Timing of B and O Suppositories to Help Relieve Post-operative Bladder Spasms and Urinary Discomfort in Patients Undergoing Lithotripsy
Phase: PHASE4
Conditions: Overactive Bladder
Sponsor: Campbell Grant

1 
 
Version #4, 4/11/16 
 
TITLE: The effects of timing of administration of belladonna and opium 
suppositories on post-operative bladder spasms and urinary discomfort in patients 
undergoing lithotripsy. 
 
RESEARCH PLAN 
 
A. Specific Aims  
 
List the broad, long-term objectives and describe concisely and realistically what the  
specific research described in your proposal is intended to accomplish, and the 
hypothesis to be tested. 
 
The long-term objectives of the study are to determine whether earlier 
administration of Belladonna and opium (B and O) suppositories ameliorates the 
discomfort associated with bladder spasms and reduces the need for oral narcotics 
and antimuscarinics in the post-operative setting.  
 
Most patients who receive B and O suppositories in the post-operative period 
receive them in the PACU after expressing discomfort. The administration of B and O 
suppositories in these cases can often be hours from surgery end time.  
The hypothesis to be tested is that giving patients B and O suppositories prior to 
surgery or post-operatively while still in the operating room will reduce the amount 
of pain medications that people will need post-operatively, reduce the amount of 
discomfort that patients experience from bladder spasms, and possibly reduce the 
length of hospital stay. 
 
B. Background and Significance  
 
Briefly give the background to the present proposal, critically evaluate existing 
knowledge, and specifically identify the gaps which the project is intended to fill.  
Cite literature and include a list of references. 
 
Bladder Spasms are a frequent cause of discomfort in the post-operative setting 
after lithotripsy, and while B and O suppositories are occasionally used post-
operatively to relieve bladder spasms, there are no studies that show how effective 
they are. There are two studies that evaluated the use of B and O suppositories in a 
perioperative setting after robotic prostatectomies: 
 
Lukasewycz S, Holman M, Kozlowski P, Porter CR, Odom E, Bernards C, Neil N, 
Corman JM. Does a perioperative belladonna and opium suppository improve 
postoperative pain following robotic assisted laparoscopic radical prostatectomy? 

2 
 
Results of a single institution randomized study. Can J Urol. 2010 Oct;17(5):5377-
82. PubMed PMID: 20974030 
 
Scavonetto F, Lamborn DR, McCaffrey JM, Schroeder DR, Gettman MT, Sprung J, 
Weingarten TN. Prophylactic belladonna suppositories on anesthetic recovery after 
robotic assisted laparoscopic prostatectomy. Can J Urol. 2013 Jun;20(3):6799-804. 
PubMed PMID: 23783051. 
 
These two studies show a possible benefit to perioperative belladonna and opium 
suppositories. However, these studies have never evaluated the use of the 
suppositories in lithotripsy procedures where the bladder is dilated and drained 
multiple times during a procedure. The constant distension leads to bladder spasms 
in the post-operative setting, which require narcotics and anti-muscarinics. There 
are also no studies to evaluate the effect of timing of administration of these 
suppositories in lithotripsy cases on postoperative pain, the use of narcotics in the 
post-operative period, and length of hospital stay.  
 
C. Preliminary Studies  
 
Provide an account of the PI/IS's preliminary studies pertinent to the protocol 
and/or any other information that will help to establish the experience and 
competence of the PI/IS to pursue the proposed project.  The titles and complete 
references to appropriate publications and manuscripts submitted or accepted for 
publication may be listed. 
 
There have not been any preliminary studies done by the PI on this subject. 
However Dr. Mufarrij has several years experience dealing with lithotripsy patients 
in the post-operative setting. All attending physicians participating in this study 
have years of experience dealing with lithotripsy patients.  
 
D. Research Design and Methods  
 
Describe the research design and the procedures to be used to accomplish the 
specific aims of the project.  Include the means by which the data will be collected, 
analyzed, and interpreted.  
 
-1. Subjects will be identified as meeting inclusion criteria for this study during an 
office visit at the MFA urology clinic. Opportunity to participate in the study will be 
offered to the subject and informed consent obtained as appropriate. As noted 
above, patients will be informed of their right to not participate in the study. 
Ureteroscopy will still be offered to all patients who meet the appropriate 
indications, regardless of their participation in this study. Patients will be give a pre-
operative survey to determine the severity of any bladder spasms they are 

3 
 
experiencing before surgery and to gauge their level of narcotic usage in the acute 
setting pre-operatively.  
  
-2. The patients will be divided into three research arms. Patients will be randomly 
selected for one of the groups using a random number generator between 1 and 3. 
There will be a “Control Group” which will receive a rectal exam while still in the 
operating room in the lithotomy position after the procedure. There will be a 
“Postoperative OR” group which will receive a B and O suppository while still in the 
operating room in the lithotomy position after the procedure. Finally, there will be a 
“Preoperative OR” group which will receive a B and O suppository after the 
induction of anesthesia prior to beginning the urologic procedure in the lithotomy 
position. The “Control Group” will receive a rectal exam in the operating room after 
the procedure but before extubation to simulate the effects of suppository 
administration so that we know that any effects are due to the medication and not to 
the placement of the suppository itself. Those patients in the “control group” may 
receive a B and O suppository as part of standard procedure in the post-operative 
period if these individuals experience any bladder spasms and wish to have this as a 
treatment. This administration will be at the discretion of the operating surgeon as 
it is in standard cases. Patients may also receive Ditropan in the post-operative 
setting, which is part of the standard procedure for treating bladder spasms 
following urologic procedures. Patients in the postoperative and preoperative OR 
groups will be offered Ditropan for any bladder spasms in the post-operative setting 
to control symptoms, which is part of the normal standard of care for anyone who 
has already received a B and O suppository with inadequate control of symptoms. 
All patients will be treated with a normal post-operative pain regimen which may 
include narcotics. This will be at the discretion of the treating physician. 
  
-3. In the post-operative setting, all subjects will be given a quick survey within 24 
hours to assess their amount of discomfort related to bladder spasms/urinary 
discomfort.  In addition, subjects medical charts will be reviewed to determine the 
amount of antimuscarinics that the patient received 24 hours post-operatively and 
the amount of narcotic and non-narcotic pain medication that subjects required. 
Patients not in the experimental arm will be given oral anti-muscarnics to treat any 
bladder spasms that they may have, but will not be given suppositories.    
  
-4. Data will be entered into the database following the procedure as available. 
  
-5. Subjects will have clinically appropriate follow-up per the attending urologist. If, 
as part of that follow-up, clinically relevant events occur, the corresponding data 
will be recorded in the database.   
  
Note that, with the exception of which particular study arm the subjects are enrolled 
into and the recording of data as detailed above and below, there will be absolutely 

4 
 
no difference in the care received by patients choosing to participate in this study 
and those who elect not to participate. 
 
 
Data will be analyzed using commercially available statistical software. T-tests will 
be performed for continuous variables and Pearson's Chi-squared tests for 
categorical variables. Analysis will be tailored to compare B and O Supprettes 
Suppositories and placebo/no suppository in order to best answer the research 
question. 
 
1. Describe any new methodology and its advantage over existing methodologies.  
 
There are no methodologies in this protocol which are new.  
 
2. Discuss potential difficulties and limitations of the proposed procedures and 
alternative approaches to achieve the aims.   
 
The procedure is designed so that patients receive a B and O suppository as they 
would as part of standard protocol in the post-operative period if bladder spasms 
were experienced. The only difference is regarding timing of administration. 
Therefore, there are no potential difficulties or limitations of the proposed 
procedure since B and O administration is already a well-accepted treatment for 
bladder spasms following urologic procedures.  
 
3. Provide a tentative sequence or time table for the study.  
 
November 2015 - IRB approval and begin recruiting patients for study 
December 2015 - June 2016 Conducting study according to aforementioned 
protocol 
July 2016 - Begin data analysis and manuscript preparation  
 
4. Specify procedures, situations, or materials that may be hazardous to personnel 
and the precautions to be taken to ensure safety.  
 
None 
 
5. Provide justification of the sampling procedure and sample size.  Gender and 
Minority Inclusion, it is required that all research involving human subjects and  
human materials include minorities and women, as well as males and females of all  
ages.  If one gender and/or minorities are excluded or are inadequately represented  
in a protocol, particularly in proposed population-based studies, a clear compelling 
rationale for exclusion or inadequate representation should be provided. The 
composition of the study population must be described in terms of gender and 

5 
 
racial/ethnic group, together with a rationale for its choice (by age distribution, risk 
factors, incidence/prevalence, etc.)   
 
All participants undergoing lithotripsy procedures at GW hospital with the included 
physicians will be asked to participate in the study.  
 
We determined the expected effect sizes based on previous studies of this same  
treatment in patients who received robot-assisted laparoscopic surgery for prostate 
CA.   
Based on morphine equivalent dose in both Scavonetto, Lamborn, McCaffrey et al.  
(Can J. Urol 2013) and Lukaswycz, Holman, Kozlowski et al. (Can J Urol 2010), we  
would like to detect a 4 mg eq. difference between groups, with an expected 
standard deviation (sd) of 5, i.e., an effect size (d) of 0.8. For post-op pain rated on a 
10-point scale both of the previous studies found sd ~2.0. We would like to detect a 
1-point difference, so will power for an effect size of 0.5.  Scavonetto et al. found 
approximately 20% of patients required use of rescue B&O suppositories and 60% 
requiring Oxybutynin for post-op bladder spasm. Thus, for this outcome we will try 
to detect a difference in percent positive of 20%.  For all comparisons, we will use 2-
tailed tests with alpha=.05.  
 
Immediate post-op morphine equivalent dose.  
In order to have power >.80 to detect an effect size of 0.8 in morphine eq. dose, we 
would need n=26 per group, or total N=51. For power >.90, we would need 34 per 
group or total N=68. 
 
Post-op pain.  
For an effect size of 0.5, in order to have power >.80, we would need 64 per group, 
or total N=128. For power >.90, we would need 86 per group, or total N=172.  
 
Use of medication for bladder spasms.  
Here, we will want to detect a 20% difference between groups. Assuming that in the 
treatment group, 20% of patients need rescue medication for bladder spasm, while 
40% need such meds in the control group, we would need n=82 per group (total 
N=164) in order to detect a difference this large with power >.80.  
 
 Therefore, in order to have adequate power across all 3 outcome measures, we plan 
to enroll a total of 180 subjects, randomized equally across treatment and control 
groups. 
 
 
6. Identify all drugs and devices to be used, if applicable,.  If the drug or device is 
investigational under FDA policy, list the actual IND/IDE number and respective 
source, supplier, and/or sponsor.  If an IND/IDE has been assigned provide the FDA 

6 
 
stage status.  Note the proposed dosage related information including instructions 
for administering, adverse effects, compatibility in infusions, and stability. 
 
Please see package inserts for B and O supprette suppositories attached to this 
submission. We are also including Ditropan, which is the oral anti-muscarinic to be 
included in this study. The dosage of B&O will be 16.2mg/30mg which is in the 
formulary at GW. Ditropan will be given in the normal 5 mg dosage.  
 
7. Identify all procedures that will be used for the purpose of this research.  If blood 
is to be drawn, indicate amount to be withdrawn per single withdrawal, and the 
total amount of blood to be drawn.  If transfusions are anticipated, include 
assurance that the volume of blood removed for research purposes will not 
necessitate a transfusion. [Refer to Section 1.5.5] 
 
E. Study Population –(Gender and Minority Inclusions):  
 
1. Describe the characteristics of the subject population, include the anticipated 
number of normal volunteers, age ranges, sex, ethnic background, and health status.  
 
Identify the criteria for inclusion or exclusion (especially women and/or 
minorities).  
 
Explain the rationale for the use of special classes of subjects, such as fetuses, 
pregnant women, or others who are likely to be vulnerable, especially those whose 
ability to give voluntary informed consent may be questionable.  
 
The subject population will be patients seen at GW for lithotripsy procedures. This 
will include men and women ages 18-89. It will include all ethnic backgrounds, and 
anyone who has been cleared for surgery. 
 
The criteria for exclusion for those patients who agree to participate in the study 
will be patients with glaucoma, severe hepatic or renal disease, bronchial asthma, 
respiratory depression at the time of administration, convulsive disorders, allergy to 
anti-muscarinics or opiates, history of anorectal surgery, pre-operative use of 
antimuscarinics, chronic pain, chronic use of analgesics, or a history of alcohol or 
opioid dependency, pregnant women and nursing mothers. 
 
F. Human Subjects (Risks & Benefits)  
 
1. Identify sources of research material obtained from individually identifiable living 
human subjects in the form of specimens, records or data.  Indicate whether the 
material or data will be obtained specifically for research purposes or whether use 
will be made of existing specimens, records or data.  Subjects with specific diseases 
or conditions are often identified as potential subjects through some type of record 

7 
 
(e.g., medical records, patient charts, registries for cancer cases, surgical or X-ray log 
books, school records).   Controls may come from the same population as the 
subjects (which is always the case in a randomized clinical trial), be persons with 
unrelated conditions or be volunteers from the general population.  
  
No material from individual human subjects will be used. All information obtained 
will be through patient surveys and the patient’s medical records.  
 
2. Describe plans for recruitment of subjects and the consent procedures to be 
followed; including the circumstances under which consent will be sought and 
obtained, who will seek it, who will give consent, the age range of the individual who 
will give consent, the nature of the information to be provided to prospective 
subjects, payment for participation (if applicable), the prospective subjects, and the 
method of documenting consent. (State if you are requesting a 'waiver of consent' 
from the IRB and why.)  [Refer to Section 3.0]   
 
Subjects will be recruited from patients who are determined to need a lithotripsy 
procedure with the above attending Urologists. They will be asked to consent to 
participate in the study at some time before their procedure. This could be in the 
clinic weeks beforehand, this could be in the ER when the patient presents with a 
stone, and it could be pre-operatively while the patient is being consented for the 
procedure. The consent will be done in a quiet area one on one with the patient and 
the patient will be given time to ask questions. The consent form, which is attached, 
will be given to the patient. 
 
G. Risks and Side Effects:  
 
1. Describe any potential risks--physical, psychological, social, legal, or other and 
assess their likelihood and seriousness.  Describe the alternative treatments and 
procedures that might be advantageous to the subjects.  
 
The potential risks of this study are mainly those associated with the B & O 
suppositories: Belladonna may cause drowsiness, dry mouth, urinary retention, 
photophobia, rapid pulse, dizziness and blurred vision. Opium usage may result in 
constipation, nausea or vomiting. Pruritis and urticaria may occasionally occur. 
These risks are relatively mild as far as medication side effects go. Alternative 
treatments or procedures for patients undergoing lithotripsy who may experience 
bladder spasms include the option of treating bladder spasms with narcotic pain 
medications, oxybutynin, an oral antimuscarinic, or not treating the patient at all. 
Any of these choices carry side effects or negative consequences. Not all patients 
who undergo lithotripsy procedures will experience bladder spasms post-
operatively, but those that do will be exposed to possible side effects with 
treatment. Side effects of oxybutinin are included on the package insert attached to 
this form. 

8 
 
 
2. Describe the procedures for protecting against or minimizing any potential risks, 
including risks to confidentiality, and assess their likely effectiveness.  Discuss 
provisions for ensuring necessary medical or professional intervention in the event 
of adverse effects to the subjects.  Describe the provisions for monitoring the data to 
insure the safety of subjects. 
 
Risk will be minimized by strictly adhering to the exclusion protocol to ensure that 
patients at an increased risk for adverse effects are not exposed to the 
suppositories.  
 
To reduce the risks to confidentiality, all data will be recorded in electronic format, 
kept on a computer meeting the GW university standards for antivirus software, and 
will require password entry for access to the computer itself as well as the 
document in which the data is stored. Data transferred from the electronic medical 
record system to the computer database will be de-identified and given a new 
unique identifier. The key document to justify the new unique identifier with the 
subject MRN and DOB idenitifying information will be stored on a separate 
computer with the same protections in place as described above. This key will be 
deleted at the conclusion of the study. If at any time during the study any materials 
or the computers with the electronic documents pertaining to the study are found to 
be missing or otherwise compromised, the GW OHR will be immediately notified. 
 
Patient’s will be monitored in the post-operative setting, and any adverse effects 
will be treated as part of the normal post-operative course of care.  
 
 
3. Discuss why the risks to subjects are reasonable in relation to the anticipated 
benefits to subjects and in relation to the importance of the knowledge that may be 
reasonably expected to result. 
 
The risk to subjects are very minor side effects, while the benefit is that they could 
gain relief from the severe discomfort of bladder spasms in the post-operative 
setting. The importance of this knowledge is in trying to find a better, more efficient 
way to prophylactically treat bladder spasms.  
 
4. List all risks that are more than minimal (no greater probability or magnitude 
than those ordinarily encountered in daily life or during routine medical tests).  
Include physical, psychological, social, economic, legal or other risks, where present. 
 
The physical risks that are more than minimal include those side effects listed 
above. Psychological risk should be minimal. Social risk will be none. Economic risk, 
patient’s only are exposing themselves to a slightly added cost. Legal risk should be 
none. 

9 
 
 
5. Describe the severity and probability of all material risks, and the implications, in  
understandable terms.  Use a table for Common (21-100/100), Occasional (5-
20/100) and Rare (<5/100) risks sorted by Immediate (1-2 days of treatment), 
Prompt (within 2-3 weeks before next course), Delayed (any later time during 
treatment) and Late (after completion of treatment) onset wherever possible. 
 
All risks are considered immediate (1-2 days of treatment).  
Common: constipation, dry mouth 
Occasional: difficulty urinating 
Rare: blurred vision, dizziness, nausea, vomiting, sensitivity to light 
 
H. Benefits:   
 
1. The risks must be reasonable in relation to anticipated benefits, if any, to subjects, 
and to the importance of the knowledge reasonably expected to result.   
 
2. The use of modest compensation for the burdens imposed by the research may be 
permitted, especially if benefits are minimal, but should be incremental and not 
conditioned on completion of the entire study.   
 
3. Explain the expected benefits, if any, and their likelihood.  If none, say so.  
 
4. You may mention general benefits for science, or for other persons, if any. 
 
These results will potentially help inform protocol for urologic procedures in the 
future. The use of B&O suppositories according to this protocol could help reduce 
the pain and discomfort of bladder and ureteral spasms that patients experience 
following lithotripsy procedures as well as decrease these patients’ need for pain 
medication and thus reduce associated side effects of those medications in the post-
operative period.  
 
I. Outside Consultants/Collaborators  
 
Attach a letter from the consultant(s) and/or their signature(s) on the Application  
(Sign-Off) Form confirming their role in the project.  
 
The anesthesia department at GW has attached a letter to say they have objectively 
reviewed the study and have listed any potential interactions with anesthetics.  
 
J. Contractual Agreements     
 
Describe the nature of these collaborations.  Attach an appropriate letter from each 
individual/institution involved confirming the agreement.  If the protocol originates 

10 
 
at another institution, explain how that institution will be involved and provide the 
name and department of the Institutional Sponsor.  The assigned PI/IS must be a 
faculty/staff member of that institution.  
 
None 
 
K. Costs To Subjects: 
 
Patients will not be billed for B and O suppositories, and they will not incur any 
additional costs above their hospitalization. All costs for B and O suppositories will 
be paid for by the research project. 
 
1. The Research Plan and the consent documents must describe the costs to such 
compensation plans in detail, including the provision of free care or medicines 
related to the study. 
 
Example: Children's Hospital will give you the medicine used in this study for free. 
You will not be charged for anything else we do that is part of the study.  You will 
still have to pay for any medical care that is not part of the study.   
 
See associated consent document.  
 
L. Conflicts Of Interest: 
 
1. Describe any financial or other conflicts of interest as indicated.  Any interests of 
the investigators or provider institutions in the outcome of the research, the study 
product, or the sponsoring entities, any support received by the researchers or 
provider institutions from same in excess of $10,000 per year, and any other 
relationship to the sponsor or the research that could be material to any subject.   
 
None 
 
2. Where such interests exist, describe the disclosures that will be made to subjects 
in the consent process and consent documents and discuss the factors considered in 
selecting the appropriate disclosures.  Consult §2.3 of the Manual for a discussion of 
materiality and appropriate disclosure to subjects, including disclosure of sponsor 
identity and source of funding where potentially material to subjects. 
 
None 
 
3. Review the Financial Interest Disclosure form submitted to the Office of 
Sponsored Programs to ensure that it is current and consistent with the Application 
disclosure. 
 

11 
 
M. Confidentiality: 
 
Include appropriate provisions to protect the privacy of subjects and maintain the 
confidentiality of data, and include safeguards to protect the rights and welfare of 
vulnerable subjects. 
 
N. Subject Compensation:  
 
The Research Plan must describe such compensation plans in detail, including the 
provision of free care or medicines related to the study. 
 
There will be no monetary compensation for participation in this study.  
 
O. Facilities and Equipment  
 
Describe the facilities and equipment to be used.  Indicate the extent to which these 
facilities and equipment are available or will be obtained for the project. 
 
Ditropan is readily available from the hospital pharmacy. B and O suppositories will 
be supplied through the Investigational Drug Pharmacy. Therefore, in order to 
obtain the medication for the patient, we will submit a written prescription for the 
suppository that will then be filled in the retail pharmacy at the MFA out of their 
supply. The cost of the fill(s) will be billed to the study’s cost center quarterly. 
  
The packaged suppository  will then be taken to the pharmacy in GWUH to be put 
into the computer system as a “Research Drug” and labeled with a scan code for 
floor administration.  Once labeled IDS will reach out to a contact on the study (Dr. 
Mufarrij or Dr. Grant) and give the medication to that person to take to the floor 
where the patient is located.  Because this is a schedule II drug, IDS will ask the 
person that they dispense the medication to to sign a chain of custody log indicating 
change of possession.  IDS will also create a general log of subject dispensation and a 
study binder to hold all relevant study materials. 
There will be no additional equipment required for the study outside of the 
standard operating procedure used for lithotripsy in the GW OR and hospital.  
 
P. References & Literature Cited  
 
Compile a judicious list of relevant literature citations.  Each literature citation must 
include the title, names of authors, book or journal, volume number, page numbers, 
and year of publication. 
 
Lukasewycz S, Holman M, Kozlowski P, Porter CR, Odom E, Bernards C, Neil N, 
Corman JM. Does a perioperative belladonna and opium suppository improve 
postoperative pain following robotic assisted laparoscopic radical prostatectomy? 

12 
 
Results of a single institution randomized study. Can J Urol. 2010 Oct;17(5):5377-
82. PubMed PMID: 20974030 
 
Scavonetto F, Lamborn DR, McCaffrey JM, Schroeder DR, Gettman MT, Sprung J, 
Weingarten TN. Prophylactic belladonna suppositories on anesthetic recovery after 
robotic assisted laparoscopic prostatectomy. Can J Urol. 2013 Jun;20(3):6799-804. 
PubMed PMID: 23783051. 
 
 
Q. Appendix  
 
Attach the letters of confirmation from collaborating institutions, consultants, 
research documents (e.g., questionnaires, scales, tables, charts, diagrams, 
manufacturers brochures, etc.) in this section.