic enzymes, typical of 
an anaphylactic reaction, may exacerbate bladder inflammation.   
Certolizumab pegol (Cimzia) has some advantages over other TNFα blocking agents for 
the treatment of IC/BPS including better distribution in inflamed tissue46, development of low 
levels of neutralizing autoantibodies47, greater affinity to TNFα 48, and efficacy when used in 
monotherapy49. Patients with rheumatoid arthritis treated with certolizumab pegol demonstrated 
a rapid clinical response, often within 2 weeks. Certolizumab pegol inhibits cytokine 
production.44 Certolizumab pegol has a unique mechanism of action that should be beneficial in 
the treatment of IC/BPS in that it has no complement-dependant cytotoxicity and antibody-
dependant cell-mediated cytotoxicity.44,50 IC/BPS histologically demonstrates a pancystitis with 
mast cell infiltration.45 The polyethylene glycol moiety of certolizumab pegol inhibits mast cell 
degranulation.51 TNFα blocking agents that do not cause cytolysis and prevents degranulation of 
these inflammatory cells should be therapeutically beneficial in the treatment of IC/BPS. 
Most trials in IC/BPS use a patient-reported global response assessment (GRA) such as 
“Compared to when you began this trial, how would you rate your IC symptoms now?” as the 
primary endpoint.52,53 The O'Leary-Sant Interstitial Cystitis Symptom Index and Problem Index 
(OSPI) questionnaire evaluates overall symptoms in IC/BPS patients.54  The OSPI results 
confirm the clinical diagnosis of IC/BPS and establish the severity of the participants IC/BPS 
baseline symptoms.  The Interstitial Cystitis Symptom Index (ICSI) is one of the two O'Leary-
Sant Interstitial Cystitis Symptom and Problem Indexes. ICSI has been validated as a reliable 

5 
 
and responsive measure of changes in IC/BPS symptoms.53,55 ICSI is recommended as an 
endpoint in IC clinical trials. 
 
Research has searched unsuccessfully for an inflammatory urine biomarker for the 
diagnosis of IC/BPS. However, Felson34 demonstrated elevated urine TNFα levels measured by 
ELISA in patients with IC/BPS compared to controls. It would be interesting to measure urine 
TNFα levels with modern techniques in IC/BPS patients and see if those levels go down with 
certolizumab pegol treatment. 
 
The FDA asked for more outcome measures so ICPI and numeric rating scale for pain 
and urgency was added. They asked for monitoring of patient with outcome data to week 18. We 
also agreed to change the potential total number of patients from 44 to 42 as this would maintain 
the 2:1 study medication ratio. 
 
Condition  
Intervention  
Phase  
Cystitis, Interstitial 
Bladder Pain Syndrome 
Biological: Certolizumab pegol (Cimzia) 
Other: Placebo 
Phase III 
 
Study Type: 
Interventional 
Study Design:
Randomized, Double-Blind, Placebo Controlled Treatment, Efficacy Study 
 
Primary Outcome Measures  
The primary endpoint is improvement in global response assessment (GRA) at week 2 
  
Secondary Outcome Measures 
Improvement in GRA at week 4, 10, and 18 
Improvement in the Interstitial Cystitis Symptom Index (ICSI) Interstitial Cystitis Problem Index 
(ICPI) from baseline to week 2, 4, 10, and 18 
11-point numeric pain and urgency scale at baseline, week 2, 4, 10, and 18 
Midstream first void urine specimen level of TNFα normalized to urinary creatinine, at week 2, 
4, 10, and 18 compared to baseline levels 
Adverse events from time of Screening through the last clinic and phone call visit 
 
 

6 
 
Estimated enrollment      42 patients  
After subjective evaluation of efficacy and safety in the initial 30 patients, the total study sample 
size will be 42 study patients.  
Previous IC/BPS studies demonstrated an approximate 20% placebo response rate.56 
Monotherapy response rate of certolizumab pegol in rheumatoid arthritis was 45%.49 To achieve 
an 80% power using 2:1 randomization and a 2-sided p = .05 a minimum of 39 subjects was 
required. The sample size was increased by 3 subjects to account for potential participant 
withdrawals.  
 
 
 
Arms 
Assigned Intervention 
Group 1: 
Experimental  
Biological: Certolizumab pegol (Cimzia) 400 mg pre-filled syringe loading 
dose given subcutaneously at week 0, 2, and 4 followed by a maintenance 
dose at week 8 
Group 2: Placebo 
Comparator 
Placebo: given subcutaneously at week 0, 2, 4, and week 8 
 
 
Eligibility   
Ages Eligible for Study:   18-65 
Genders Eligible for Study: Female 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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.  

8 
 
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.  
 
 
 
 
 
Study Design 
 
Patients enter a one month Screening period to assess inclusion/exclusion criteria, sign informed 
consent, and determine study eligibility.  At the initial screening visit, patients will be instructed 
in behavior modification techniques to improve IC/BPS symptoms.43  Patients are reassessed at 
least one month later for inclusion/exclusion criteria and determine study eligibility.  Patients 
who do not improve with standard IC/BPS advice and pass clinical and laboratory screening can 
be participants in the study.  Baseline evaluation of the included patients will be done with the 
O'Leary-Sant Interstitial Cystitis Symptom Index and Problem Index (OSPI). At the baseline 
visit (week 0), all eligible IC/BPS patients will be randomized in a blinded fashion to receive in a 
2:1 ratio either SQ certolizumab pegol 400mg or SQ placebo at weeks 0, 2, 4 followed by a 
maintenance dose at 8 weeks. The length of the study will be 18 weeks. The effectiveness of 
certolizumab pegol will be assessed at week 2, 4, 10, and 18 using GRA, ICSI, ICPI, and the 
numeric pain and urgency scale. After subjective evaluation of efficacy and safety in the initial 
30 patients, the total study sample size will be 42 study patients.  
 
 

9 
 
A midstream urine will be collected at baseline and weeks 2, 4, 10, and 18 from all participants.  
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA or similar lab will perform an 
ELISA TNFα and creatinine levels on these samples. 
 
 
 
 
 
 
Pilot Study Evaluating the Efficacy of CZP for Interstitial Cystitis 
Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial evaluation 
Medical screening 
Informed consent 
Standard IC advice 
 
Reevaluation >one month later 
Baseline OSPI 
Laboratory screening 
Randomization of eligible 
participants 
(n=30) 
 
Certolizumab pegol 400mg SQ 
at week 0, 2, 4, and 8 
(n=20) 
Placebo SQ at week 0, 2, 4, 
and 8 
(n=10) 
Outcome Measures 
GRA at week 2, 4, 10, 18 
ICSI at week 2, 4, 10, 18 
Outcome Measures 
GRA at week 2, 4, 10, 18 
ICSI at week 2, 4, 10, 18 
 

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Trial Schedule 
 
  
Screen 
>One Month 
Reevaluation 
Baseline 
Visit 
1 
Visits  
2, 3 
Visit 4 
Phone 
Follow-
up6 
Phone 
Follow-
up6 
Study Day 
-37 
-7 
0 
14 
28,56 
 
70 
 
98 
126 
Study Week 
-5 
-1 
0 
2 
4,8 
 
10 
 
14 
18 
Study 
procedures: 
 
 
 
 
 
 
 
 
 
 
Obtain Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Medication 
Review 
X 
X 
X 
X 
X 
 
X 
 
 
 
Vitals1 
X 
X 
X 
X 
X 
 
X 
 
 
 
Physical Exam  
X 
 
 
 
 
 
 
 
 
 
OSPI2 
X 
X 
 
 
 
 
 
 
 
 
anti-HCV, HBsAG 
 
X 
 
 
 
 
 
 
 
 
PPD 
 
X 
 
 
 
 
 
 
 
X 
CBC 
 
 
 
 
 
 
X 
 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
 
X 
 
 
 
Urine Culture 
 
X 
X 
X 
X 
 
X 
 
 
 
Urine Pregnancy 
Test  
 
X 
 
 
 
 
 
 
 
 
Eligibility 
Assessment 
X 
X 
 
 
 
 
 
 
 
 
Dispense Study 
Drug 
 
 
X 
X 
X 
 
 
 
 
 
Injection Site 
Evaluation3 
 
 
X 
X 
X 
 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
 
X 
 
X 
X 
GRA4 
 
 
 
X 
X 
 
X 
 
 
X 
ICSI,  ICPI5 
 
 
 
X 
X 
 
X 
 
 
X 
Numeric scale of 
pain and urgency 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1.  Height, weight, blood pressure, pulse, temperature 
 
 
2. O'Leary-Sant Interstitial Cystitis Symptom Index and Problem Index 
3. Monitor subjects for systemic and local hypersensitivity reactions for one hour after injection 

11 
 
 
 
4. Global response assessment 
 
 
5. Interstitial Cystitis Symptom Index, Interstitial Cystitis Problem Index  
6. In-office visit if determined to be clinically necessary 
 
 
 
Statistical Analysis 
 
All statistical summaries and 2-sample t-tests were performed using the Data Desk® version 6.3. 
Comparison of these changes between treatment groups are also shown as 95% confidence 
intervals (CI). The chi-square test or Fisher’s exact test was applied to analyze baseline 
demographics, improvement with GRA treatment responders, and the proportion of patients with 
a reduction from baseline of 30% or greater in their pain intensity score between treatment 
groups. 
 
 
Safety Evaluation 
 
Patients will be assessed at office visits and by continuous availability by phone for adverse events.  
Adverse effects may include rhinitis, headache, rash, pruritus, injection site reaction, infections, 
tuberculosis, cancer, and demyelinating diseases.   
 
Stopping Criteria for Adverse Events 
 
Serious infections: 
These include TB and infections caused by viruses, fungi, or bacteria. Symptoms related to TB 
include cough, low-grade fever, weight loss, or loss of body fat and muscle.  
 
Allergic reactions:  
 
Signs of a serious allergic reaction include skin rash, a swollen face, or trouble breathing.  
 
Nervous system problems:  

12 
 
Signs and symptoms include numbness or tingling, problems with your vision, weakness in your 
arms or legs, and dizziness.  
 
 
Blood problems:  
Symptoms include a fever that does not go away, bruising or bleeding very easily, or looking 
very pale.  
 
New heart failure or worsening of heart failure you already have:  
Symptoms include shortness of breath or swelling of your ankles or feet, or sudden weight gain.  
 
Immune reactions including a lupus-like syndrome: 
Symptoms include chest discomfort or pain that does not go away, shortness of breath, joint pain, 
or rash on your cheeks or arms that gets worse in the sun. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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