Conditions: Cystitis, Interstitial
Keywords: Interstitial Cystitis Bladder Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 42
Healthy volunteers: yes

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.

Arms:
arm 1: Biological: Certolizumab pegol (Cimzia) 400 mg loading dose given subcutaneously at week 0, 2, and 4 followed by a maintenance dose at week 8 arm 2: Placebo: given subcutaneously at week 0, 2, 4, and week 8

Interventions: intervention 1: Certolizumab pegol intervention 2: Placebo
Intervention descriptions: intervention 1: 400 mg intervention 2: Normal saline

Protocol document:
ICF_002.pdf: 
Protocol Number: IC-201                                                                                                             Page 1 of 13 
Version Date July 21, 2015 
Approved 
July 21, 2015 
Aspire IRB 
 
Experimental Research Subject’s Bill of Rights  
California law, under Health & Safety Code Section 24172, requires that any 
person asked to take part as a subject in research involving a medical 
experiment, or any person asked to consent to such participation on behalf of 
another, is entitled to receive the following list of rights written in a language in 
which the person is fluent. This list includes the right to:  
1. Be informed of the nature and purpose of the experiment.  
2. Be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized.  
3. Be given a description of any attendant discomforts and risks reasonably to 
be expected from the experiment.  
4. Be given an explanation of any benefits to the subject reasonably to be 
expected from the experiment, if applicable.  
5. Be given a disclosure of any appropriate alternative procedures, drugs or 
devices that might be advantageous to the subject, and their relative risks and 
benefits.  
6. Be informed of the avenues of medical treatment, if any, available to the 
subject after the experiment if complications should arise.  
7. Be given an opportunity to ask any questions concerning the experiment or 
the procedures involved.  
8. Be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation in the 
medical experiment without prejudice.  
9. Be given a copy of the signed and dated written consent form.  
10. Be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, 
duress, coercion, or undue influence on the subject’s decision.  
 
 
________________________________________________     ______________ 
Signature of Subject 
 
 
 
                                   Date 
 
_______________________________________________       ______________ 
Signature of Witness 
                  
                     
             Date 


Protocol Number: IC-201                                                                                                             Page 2 of 13 
Version Date July 21, 2015 
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INFORMED CONSENT TO PARTICIPATE IN  
CLINICAL RESEARCH STUDY 
 
 
Title: An Investigator Initiated, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Efficacy of Certolizumab Pegol (Cimzia) 
For the Treatment of Interstitial Cystitis(IC) 
 
Sponsor:  Philip C. Bosch, M.D.   
 
 
 
 
Protocol Number:  IC-201  
 
Principal Investigator:  Philip C. Bosch, M.D. 
                                        651 E. Pennsylvania Ave. Ste. 201 
                                        Escondido, CA 92025 
 
 
 
  
24-Hour Telephone Number:   (760) 743-3135 
 
 
 
You are being asked to take part in this research study to evaluate an 
investigational treatment for interstitial cystitis (IC).  This study includes only 
individuals who voluntarily choose to participate.  Please take your time to make 
your decision.  You may choose to discuss this with your regular doctor, your 
friends and your family.  You are free to ask questions concerning this document. 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
The purpose of this research study is to evaluate an investigational treatment for 
interstitial cystitis (IC). IC is a chronic bladder disease that includes the following 
symptoms:  
 
• Urinary frequency during the day 
• Urinary frequency at night 
• Urinary urgency 
• Bladder discomfort relieved by voiding 
 
Presently, there is no cure for IC.   The responses to current approved 
treatments are poor.  Patients with IC have a poorer quality of life.  The cause of 
interstitial cystitis is unknown.  
 


Protocol Number: IC-201                                                                                                             Page 3 of 13 
Version Date July 21, 2015 
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This study is evaluating the drug certolizumab pegol (Cimzia) for improving the 
symptoms of patients with IC.  Certolizumab pegol is an injectable anti-
inflammatory medication. It has been available for use in the United States since 
the US Food and Drug Administration (FDA) approval for the treatment of 
Crohn’s disease on April 22, 2008. Certolizumab pegol (Cimzia) has 
subsequently been FDA approved for the treatment of rheumatoid arthritis, 
psoriasis, and ankylosing spondylitis.  These diseases have similar 
characteristics to IC.  This study is experimental as it will evaluate a new 
investigational use of certolizumab pegol (Cimzia) for the treatment of IC. Cimzia 
(certolizumab) is not approved for the treatment of IC.  
 
Patients participating in this study will be randomized (assigned randomly like 
flipping a coin) to receive injections of one of the following products:  
 
1. Certolizumab pegol (Cimzia)    
or 
2. Placebo (a substance containing no active medication) 
 
This is considered a double-blind, randomized study in which neither the patient 
nor the study doctor will know which injection the patient will receive.  Neither 
you, nor the doctor can choose whether you receive the active medication or the 
placebo. This allows for an unbiased evaluation of the results of the study.  In 
case of an emergency, the study doctor will be able to find out which injection the 
patient was given.   
 
HOW LONG IS THIS STUDY?  
 
There will be 4-6 weeks of screening, 10 weeks of the actual study, and then a 
follow up 4 and 8 weeks after the completion of the study. The total time involved 
is about 5 months. 
 
HOW MANY OTHER PEOPLE WILL BE IN THIS STUDY?  
 
There will be 20 patients receiving certolizumab pegol (Cimzia) and 10 patients 
receiving placebo for a total of 30 patients. After evaluation in the initial 30 
patients, the Study may potentially increase the study sample size to a total of 42 
study patients (an added 8 patients receiving certolizumab pegol (Cimzia) and 4 
patients receiving placebo). 
  
WHAT IF NEW INFORMATION BECOMES AVAILABLE? 
 
If new information in relation to this study becomes available that may be 
relevant to the purpose and safety of the study and  your willingness to continue 
participation in this study, you will be informed by the study doctor.   


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WHO IS ELIGIBLE FOR THE STUDY? 
 
Females who have been diagnosed with interstitial cystitis for more than six 
months and are between the ages of 18 and 65 are eligible to participate in this 
research study.   
 
WHAT WILL HAPPEN DURING THE STUDY? 
 
If you agree to take part in this research study, you will be required to sign and 
date this informed consent form before any procedures take place.   
 
Initial evaluation: 
 
1. You will complete an initial questionnaire detailing your personal and 
medical history. 
2. A complete medical history will be obtained. 
3. You will be given a complete physical exam by the study doctor. 
4. You will be instructed in behavior modification techniques to improve IC 
and/or Bladder Pain Syndrome (BPS) symptoms 
5. You will be required to take a tuberculosis (TB) skin test. 
6. You will be tested for Hepatitis B & C. 
7. You may be asked to have an HIV test.  This will dependent on how 
recent and/or how thorough your available medical records are. 
You will be told if the test results for TB, Hepatitis B, Hepatitis C, or HIV are 
positive.  A positive result from these tests will be reported to the local health 
department as required by state law.  The results from these tests are 
confidential and results will not be shared outside of this study except as required 
by state law.  There is always a chance that a breach in confidentiality could 
happen; this means that people that were not originally supposed to have this 
information could see these results.  Please speak to the study staff or your 
personal doctor, if you want to know more about what it could mean to you if 
somebody outside of this research study has access to this information. 
 
Re-Evaluation Visit  
You will be reassessed at least one month later for inclusion/exclusion criteria 
and determine study eligibility.  At this Re-Evaluation Visit: 
 
1. You will undergo laboratory work including blood and urine samples.  
2. If you are able to become pregnant your blood will be tested for 
pregnancy. You should not participate in this research if you are pregnant, 
or planning to become pregnant while in the study.  
 
 


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Study Visits: 
 
If after your re-evaluation visit, you are still eligible to participate in this study, you 
will come back approximately one week later (Baseline, Week 0) to begin the 
study. 
 
Baseline and Visits 1-3 (Weeks 0,2,4,8) 
At your Baseline Visit, you will be randomized to receive a skin (subcutaneous) 
injection of either certolizumab pegol (Cimzia) or the placebo.    
At this study visit and again at your visit on Week, 2, 4 and 8, the following 
procedures will take place:  
1. You will receive your injection 
2. You will be required to complete two questionnaires evaluating your 
interstitial cystitis symptoms at each visit. 
3. A urine sample will be done at each visit. 
4. A general health questionnaire will be done at each visit. 
5. A physical exam will be performed if indicated. 
 
Visits 4 (Weeks 10) 
At this study visit, the following procedures will take place:  
1. You will be required to complete two questionnaires evaluating your 
interstitial cystitis symptoms at each visit. 
2. A general health questionnaire will be done at each visit. 
3. A physical exam will be performed if indicated. 
 
Follow-Up 
A follow-up phone evaluation will be done with you four weeks (Week 14 and 18) 
after completion of the study. A final blood test, urine analysis, and tuberculosis 
skin test will be done. 
 
You are advised to tell your regular health care providers and any emergency 
care providers that you are participating in this research study. 
 
WHAT ARE THE POSSIBLE RISKS WITH THIS STUDY? 
 
The study drug has been associated with the following side effects, including 
redness or swelling at the injection site, rash, upper respiratory infection, or 
urinary tract infection. Serious side effects reported include infections caused by 
viruses, fungi, or bacteria, tuberculosis, cancer and demyelinating diseases (any 
condition that results in damage to the protective covering called a myelin sheath 


Protocol Number: IC-201                                                                                                             Page 6 of 13 
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that surrounds nerve fibers in your brain and spinal cord). Please ask the study 
doctor if you have any questions.    
More rare side effects may include, but not limited to: 
• shortness of breath;  
• swelling of the ankles, hands, or feet;  
• unexplained weight loss or weight gain;  
• swelling or itching of the face, tongue, lips, or throat;  
• trouble breathing;  
• skin or eyes look yellow: 
•  tiredness (fatigue);  
• poor appetite or vomiting;  
• pain on the right side of your stomach (abdomen);  
• dizziness;  
• numbness or tingling;  
• problems with your vision;  
• weakness in your arms or legs;  
• fever 
• bruising or bleeding;  
• unusually pale skin;  
• new or worsening joint pain; 
• butterfly-shaped rash on the nose and cheeks. 
 
Please notify the study doctor immediately if any of these side effects occur. 
 
The package insert of Certolizumab Pegol (Cimzia) is available for you to read. 
Please ask the study doctor for a copy and for more information that is available 
for patients taking this drug, so that you can read about the potential side effects 
and warnings associated with taking this study drug.  
  
Any of the drugs used in this study can interact with other medications, including 
over-the-counter, herbal and vitamin medicines.  Please inform the study doctor 
of all the medications you are currently taking.   
 
Especially tell your healthcare provider if you take the following medicines due to 
a higher chance for serious infections:  
• Kineret
 
(anakinra), Orencia
 
(abatacept), Rituxan
 
(rituximab), or Tysabri
 
(natalizumab).  
• Medicines called Tumor Necrosis Factor (TNF) blockers such as 
Remicade
 
(infliximab), Humira (adalimumab), Enbrel
 
(etanercept), or 
Simponi
 
(golimumab).  
 


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An allergic reaction is possible.  This reaction can be a mild rash or itching to a 
severe rash, including trouble breathing or swallowing. Please tell the study 
doctor immediately if you experience any of these symptoms.   
 
Blood sampling has  risks which include bruising, dizziness, or pain.  
 
There may be risks to being in this study that cannot be predicted.   
 
Please discuss these risks with the study doctor and your regular doctor. Many 
side effects subside shortly after the study drug is stopped, however, in some 
cases side effects can be serious or long-lasting.  Rarely are side effects 
permanent.  
 
Side effects occurring during the trial can be treated by the study doctor, if this is 
deemed necessary. It is important to inform the study doctor of any side effects.   
 
ARE THERE PREGNANCY RISKS? 
 
Women of child-bearing age may not participate in this study if they are pregnant 
or nursing.  Since no adequate and well-controlled studies of the study drug in 
pregnant women have been performed, women should not become pregnant 
while participating in this study.   
 
Women who think they are pregnant must tell the study doctor immediately. If 
you are of able to become pregnant, please discuss adequate methods of birth 
control with the study doctor.  
 
For more information about these risks and side effects, contact the study doctor. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
There will be no direct benefit from participating in this study.  Your symptoms 
may improve, stay the same or get worse.    
 
ALTERNATIVES: 
 
Your alternative is to NOT participate in this study and remain on your current 
treatment for IC. Your study doctor can give you more information on alternative 
current treatments for IC, and their risks. 
 
CONFIDENTIALITY 
 
Your personal information will be kept confidential to the extent permitted by law. 
The study cannot guarantee absolute confidentiality.  By signing this document,  


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you give permission to access your medical records at any time for data 
verification purposes.   
 
Organizations that may inspect and/or copy  your research records for quality 
assurance and data analysis include: 
 
• The study staff and researchers involved in the study 
• UCB- the pharmaceutical company that produces certolizumab pegol 
(Cimzia) 
• The U.S. Food and Drug Administration (FDA) 
• Aspire Independent Review Board (IRB) 
 
The results from the study, including laboratory tests, may be published for 
scientific purposes. Your identity will be kept confidential. 
 
In the rare event that your information is required to be disclosed by law to 
another entity, privacy laws may not apply. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can 
identify you.  At most, the Web site will include a summary of the results.  You 
can search this Web site at any time. 
 
WHAT ARE THE COSTS? 
 
There are no costs associated with being in this study.  You are responsible for 
your regular health care while in this study.   
 
INVESTIGATOR PAYMENT                                        
 
The study doctor and the study site have received grant funding to conduct this 
study. 
 
WILL YOU BE COMPENSATED DURING THE STUDY? 
 
You will not be compensated for participating in this research study.  
 
WHAT HAPPENS IF THERE ARE COMPLICATIONS OR INJURIES? 
 
If you experience a serious side effect, complications, or are injured because of 
participation in this study, please contact the study doctor promptly.  The study 
doctor can be reached at the phone number listed on page 1 of this document.  
The study doctor will provide any necessary medical treatment to help you 
promptly recover from the injury.    


Protocol Number: IC-201                                                                                                             Page 9 of 13 
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RIGHTS AS A RESEARCH SUBJECT 
 
Taking part in this study is voluntary.  You may choose not to take part or may 
leave the study at any time.  Leaving the study will not result in any penalty or 
loss of benefits to which  you are entitled.  However, if  you decide to stop 
participating in the study, you are encouraged to talk to the study doctor and your 
regular doctor first.   
 
 RESPONSIBILITIES AS A RESEARCH SUBJECT 
 
You will be asked to adhere to all instructions issued by the study doctor and 
study staff.  
 
You should answer all asked questions truthfully.  
 
If you do not comply with instructions, may be removed from the study.  
 
The study doctor may also exclude you from this study if he deems it detrimental 
to your health, or if you do not meet the study requirements.    
 
WHO TO CALL WITH QUESTIONS 
 
For questions, concerns or complaints about the study or a research-related 
injury, contact the study doctor (760) 743-3135. 
 
This study was reviewed by IRB.  The IRB will review the study to protect the 
rights and welfare of study participants.  If you have problems, concerns, 
suggestions, questions, or information about the study, or for information 
regarding study subject's rights, please call Aspire’s Study Participant Advocate 
at 1-877-366-5414 (toll free). 
 
Aspire IRB has approved the information provided in this informed consent form 
and has granted approval for the investigator to conduct the study.  IRB does not 
approve your participation in the study.  It is your responsibility to evaluate the 
information in this informed consent form and decide if you wish to participate in 
this study. 
 
SIGNATURE AND CONSENT TO BE IN THE STUDY 
 
Your signature below means that you have read the above information and have 
had the opportunity to ask questions concerning your participation in the study. 
Your questions have been answered to your satisfaction. Your signature confirms 
that you have received and read a copy of the California Experimental Bill of 
Rights.  Your signature confirms that you agree to participate in this research and 


Protocol Number: IC-201                                                                                                             Page 10 of 13 
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that you have been told that you can discontinue this study at any time.  You will 
be given a signed and dated copy of this agreement.  By signing this consent 
form you are not giving up any of your legal rights. 
 
 
___________________________________________ 
_____________ 
SIGNATURE OF SUBJECT 
 
 
 
 
 
DATE  
 
 
 
________________________________________________ 
PRINTED NAME OF SUBJECT 
 
 
I confirm that a copy of this consent form has been given to this person to read 
and that this person has been told about the study.  The contents of the consent 
form describing the study has been discussed with this person and I have made 
every effort to answer all questions to his or her satisfaction.  I have watched this 
person sign the consent form. 
 
 
 
___________________________________________ 
_______________ 
INVESTIGATORS SIGNATURE  
 
 
 
 
DATE  
 
Philip C. Bosch, MD 
INVESTIGATOR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Authorization to Use and Disclose Your Personal Health 
Information 
 
Title: An Investigator Initiated, Randomized, Double-Blind, 
Placebo-Controlled Study Evaluating the Efficacy of 
Certolizumab Pegol (Cimzia) For the Treatment of Interstitial 
Cystitis(IC) 
 
Sponsor:  Philip C. Bosch, M.D.  
 
 
Protocol Number:   IC-201 
 
Principal Investigator:   Philip C. Bosch, M.D. 
 
                     651 E. Pennsylvania Ave., Suite 201 
   Escondido, CA  92025 
 
24-Hour Telephone Number:   (760) 743-3135 
 
 
  
 
INTRODUCTION 
This authorization may have words that you do not understand.  Please ask 
the study doctor or staff to explain any words or information that you do 
not understand. 
 
The purpose of this form is to explain how details about your health and your 
personal information that you give us during this study will be used and shared 
with others.  
 
By signing this form, you allow the study doctor to use and share your personal 
health information collected during the course of this study. Please read this with 
the Informed Consent that you already signed for the above-mentioned study. All 
participation information is explained in that consent form.  
You do not have to sign this form.  However, if you choose not to sign this 
authorization, you may not participate in the study. 
 


Protocol Number: IC-201                                                                                                             Page 12 of 13 
Version Date July 21, 2015 
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Aspire IRB 
 
 
INFORMATION THAT MAY BE USED AND SHARED 
Information that may be used and given to others may include past, present and 
future health information collected during this study. Your personal information 
includes, but is not limited to the results of study related procedures as described 
in the informed consent. [e.g., subject questionnaires, laboratory tests, medical 
history and other study-related materials that are unique and specific to your 
participation in this clinical study]. 
 
Your personal health information will be used to carry out the research, to review 
records on the information collected in this study, to check how the study was 
carried out, or for other uses permitted by law.  
 
THIS INFORMATION MAY BE SEEN BY 
 
o The study doctor and staff 
o The study sponsor, UCB, Quest Labs 
o Aspire Independent Review Board (IRB) 
o The U.S. Food and Drug Administration 
o The Department of Health and Human Services 
o Government agencies that require reporting of reportable diseases 
o Individuals or companies that monitor the quality of research practice 
 
There may be other information that may be used and given to others that have 
not been stated above.  You should discuss this with the study doctor or a 
member of the staff and ask any questions that you may have about the sharing 
of your health information. 
 
 
HOW LONG IS THIS AUTHORIZATION IN EFFECT 
This authorization to use and disclose your personal health information expires 
when the study is finished, which should be complete by 1/1/2019. You must 
notify the study doctor in writing that you no longer want to share your 
information.  Information collected before the termination of your authorization 
may still be used for study purposes.    
 
If you decide that you no longer wish to have your personal health information 
shared, you may withdraw at any time.  However, once you do so, you can no 
longer continue to participate in the study.    
 
In addition: 
o You must provide a written request to the study doctor, listed on page 1, 
and tell him or her that you no longer want to share your information.  


Protocol Number: IC-201                                                                                                             Page 13 of 13 
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Revoking your authorization and choosing to no longer participate in this 
study, does not affect your treatment or any other benefits to which you 
would otherwise be entitled. 
o You will no longer be a part of this research study  
o The study doctor and staff can continue to share any of the information 
that they already have. 
 
Once the study doctor has shared your information with someone outside the 
study, it may no longer be protected. There is a chance that your information will 
be shared with others in ways that are not listed here and released without your 
permission.   
 
You have a right to see and copy of your information; however, you will not be 
able to see it while the research study is going on.   
 
 
 
AUTHORIZATION 
I agree to share my information as described in this form and I have 
received a signed and dated copy for my records. 
 
________________________ _________________________ 
 
_________ 
Printed Name of Study Participant  
 
Signature of Study Participant  
 
     Date 
 
 
The information contained in this document was fully and carefully 
explained to the study participant or the study participant’s legal 
representative. If applicable, I certify to the best of my knowledge that 
the study participant’s legal representative is authorized to sign this 
informed consent. 
 
 
Philip C. Bosch, MD               _____________________   _________ 
Investigator                                      Signature of Investigator 
      Date 
 

Prot_001.pdf: 
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. 


3 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 


7 
 
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 
 


10 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


13 
 
 
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16 
 
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SAP_000.pdf: 
Statistical Analysis Plan 
Pilot Study Evaluating the Efficacy of Certolizumab Pegol for Interstitial 
 
Sample size 
Previous IC/BPS studies demonstrated an approximate 20% placebo response rate [29]. 
Monotherapy response rate of certolizumab pegol in rheumatoid arthritis was 45% [21]. 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.  
 
Randomization 
Eligible participants were computer randomized and received either subcutaneous certolizumab 
pegol 400gm or placebo (sterile saline) in a 2:1 ratio at weeks 0, 2, 4, and 8. The study drug and 
placebo were provided in ready to use syringes that were identical other than the blinded ID 
number on the side of the syringe. 
 
Statistical analysis  
 
Any patient who withdrew from the study, for whatever reason, was classified as a non-
responder. 
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.