Conditions: Constipation Fecal Incontinence Multiple Sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
The investigators seek to test whether incorporating the scheduled dosing of a bisacodyl 10 mg rectal suppository every other day improves bowel-related symptoms in patients with multiple sclerosis. Patients will be randomized to receive either a placebo suppository or bisacodyl suppository dosed every other day for 4 weeks.

Detailed description:
The majority of patients with multiple sclerosis (MS) suffer from some form of anorectal dysfunction, and these difficulties with bowel function are often ranked as negatively impactful on quality of life as impaired mobility. Despite the significant clinical burden of these symptoms, there remains a paucity of published literature supporting specific therapeutic options to manage anorectal dysfunction in this clinical population. Most bowel regimens rely on either oral laxatives (i.e. PEG-3350) or anti-diarrheal agents (i.e. loperamide). In their study, the investigators propose to establish the efficacy of a bowel regimen that combines both oral agents (as needed; standard care) with scheduled, every other day dosing of a placebo or stimulant laxative rectal suppository -- bisacodyl 10 mg.

Bisacodyl is a stimulant laxative medication that is available over-the-counter. It works by activating nerves in the rectum to elicit rectal contractions which ultimately leading to defecation.

Arms:
arm 1: Every other day placement of a placebo rectal suppository for 4 weeks arm 2: Every other day placement of a bisacodyl 10 mg rectal suppository for 4 weeks

Interventions: intervention 1: Bisacodyl intervention 2: Placebo
Intervention descriptions: intervention 1: Rectal suppository intervention 2: Rectal suppository

Protocol document:
Prot_SAP_000.pdf: 
Section: Triage 
Provide a short title for this study (200 characters or less): 
MS Bowel Study 
T1.0 
Select the type of application: 
New Research Study   
 
  
T2.0 
Is the proposed research study limited to the inclusion of deceased individuals? 
* No 
 
T2.1 
 
Are any research activities being conducted at the VA Pittsburgh Healthcare 
System or with VA funds?  
 
* No 
  
  
    [reviewer notes¬]  
T3.0 
What is the anticipated risk to the research participants? 
 
 
 
Greater Than Minimal Risk 
 
  
  
Section: Cover Sheet
    [reviewer notes¬]  
CS1.0 
What is the reason for this submission? 
 
New Research Protocol Submission 
  
CS1.1 
Has this research study been approved previously by the University of Pittsburgh 
IRB? 
*  No 
 
 
Last Update: 10/26/2018 
NCT02609607: Treating Anorectal Dysfunction in MS 
PI: David J. Levinthal, MD, PhD 
 
 


Section: Cover Sheet
CS1.1.1 Has this research study (or a substantially similar research study) been previously 
disapproved by the University of Pittsburgh IRB or, to your knowledge, by any other 
IRB? 
*  No 
  
  
    [reviewer notes¬]  
CS2.0 
Title of Research Study: 
Treating Anorectal Dysfunction Associated with Multiple Sclerosis 
CS2.0.1     
Requested approval letter wording: 
 
CS2.1 
Research Protocol Abstract: 
 
The majority of patients with multiple sclerosis (MS) suffer from constipation and/or fecal 
incontinence (“anorectal dysfunction”), and these difficulties are often ranked as negatively 
impactful on quality of life as impaired mobility. Despite the significant clinical burden of 
these symptoms, there remains very little research to support specific therapeutic options in 
managing anorectal dysfunction in MS patients. To address this gap in knowledge, we 
propose to establish the efficacy of a standardized, cost-effective, and easily implemented 
bowel regimen to treat anorectal dysfunction in patients with MS. 
 
Specifically, this double-blind, randomized placebo controlled study will determine the impact 
of adding the regular administration of rectal suppository laxatives (e.g., a "timed rectal 
evacuation" strategy) on MS patients’ subjective assessment of bowel symptoms. The “timed 
rectal evacuation” aspect of a bowel regimen has never been rigorously studied, but it could 
have a major clinical impact. In our study, patients with MS will receive oral laxatives or anti-
diarrheal agents to normalize stool form (as indicated), and then be randomized to receive 
either placebo or bisacodyl 10 mg rectal suppositories administered every other day for 4 
weeks. Patients also will undergo tests of anorectal function (per routine clinical practice) and 
standardized questionnaire assessments of bowel symptoms and their impact on quality of 
life. We will use this information to try to predict which groups of patients benefitted from the 
intervention. This proposal will significantly advance MS care and management by developing 
the evidence to support a simple and effective clinical treatment algorithm for anorectal 
dysfunction in the MS population. 
  
  
CS2.2 
Select the category that best describes your research: 
 
    [reviewer notes¬]  
CS3.0 
Name of the Principal Investigator: 
David Levinthal 
Note: Adjunct faculty of the University, including lecturers and instructors, are not 
permitted to serve as a PI or Faculty Mentor but may serve as co-investigators. Refer 
to Chapter 4 on the HRPO website for more information. 
CS3.1 
Affiliation of Principal Investigator: 
UPitt faculty member 
  


Section: Cover Sheet
 
If you chose any of the Pitt options, please indicate the specific campus: 
Main Campus - Pittsburgh 
 If you chose the UPitt faculty member option, provide the PI’s University Faculty Title: 
Asssistant Professor   
  
CS3.2 
Address of Principal Investigator: 
 
M2 C-Wing PUH 
200 Lothrop Street 
Pittsburgh, PA 15213 
CS3.3 
Recorded Primary Affiliation of the Principal Investigator: 
U of Pgh | School of Medicine | Systems Neuroscience Institute 
CS3.4 
Identify the School, Department, Division or Center which is responsible for 
oversight of this research study: 
U of Pgh | School of Medicine | Medicine | Gastroenterology 
  
  
CS3.5 
Telephone Number of Principal Investigator: 
 
412-303-0525 
  
CS3.6 
Recorded Current E-mail Address of Principal Investigator to which all 
notifications will be sent: 
 
DLEVINTH@pitt.edu 
CS3.7 
Fax Number: 
  
 
412-648-9378 
  
CS3.8 
Does this study include any personnel from Carnegie Mellon University, and/or 
use any CMU resources or facilities (e.g., Scientific Imaging and Brain Research 
Center (SIBR)? 
 
*  No 
  
CS3.9 
Is this your first submission, as PI, to the Pitt IRB?   
 
*  Yes 
  
  
    [reviewer notes¬]  
CS4.0 
List of Co-Investigators: 
 
 
Last First Organization 
There are no items to display 
  
  
  
    [reviewer notes¬]  


Section: Cover Sheet
CS5.0 
Name of Primary Research Coordinator: 
 
 
    
  
CS5.1 
Address of Primary Research Coordinator: 
 
CS5.2 
Telephone Number of Primary Research Coordinator: 
 
CS6.0 
Name of Secondary Research Coordinator: 
 
CS6.1 
Address of Secondary Research Coordinator: 
  
 
 
CS6.2 
Telephone Number of Secondary Research Coordinator: 
  
 
  
 
CS6.3 
Key Personnel/Support Staff (Only list those individuals who require access 
to OSIRIS): 
 
Last 
First 
Organization 
Diable 
Caitlin UPMC | Physician Services Division | UPP | Other 
Heyman Rock U of Pgh | School of Medicine | Neurology 
O'Leary Margie UPMC | Other 
ORIE 
RYAN UPMC | Other 
 
    [reviewer notes¬]  
CS7.0 
Will this research study use any Clinical and Translational Research Center 
(CTRC) resources? 
No 
  
    [reviewer notes¬]  
CS8.0 
Select the entity responsible for scientific review. 
 
  
Department Review - (a dean, department chair, division chief, or center head) 
Note: DoD funded studies require departmental review 
  
CS8.1 
Select the school, department or division which is responsible for scientific 
review of this submission. 
U of Pgh | School of Medicine | Medicine | Gastroenterology 
  
 
  
  
    [reviewer notes¬]  
CS9.0 
Does this research study involve the administration of an investigational drug or an 
FDA-approved drug that will be used for research purposes? 
* Yes   


Section: Cover Sheet
CS9.1 
Do you plan to utilize the Investigational Drug Service (IDS) to dispense the drug?  
* Yes 
  
  
CS10.0 Is this research study being conducted under a University of Pittsburgh-based, 
sponsor-investigator IND or IDE application? 
  
*  No 
 
If YES, you are required to submit the IND or IDE application and all subsequent FDA 
correspondence through the Office for Investigator-Sponsored IND and IDE Support 
(O3IS).  Refer to applicable University policies posted on the O3IS 
website  (www.O3IS.pitt.edu). 
  
    [reviewer notes¬]  
CS11.0 
Use the 'Add' button to upload one or more of the following: 
• 
the sponsor protocol (including investigator initiated studies) and/or 
other brochures 
• 
the multi-center protocol and consent form template, if applicable 
Name Modified Date 
Is this research study supported in whole or in part by industry?  This includes 
the provision of products (drugs or devices).   
  
*  No 
Is this a multi-centered study? 
 
*  No 
 
  
  
    [reviewer notes¬]  
CS12.0 
Does your research protocol involve the evaluation or use of procedures that 
emit ionizing radiation? 
 
*  No 
  
CS13.0 
Does this research study involve the deliberate transfer of recombinant or 
synthetic nucleic acid molecules into human subjects? 
  
*  No 
Upload Appendix M of NIH Guidelines: 
Name 
Modified Date 
 
  
CS14.0 
Are you using UPMC facilities and/or UPMC patients during the conduct of your 
research study? 
  


Section: Cover Sheet
*  Yes 
 
If Yes, upload completed Research Fiscal Review Form: 
Name 
Modified Date 
FRIAR - OSPARS Form -- LEVINTHAL 2015.docx 
11/3/2015 3:01 PM 
  
    [reviewer notes¬]  
CS15.0 Indicate the sites where research activities will be performed 
and/or private information will be obtained. 
 
Choose all sites that apply and/or use Other to include sites not listed: 
 
Sites: 
UPMC 
 
  
  
 
 
 
 
UPMC 
 
Sites: 
UPMC Presbyterian 
UPMC Montefiore 
Other UPMC Site- Specify below: 
Kaufman Building (Department of Neurology outpatient suite) 
 
  
  
  
 
 
 
If you selected School, International or Other, list the sites: 
 
  
*For research being conducted at non Pitt or UPMC sites, upload 
a site permission letter granting the researcher permission to 
conduct their research at each external site: 
Name Modified Date 
 
  
 
 
CS15.1 Have you, David Levinthal , verified that all members of the 
research team have the appropriate expertise, credentials, and if 
applicable, hospital privileges to perform those research 
procedures that are their responsibility as outlined in the IRB 
protocol? 
*  Yes 
  
CS15.2 Describe the availability of resources and the adequacy of the 
facilities to conduct this study: 
*  Our study enrolls patient subjects that are already embedded within 
existing clinical care pathways at UPMC. Patients with multiple sclerosis 
(MS) already receive care in the Division of Neuroimmunology/MS in the 
Department of Neurology at UPMC, who maintains a large (2000+ 
patients) database of their MS patients with associated clinical data. 
Importantly, the registry also records information on patients' expressed 
  


Section: Cover Sheet
interest in participating in clinical research studies. During routine care, 
MS patients with anorectal dysfunction are already regularly referred to 
the Neurogastroenterology and Motility Group (PI and co-PI) within the 
Digestive Disorder Center at UPMC and undergo anorectal manometry 
testing and treatment in the DDC. We will use both routine care 
pathways and the MS database to recruit patients into the study (goal: 
70 patients). We have contracted with Hieber's pharmacy and Falk 
Pharmacy to forumulate and distribute the study drug in a blinded 
fashion. We are currently in the process of identifying a study 
coordinator. The funding mechanism for this project has ample 
resources to support both of these efforts (study drug and coordinator). 
Thus, all of the resources that are required to conduct this study are 
easily available and fully adequate. 
  
    [reviewer notes¬]  
CS16.0 
Special Research Subject Populations:  
 
 
Categories 
None 
    [reviewer notes¬]  
CS17.0 
Does your research involve the experimental use of any type of human stem cell? 
 
*  No 
 
  
    [reviewer notes¬]  
  
 
NIH Definition of a Clinical Trial 
A research study1 in which one or more human subjects2 are prospectively 
assigned3 to one or more interventions4 (which may include placebo or other 
control) to evaluate the effects of those interventions on health related biomedical 
or behavioral outcomes.5 
1 See Common Rule definition of research at 45 CFR 46.102(d) . 
2 See Common Rule definition of human subject at 45 CFR 46.102(f) . 
3 The term “prospectively assigned” refers to a pre-defined process (e.g., randomization) 
specified in an approved protocol that stipulates the assignment of research subjects 
(individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) 
of a clinical trial. 
4 An intervention is defined as a manipulation of the subject or subject’s environment for the 
purpose of modifying one or more health-related biomedical or behavioral processes and/or 
endpoints.  Examples include:  drugs/small molecules/compounds; biologics; devices; 
procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face 
interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, 
exercise, development of new habits); treatment strategies; prevention strategies; and, 
diagnostic strategies. 


Section: Cover Sheet
5 Health-related biomedical or behavioral outcome is defined as the pre-specified goal(s) or 
condition(s) that reflect the effect of one or more interventions on human subjects’ 
biomedical or behavioral status or quality of life.  Examples include:  positive or negative 
changes to physiological or biological parameters (e.g., improvement of lung capacity, gene 
expression); positive or negative changes to psychological or neurodevelopmental parameters 
(e.g., mood management intervention for smokers; reading comprehension and /or 
information retention); positive or negative changes to disease processes; positive or 
negative changes to health-related behaviors; and, positive or negative changes to quality of 
life. 
CS18.0 * Based on the above information, does this study meet the NIH definition of a 
clinical trial? 
  
Yes 
No 
  
  
 
If Yes, click Save and then Click Here For Study Team's CITI Training Records .  Please 
ensure all personnel's training is up to date 
Section: Section 1 - Objective, Aims, Background and Significance
    [reviewer notes¬]  
1.1 
Objective: What is the overall purpose of this research study?  (Limit response to 
1-2 sentences.) 
The goal of this proposal is to determine the impact of adding timed rectal evacuation as a 
treatment for anorectal dysfunction symptoms in patients with mild-to-moderate severe 
MS. 
  
 
  
1.2 
Specific Aims: List the goals of the proposed study (e.g., describe the relevant 
hypotheses or the specific problems or issues that will be addressed by the 
study). 
MS-related disability and impaired quality of life is derived from both motor and non-motor 
symptoms associated with the disease. One of the most common, chronic non-motor 
symptoms in MS patients is anorectal dysfunction, broadly defined as the presence of 
chronic constipation and/or fecal incontinence. Anorectal dysfunction is experienced in 
some form by a majority of MS patients and is likely driven by subtle impairments in 
sensorimotor function that undermines patients’ ability to sense rectal filling and/or 
appropriately coordinate pelvic muscles required for normal defecation. Collectively, 
because of the pervasive presence of common symptoms with a daily impact, anorectal 
dysfunction places a tremendous burden on MS patients and their caregivers. Yet, there is 
exceptionally little high quality evidence to suggest a specific therapeutic approach to MS 
patients with anorectal dysfunction. Thus, there is a compelling need to establish the 
evidence to support a safe, effective, and easily implemented treatment option for 
anorectal dysfunction in MS patients. As a first step to meeting this need, this proposal 
aims to determine the efficacy of timed rectal evacuation in an algorithm-based bowel 
regimen for treating anorectal dysfunction in patients with mild-to-moderate severity MS. 
 
AIM 1: Determine the impact of timed rectal evacuation on anorectal dysfunction in MS 
patients 
 
We will conduct a four week, single-center, randomized, double-blind placebo controlled 
clinical trial designed to assess the efficacy of timed rectal evacuation in improving the 
subjective global assessment of bowel symptoms in a cohort of patients with mild-to-
moderate severity MS disease. Patients will be randomized 1:1 to administer either 
placebo or bisacodyl 10 mg rectal suppositories every other day during the 4 week trial. 
The primary endpoint will be the change in patients’ rating of bowel symptom severity (10 
point rating scale) at end of 4 weeks compared to baseline values. We will define an 
adequate treatment response as greater than a 30% reduction in symptom severity using 
an intention-to-treat analysis. 
 
AIM 2: Determine the predictors of treatment response and impacts on quality of life 


Section: Section 1 - Objective, Aims, Background and Significance
 
We plan to collect information on the patients' assessed severity of baseline and 
treatment-associated anorectal dysfunction, their impact on quality of life, as well as daily 
bowel diaries. Patients also will undergo anorectal sensory and manometric testing as a 
part of their routine clinical care. Enrolled patients that complete the study will be 
assessed for study medication compliance. All of these measures will be used to explore 
factors that are associated with treatment response. Changes in assessments of anorectal 
dysfunction-related quality of life will serve as key secondary end-points. 
 
This proposal will significantly advance MS care and management by developing the 
evidence to support the adoption of a simple, safe, and cost-effective clinical treatment 
algorithm for anorectal dysfunction in the MS population. This paradigm for anorectal 
dysfunction management could be applicable to a majority of MS patients, and the 
treatment algorithm could be introduced to patients by nurses or mid-level clinical 
providers during points of routine MS patient care. Importantly, the treatment could be 
effectively accomplished by most patients and their caregivers at home. The findings of 
this investigation could also have a broader influence on care models for anorectal 
dysfunction associated with a range of other neurological illnesses, such as Parkinson’s 
Disease, ALS, or stroke. 
  
1.3 
Background: Briefly describe previous findings or observations that provide the 
background leading to this proposal. 
There is growing recognition that the factors driving multiple sclerosis (MS)-related 
disability extend beyond impairments in mobility to include both psychological and 
physical symptoms that negatively impact patients’ quality of life. Anorectal dysfunction, 
broadly defined as the presence of chronic constipation and/or fecal incontinence, is a 
common symptom experienced by MS patients that is often ranked as negatively impactful 
on quality of life as impaired mobility. About 40% of MS patients suffer from chronic 
constipation, while ~25% of patients experience frequent episodes of fecal incontinence. 
Mixed forms of anorectal dysfunction are less common, occurring in at least 10-15% of MS 
patients, but pose a particular therapeutic challenge. Because of the daily impact of these 
common symptoms, anorectal dysfunction places a tremendous burden on MS patients 
and their caregivers. 
 
Normal defecation patterns require precise conscious and unconscious sensorimotor 
functions to support the perception of rectal filling, to retain stool in the rectum without 
anal leakage, and to allow for volitional elimination of stool without difficulty. MS patients 
may be especially prone to developing anorectal dysfunction because even subtle 
impairments in sensation from the anorectum and/or the timing and efficacy of 
coordinated abdominal, pelvic floor, and anal muscle contractions are sufficient to 
generate symptoms. Regardless of subtle differences in the underlying mechanisms that 
lead to anorectal dysfunction in any one MS patient, an ideal therapeutic approach should 
be safe, flexible, straightforward, and effective enough to help most patients. 
  
 
 
  
1.4 
Significance: Why is it important that this research be conducted? What gaps in 
existing information or knowledge is this research intended to fill? 
Despite its significant burden on MS patients, there remains a paucity of published studies 
to provide strong evidence for any specific therapeutic option for anorectal dysfunction in 
this population. The few available studies are mostly small, uncontrolled trials, including 
studies focused on behavioral interventions and biofeedback, which demonstrated some 
limited benefit restricted to those with mild MS disease. This finding may not be 
surprising, as biofeedback requires intact central neural control over motor systems that 
are likely to be disrupted in MS patients with more advanced disease and more severe 
forms of anorectal dysfunction. Although abdominal massage may improve constipation in 
MS patients, this intervention is time consuming and difficult for MS patients with 
advanced disease to accomplish. Transanal irrigation in MS patients with anorectal 
dysfunction showed some promise of benefit in a substantial number of patients, but this 
approach requires specialized equipment, can be cumbersome for patients and caregivers 
to implement and poses some inherent risk of colonic perforation. Therefore, there is 
compelling need to establish evidence supporting a safe, effective, and easily implemented 
  


Section: Section 1 - Objective, Aims, Background and Significance
treatment option for anorectal dysfunction in MS patients. 
 
One strategy often used in routine clinical practice to manage anorectal dysfunction is to 
normalize stool form while providing a means for “timed rectal evacuation” using a 
stimulant laxative rectal suppository. The benefit of this dual approach is to both minimize 
the difficulties with evacuation and to allow patients some flexibility in planning their 
schedule. With regular emptying of the distal colorectum, patients should be able to avoid 
rectal fecal impaction and minimize episodes of fecal incontinence. However, such a 
practical approach to anorectal dysfunction, particularly regarding the use of timed rectal 
evacuation, has not been subjected to rigorous clinical evaluation. The goal of this 
proposal is to determine the efficacy of timed rectal evacuation in an algorithm-based 
bowel regimen for treating anorectal dysfunction in patients with mild-to-moderately 
severe MS. 
  
Section: Section 2 - Research Design and Methods 
    [reviewer notes¬]  
2.1 
Does this research study involve the use or evaluation of a drug, biological, or 
nutritional (e.g., herbal or dietary) supplement? 
*  Yes 
2.1.1 
Does this research study involve an evaluation of the safety and/or effectiveness 
of one or more marketed nutritional (e.g., herbal or dietary) supplements for the 
diagnosis, prevention, mitigation or treatment of a specific disease  or condition 
or symptoms characteristic of a specfic disease or condition? 
* No 
  
    [reviewer notes¬]  
2.1.2 
Does this research study involve the use or evaluation of one or more drugs or 
biologicals not currently approved by the FDA for general marketing? 
*  No 
  
    [reviewer notes¬]  
2.1.3 
Does this research involve the use or an evaluation of the effectiveness and/or 
safety of one or more drugs or biologicals currently approved by the FDA for 
general marketing? 
 
*  Yes 
  
 
  
  
2.1.3.1 
Are the FDA-approved drugs or biologicals being evaluated in this research study 
for a new clinical indication, different population, or route of administration 
and/or dosage level that is not currently specified in the FDA-approved product 
labeling? 
Drugs are often used Off-Label during routine practice.  Before answering this question, 
review the FDA product labeling (http://labels.fda.gov) for the approved "Indications and 
Usage."  If being used off-label, answer Yes to this question.  You are required to provide 


Section: Section 2 - Research Design and Methods 
information and/or upload the package insert for each drug that is administered for 
research purposes. 
* No 
 
If you respond YES, an IND number or the FDA written concurrence of IND 
exemption may be required. 
 
Upload information on FDA approved indications/doses and FDA exemption letter 
if applicable: 
 
Name 
Modified Date 
 
  
  
    [reviewer notes¬]  
2.2 
Will this research use or evaluate the safety and/or effectiveness of one or 
more devices? 
  
*  No 
  
  
    [reviewer notes¬]  
2.3 
Summarize the general classification (e.g., descriptive, experimental) and 
methodological design (e.g., observational, cross-sectional, longitudinal, 
randomized, open-label single-blind, double-blind, placebo-controlled, active 
treatment controlled, parallel arm, cross-over arm) of the proposed research 
study, as applicable. 
 
Single-center, randomized, double-blind placebo controlled clinical trial 
  
2.3.1 
Does this research study involve a placebo-controlled arm? 
*  Yes 
    [reviewer notes¬]  
2.3.1.1 
Is there a commonly used diagnostic/treatment approach that is currently 
recognized as being effective for the proposed subjects' disease or condition, and 
that will be withheld from subjects assigned to the placebo arm of this research 
study? 
No; subjects assigned to the placebo and experimental arms of the research study will 
continue to undergo a commonly used diagnostic/treatment approach 
    [reviewer notes¬]  
2.4 
Will any research subjects be withdrawn from known effective therapy for the 
purpose of participating in this research study? 
*  No 
  


Section: Section 2 - Research Design and Methods 
  
    [reviewer notes¬]  
2.5 
Will screening procedures (i.e., procedures to determine research subject 
eligibility) be performed specifically for the purpose of this research study? 
 
*  Yes 
  
2.5.1 
List the screening procedures that will be performed for the purpose of this 
research study.  Do NOT include the inclusion/exclusion criteria in this section as 
they will be addressed in section 3; questions 3.13 and 3.14. 
There are two mechanisms in which patients will be effectively screened: 
 
1) The study coordinator uses the data listed in the “UPMC Multiple Sclerosis and Related 
Disorders Registry” (PRO12010609) to identify prospective subjects. Patients have already 
consented to join this registry and this consent includes provision for information to be 
accessed by study personnel, with patients explicitly "opting in" to be contacted if they 
qualify for ongoing studies. 
 
2) The care team at the UPMC MS Center (MDs, PAs, nurses, etc.) identify subjects 
interested in joining the study during the course of ongoing, routine clinical care 
encounters. Care team members would then provide the contact information of interested 
subjected to the study coordinator to arrange for the consent process and study initiation. 
  
    [reviewer notes¬]  
 
  
2.6 
Provide a detailed description of all research activities (e.g., all drugs or devices; 
psychosocial interventions or measures) that will be performed for the purpose 
of this research study.  
 
This description of activities should be complete and of sufficient detail to permit 
an assessment of associated risks.  
 
At a minimum the description should include: 
• 
all research activities 
• 
personnel (by role) performing the procedures 
• 
location of procedures 
• 
duration of procedures 
• 
timeline of study procedures 
RESEARCH PLAN: The goal of this proposal is to determine the efficacy of timed rectal 
evacuation as a treatment for anorectal dysfunction symptoms in patients with mild-to-
moderate severe MS. The primary end-point of the randomized clinical trial is a greater 
than 30% improvement in patients’ subjective global assessment of bowel symptom 
severity after 4 weeks. In secondary analyses, we will determine the factors predicting 
treatment response, as well as assess the impact of therapy on measures of global and 
anorectal dysfunction-related quality of life. 
 
Study Design: This is a single-center, randomized, double-blind placebo controlled trial 
incorporated into routine clinical care for MS patients with anorectal dysfunction. Patients 
will be randomized to receive placebo or bisacodyl 10 mg rectal suppositories every other 
day for 4 weeks. 
 
  


Section: Section 2 - Research Design and Methods 
Study Population and enrollment: Patients at the University of Pittsburgh Medical Center 
(UPMC) MS Center with anorectal dysfunction will be recruited via either an existing 
registry, chart review, and/or ongoing care encounters. The UPMC MS Center currently 
cares for well over 2,000 patients. The study is adequately powered if enrollment reaches 
56 patients (see Power Analysis below). To ensure adequate numbers in an intention-to-
treat analysis, we will plan for a ~20% patient drop-out rate (thus, enrolling 70 patients in 
total). Normal clinical care pathways at UPMC naturally generate ~2-3 patient 
consultations per week for MS patients with anorectal dysfunction (total ~125 patients per 
year), and the pool of potential study candidates far exceeds that number. Therefore, 
enrollment of 70 patients appears quite feasible. 
 
Study flow: A schematic of the study flow is shown in the attached figure. All patient 
encounters, referrals, and tests are integrated into the flow of routine clinical care at 
UPMC. Recruited patients will meet with the study coordinator in an in-person meeting to 
discuss the details of the study and obtain informed consent (Kaufman Building MS Clinic). 
At that time (Phase 1), additional measures of baseline bowel symptom severity and 
bowel-related quality of life (QOL) will be obtained by standardized questionnaires (see 
below). The study coordinator will provide patients with instructions on maintaining a daily 
bowel diary (see Study Measures below), and then initiate referrals for anorectal function 
testing in the DDC and a later follow-up appointment with the PI/Co-PI ("NeuroGI"). The 
consent process, baseline questionnaires, and instructions on bowel diary are unlikely to 
take more than 1 hour of time. 
 
During the next 2-4 weeks after study entry, patients will complete the baseline daily 
bowel diary. 
 
During Phase 2, patients will meet the PI / Co-PI in the UPMC Digestive Disorders Center 
(DDC) for anorectal function testing (anorectal sensory and High Resolution Anorectal 
Manometry (HRAM) testing), which typically takes about 45 minutes. This is a one time, 
routine test that is performed in patients with anorectal dysfunction. It involves the 
transanal placement of a thin manometry catheter with inflatable balloon into the rectum. 
The patients' threshold to first sensation of rectal filling, urgency, and pain, basal anal 
resting pressure, voluntary anal squeeze pressure, and the rectal-anal inhibitory reflex 
(RAIR) to rectal distention and during simulated strain, as well as the ability to evacuate a 
50 cc volume rectal balloon within one minute are all recorded variables and constitute 
normal components of such testing. The PI/Co-PI will meet with patients in the DDC GI lab 
around the time of the anorectal testing, and based on the clinical assessment of 
dominant bowel symptoms, provide patients with guidance on baseline interventions 
(either laxative or anti-diarrheal use). For example, the use of oral therapies is predicated 
on patients’ typical stool form (using the Bristol Stool Scale 1-7) – the goal is to achieve a 
typical bowel movement of a 3-5 in consistency. Patients with Bristol 1-2 stools (hard) will 
use 8.5 – 42 grams of PEG-3350 laxative per day, while those with Bristol 6-7 (loose) will 
use 0.5 – 4 grams of loperamide per day, titrated to the goal. At the end of Phase 2 visit, 
patients will be given instructions on study medication use and will obtain the study drug 
(double-blinded; study drug "blister" packets would have been previously randomized by 
the pharmacy and delivered to the DDC). Patients will be encouraged to continue daily 
bowel diaries for the ensuing 4 weeks of the study trial period. Phase 2, including the 
physiological testing assessment and meeting with the PI/Co-PI, should take about 1.5 
hours in total. 
 
During the next 4 weeks, patients will use recommended oral therapies in addition to the 
every other day use of the rectal suppository study medication. They will record events in 
their daily bowel diary. 
 
Finally in Phase 3, after the 4 week study period, patients will meet with the study 
coordinator to collect unused study medication and completed bowel diaries, and then 
undergo final reassessments of bowel dysfunction severity and QOL measures. This 
process could take up to 1 hour. After the questionnaires are completed, patients and the 
PI/Co-PI will be debriefed (i.e. study arm allocation will be revealed) before having a 
routine followup clinic visit (continuity of care). 
 
PERSONNEL: 


Section: Section 2 - Research Design and Methods 
 
1) The study coordinator will identify and screen potential study subjects (by accessing the 
“UPMC Multiple Sclerosis and Related Disorders Registry” (PRO12010609) to identify 
prospective subjects), coordinate the informed consent process with the PI/Co-PI, collect 
intake questionnaires, and provide instruction on bowel diaries (Phase 1). The coordinator 
will schedule referrals for anorectal function testing and follow-up DDC visit , and contact 
patients during the 4-week trial period to verify compliance. Finally, the coordinator will 
collect bowel diaries and remaining medications at study end, administer study exit 
questionnaires, and then debrief subjects and the PI/Co-PI once the blind is broken (Phase 
3). 
 
2) DDC GI nursing staff routinely performs HRAM studies and will do so in this study. The 
PI/Co-PI will be involved in clinical care and recommendations both during Phase 2 and 
Phase 3 (and beyond). 
 
3) MS Physicians will be involved in initial identification of potential subjects and all MS-
related continuity of care. 
 
4) Falk Pharmacy serves UPMC for clinical trials, and staff will ensure the 1:1 
randomization and distribution of either twenty placebo or biscodyl 10 mg rectal 
suppositories (used every other day over 4 weeks during the study period). Falk Pharmacy 
staff is experienced in running clinical trials and maintaining double-blind study conditions 
between subjects and investigators. Patients will receive a slight excess number of 
suppositories in order to assess study medication compliance at trial end. 
 
STUDY MEASURES: We plan to obtain the following information from all enrolled patients: 
1) Primary Patient-Reported Outcome Measure: “Using a scale of 1 to 10 (1 being no 
problem and 10 being maximally impactful symptoms), how would you rate the severity of 
your bowel symptoms over the past 2 weeks?” 
2) Daily Bowel Diaries – patients will record the consistency (Bristol Stool Scale, 1-7), 
number of bowel movements (BM), and occurrence of any fecal incontinence (FI) episodes 
each day. This data will be used to abstract BM and FI weekly frequency, as well as the 
mean change in stool consistency during the study period. 
3) Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) 
4) Fecal Incontinence Severity Index (FISI) 
5) Patient Assessment of Constipation QOL (PAC-QOL) 
6) Rockwood Fecal Incontinence Quality of Life Scale (FIQL) 
7) SF-36 health status questionnaire 
8) Study Medication Compliance 
9) Anorectal Sensory and High Resolution Anorectal Manometry Testing: First sensation of 
rectal filling, urgency, and pain, basal anal resting pressure, voluntary anal squeeze 
pressure, and the rectal-anal inhibitory reflex (RAIR) to rectal distention and simulated 
strain, as well as the ability to evacuate a 50 cc volume rectal balloon within one minute. 
 
2.6.1 
Will blood samples be obtained as part of this research study? 
*  No 
 
*If submitting a protocol for expedited review, it should be clear that the planned blood 
draws are within the parameters described 
here: http://www.hhs.gov/ohrp/policy/expedited98.html  (see Expedited Research 
Category #2) 
If Yes, address the frequency, volume per withdrawal, the total volume per visit, and the 
qualifications of the individual performing the procedure: 
 
  
  


Section: Section 2 - Research Design and Methods 
 
  
 
Study Flow Chart: 
 
Name 
Modified Date 
STUDY DIAGRAM - UPDATED 10-26-15.pdf 
10/26/2015 11:13 AM 
  
    [reviewer notes¬]  
2.7 
Will follow-up procedures be performed specifically for research 
purposes?  Follow-up procedures may include phone calls, interviews, biomedical 
tests or other monitoring procedures. 
 
*  No 
  
    [reviewer notes¬]  
2.8 
Does this research study involve the use of any questionnaires, interview or 
survey instruments? 
 
*  Yes 
  
 
  
Upload a copy of all materials except for the SCID or KSADS which are on file at 
the IRB.  The use of all instruments must be addressed in question 2.6 and/or 
question 2.7 (except for an exempt submission where they should be addressed 
on the appropriate uploaded exempt form). 
 
 
Name 
Modified Date 
Primary Endpoint - PAC-SYM and FISI Questionnaires.pdf 
11/3/2015 3:24 PM 
SF-36 QUESTIONNAIRE in PDF.pdf 
11/3/2015 3:24 PM 
FIQL .pdf 
11/3/2015 3:24 PM 
PAC-QOL.pdf 
11/3/2015 3:23 PM 
Bowel Diary Pages.pdf 
11/3/2015 3:35 PM 
Previously the name and publisher for commercially available materials 
were listed in the textbox below but effective 9/1/2015, all materials (except for 
the SCID and KSADS) must be uploaded using the Add button above. 
Each of these questionnaires (PAC-SYM, FISI, PAC-QOL, FIQL, SF-36) are open access. 
    [reviewer notes¬]  
2.9 
If subjects are also patients, will any clinical procedures that are being used for 
their conventional medical care also be used for research purposes? 
 
*  yes 
  
If Yes, describe the clinical procedures (and, if applicable, their frequency) that will be 
used for research purposes:  
Anorectal function testing (anorectal sensory function and high resolution anorectal 
manometry [HRAM]) is commonly used for to help patients with anorectal dysfunction. 
The testing is typically performed once. 


Section: Section 2 - Research Design and Methods 
2.10 
The blood sample question was moved to 2.6.1. 
  
    [reviewer notes¬]  
2.11 
What is the total duration of the subject's participation in this research study 
across all visits, including follow-up surveillance? 
 
*  Up to 8 weeks 
    [reviewer notes¬]  
  
2.12 
Does this research study involve any type of planned deception?  
If Yes, you are required to request an alteration of the informed consent process (question 
4.7) 
 
*  No 
  
  
    [reviewer notes¬]  
  
2.13 
Does this research study involve the use of UPMC/Pitt protected health 
information that will be de-identified by an IRB approved "honest broker" 
system? 
  
 
*  No 
  
  
    [reviewer notes¬]  
 
  
2.14 
Will protected health information from a UPMC/Pitt HIPAA covered entity 
be accessed for research purposes or will research data be placed in the UPMC/Pitt 
medical record? 
 
*  Yes 
  
If you answer Yes, you are required to submit this study to the Research Informatics Office, 
Health Record Research Request (R3). Per UPMC Policy HS-RS0005, all research projects that 
access or involve UPMC electronic protected health information (e-PHI) must be submitted to 
R3, with the exception of clinical trials that are contracted through the UPMC Office of 
Sponsored Programs and Research Support (OSPARS).  
 
Complete the R3 intake form available at http://rio.pitt.edu/services. An R3 representative will 
conduct a review. You will be notified once your R3 review is complete or if anything further is 
needed. 
 
Describe the medical record information that will be collected from the UPMC/Pitt 
HIPAA covered entity and/or the research-derived information that will be placed in 
the medical records. 
 
Basic Demographic information (age, sex, marital status, smoking and alcohol use, etc.) 
 
MS-related information (duration of diagnosis, disease subtype, symptom assessment, current 
medication use) 
 
 
 


Section: Section 2 - Research Design and Methods 
 
Past medical history (particularly in regard to abdominal or anorectal surgeries, presence of 
inflammatory bowel disease, or recent infectious colitis) 
 
2.14.1 Will protected health information from a non-UPMC/Pitt HIPAA covered entity be 
obtained for research purposes or will research data be placed in the non-UPMC/Pitt 
medical record?   
 
*  No 
I, David   Levinthal , certify that any member of my research team accessing, 
reviewing and/or recording information from medical records have completed the 
CITI Privacy & Information Security course or, if completed within the past year, the 
Internet-Based Studies in Education and Research (ISER) HIPAA for Researchers 
(Formerly RPF Module 6). The HIPAA certificates must be available for review if 
audited but do not need to be uploaded into this OSIRIS application. 
* Yes 
2.14.2 Are you requesting a waiver of the requirement to obtain written HIPAA 
authorization for the collection of the PHI? 
 
* No 
  
    [reviewer notes¬]  
2.15 
Does this research study involve the long-term storage (banking) of biological 
specimens?  
  
 
*  No 
  
  
    [reviewer notes¬]  
2.16 
Will research participants be asked to provide information about their family 
members or acquaintances? 
*  No 
  
    [reviewer notes¬]  
2.17 
What are the main outcome variables that will be evaluated in this study? 
  
PRIMARY END POINT: The primary end-point of the randomized clinical trial is a greater 
than 30% improvement in patients’ subjective global assessment of bowel symptom 
severity after 4 weeks based on the answer to the following question: “Using a scale of 1 
to 10 (1 being no problem and 10 being maximally impactful symptoms), how would you 
rate the severity of your bowel symptoms over the past 2 weeks?” 
 
SECONDARY END POINTS: 
1) Daily Bowel Diaries – patients will record the consistency (Bristol Stool Scale, 1-7), 
number of bowel movements (BM), and occurrence of any fecal incontinence (FI) episodes 
each day. This data will be used to abstract BM and FI weekly frequency, as well as the 
mean change in stool consistency during the study period. 


Section: Section 2 - Research Design and Methods 
 
2) Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) 
3) Fecal Incontinence Severity Index (FISI) 
4) Patient Assessment of Constipation QOL (PAC-QOL) 
5) Rockwood Fecal Incontinence Quality of Life Scale (FIQL) 
6) SF-36 health status questionnaire 
7) Study Medication Compliance 
8) Anorectal Sensory and High Resolution Anorectal Manometry Testing: First sensation of 
rectal filling, urgency, and pain, basal anal resting pressure, voluntary anal squeeze 
pressure, and the rectal-anal inhibitory reflex (RAIR) to rectal distention and simulated 
strain, as well as the ability to evacuate a 50 cc volume rectal balloon within one minute. 
 
  
2.18 
Describe the statistical approaches that will be used to analyze the study data. 
  
*  Addressed below: 
Categorical data will be analyzed using Fisher’s Exact tests for differences in proportions. 
Continuous data will be analyzed using Student’s t-tests to detect differences in group 
means, with Bonferroni correction for multiple comparisons. We will use logistic regression 
to determine the factors that predict treatment responses. 
A p<0.05 will be used as the threshold for statistical significance in all cases. 
 
POWER ANALYSIS/SAMPLE SIZE: It is generally regarded that a 3-point reduction 
represents a clinically meaningful change using such a 10 point scale, and similar research 
studies using patient-reported outcomes have reported standard deviations ranging around 
~2.5 points. However, we do not have baseline data to estimate variance, and thus we 
took a conservative estimate with an expected standard deviation of 4 points. Given these 
assumptions, we will need 28 patients in each study arm to detect at least a 30% 
reduction in symptom severity, with a power of 0.80, alpha=P<0.05 in a two-tailed 
analysis. 
 
    [reviewer notes¬]  
2.19 Will this research be conducted in (a) a foreign country and/or (b) at a site (e.g., 
Navajo Nation) where the cultural background of the subject population differs 
substantially from that of Pittsburgh and its surrounding communities? 
 
*  No 
Note that copies of training records, licenses, certificates should be maintained in the study 
regulatory binder and are subject to audit by the Research Conduct and Compliance Office 
(RCCO). 
In addition, individuals planning to conduct human subject research outside the United States 
must complete an optional module on the CITI training website: International Studies.  Click 
here to access the instruction sheet for accessing optional CITI modules. 
  
 
  
    [reviewer notes¬]  
2.21 Will this research study be conducted within a nursing home located in Pennsylvania? 
*  No 
  


Section: Section 2 - Research Design and Methods 
  
Section: Section 3 - Human Subjects
    [reviewer notes¬]  
Section 3 - Human Subjects 
3.1 
What is the age range of the subject population? 
 
18-80 
   
3.2 
What is their gender? 
 
*  Both males and females 
 
 Provide a justification if single gender selected: 
 
 
3.3 
Will any racial or ethnic subgroups be explicitly excluded from participation? 
 
*  No   
 
If Yes, identify subgroups and provide a justification:  
 
 
  
 
3.4 
For studies conducted in the U.S., do you expect that all subjects will be able to 
comprehend English? 
*  Yes 
 
  
    [reviewer notes¬]  
3.5 
Participation of Children: Will children less than 18 years of age be studied? 
 
*  No 
 
  
If No, provide a justification for excluding children: 
Multiple sclerosis does not typically manifest in childhood. Childhood MS may represent a 
variant of the disease not generalizable to the typical adult MS population. 
  
    [reviewer notes¬]  
3.6 
Does this research study involve prisoners, or is it anticipated that the research 
study may involve prisoners? 
 
*  No 
  
  
    [reviewer notes¬]  
3.7 
Will pregnant women be knowingly and purposely included in this research 
study? 
 
*  No 
  


Section: Section 3 - Human Subjects
  
    [reviewer notes¬]  
3.8 
Does this research study involve neonates of uncertain viability or nonviable 
neonates? 
 
*  No 
 
  
  
    [reviewer notes¬]  
3.9 
Fetal Tissues: Does this research involve the use of fetal tissues or organs? 
 
*  No 
  
    [reviewer notes¬]  
---> 
3.10 
What is the total number of subjects to be studied at this site, including subjects 
to be screened for eligibility? 
 
Note: The number below is calculated by summing the data entered in question 3.11. Any 
additions or changes to the values entered in 3.11 will be reflected in 3.10. 
 
*  400 
  
3.11 
Identify each of the disease or condition specific subgroups (include healthy 
volunteers, if applicable) that will be studied.   
Click on the "Add" button and specify for each subgroup: 
1) how many subjects will undergo research related procedures at this site; and 
2) if applicable, how many subjects will be required to undergo screening 
procedures (e.g., blood work, EKG, x-rays, etc.) to establish eligibility.  Do Not 
include subjects who will undergo preliminary telephone screening. 
 
*  
  
Subgroup Number to undergo research 
procedures 
Number to undergo screening 
procedures 
 
View MS 
patients 
70 
400 
 
 
  
  
  
3.12 
Provide a statistical justification for the total number of subjects to be enrolled 
into this research study at the multicenter sites or this site. 
 
*  Described below: 
  
The primary outcome measure is the group mean difference in subjective severity ratings 
of bowel symptoms using a 10 point scale. It is generally regarded that a 3-point 
reduction represents a clinically meaningful change using such a scale, and similar 
  


Section: Section 3 - Human Subjects
research studies using patient-reported outcomes have reported standard deviations 
ranging around ~2.5 points on a 10 point scale. However, we do not have baseline data in 
this population to estimate variance, and thus we took a conservative estimate with an 
expected standard deviation of 4 points. Given these assumptions, we will need 28 
patients in each study arm to detect at least a 3 point reduction in symptom severity, with 
a power of 0.80, alpha=P<0.05 in a two-tailed analysis. 
 
Thus, the study is adequately powered if enrollment reaches 56 patients. However, to 
ensure adequate numbers in an intention-to-treat analysis, we will plan for a ~20% 
patient drop-out rate. Therefore, we will aim to enroll 70 patients in total. 
    [reviewer notes¬]  
3.13 
Inclusion Criteria: List the specific criteria for inclusion of potential subjects. 
 
MS patients with mild to moderately severe disease (MSIS-29 Physical domain scores <61 
or an equivalent EDSS < 6.5) aged 18-80, of any gender, disease subtype, duration of 
illness, or with any current use of disease modifying therapy and who also have anorectal 
dysfunction (chronic constipation and/or fecal incontinence) are eligible. MSIS-29 and 
EDSS scores are determined in the course of routine MS care at UPMC. 
  
3.14 
Exclusion Criteria: List the specific criteria for exclusion of potential subjects 
from participation. 
 
MS patients with severe disease, as assessed by MSIS-29 Physical domain scores greater 
than 61 or an equivalent EDSS of greater than 6.5), aged <18 or >80, or patients with 
surgically altered anorectal anatomy (i.e. proctectomy/partial colectomy, ostomy 
creation), active enteric infection (i.e. Clostidium Difficile), or inflammatory bowel disease 
(i.e. ulcerative proctitis) will be excluded. 
3.15 
Will HIV serostatus be evaluated specifically for the purpose of participation in 
this research study? 
 
*  No 
 
 
If Yes, provide a justification: 
 
  
Section: Section 4 - Recruitment and Informed Consent Procedures
    [reviewer notes¬]  
4.1 
Select all recruitment methods to be used to identify potential subjects: 
Research Registry 
Other Strategies: Described below 
 
  
  
 
  
  
 
  
  
 
  
Research Registry 
List the IRB approval number and title for each registry source: 
PRO12010609: “UPMC Multiple Sclerosis and Related Disorders Registry” 
  
 
  


Section: Section 4 - Recruitment and Informed Consent Procedures
4.2 
Provide a detailed description of your recruitment methods, including identifying 
and initiating contact with participants:   
Patients at the University of Pittsburgh Medical Center (UPMC) MS Center with anorectal 
dysfunction will be recruited via two possible mechanisms: 1) via an existing MS research 
registry of patients who have previously expressed a willingness to participate in research 
projects and/or 2) during the course of ongoing, routine clinical care encounters at the 
UPMC MS Center. 
 
Patients identified by method 1 or 2 will be contacted either in person or by phone during 
business hours by our study coordinator. We may send an email announcement of the 
study to the patients on the MS research registry. 
 
The UPMC MS Center currently cares for well over 2,000 patients and generates ~125 
outpatient consultations per year to the NeuroGI group (PI/Co-PI) to help co-manage MS 
patients with anorectal dysfunction. We should not have difficulty meeting our target 
enrollment for the study. 
  
Note: Questions jump from 4.2 to 4.6 as questions 4.3-4.5 have been removed and the information is now 
captured in 4.1 
    [reviewer notes¬]  
4.6 
Are you requesting a waiver to document informed consent for any or all 
participants, for any or all procedures? (e.g., a verbal or computerized consent 
script will be used, but the subjects will not be required to sign a written 
informed consent document.  This is not a waiver to obtain consent. 
 
*  No 
  
  
    [reviewer notes¬]  
4.7 
Are you requesting a waiver to obtain informed consent or an alteration of the 
informed consent process for any of the following?  
  
 
* No 
 
  
4.7.1 
If Yes, select the reason(s) for your request: 
There are no items to display 
 
General Requirements: The Federal Policy [45 CFR 46.116 (d)] specifies in order for a 
waiver of consent to be approved, the request must meet four criteria. For each request, 
you will be asked to provide a justification addressing how each of these criterion is met. 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  


Section: Section 4 - Recruitment and Informed Consent Procedures
  
    [reviewer notes¬]  
4.8 
Are you requesting an exception to the requirement to obtain informed consent 
for research involving the evaluation of an 'emergency' procedure? 
 
Note: This exception allows research on life-threatening conditions for which available 
treatments are unproven or unsatisfactory and where it is not possible to obtain informed 
consent. 
 
*  No 
 
  
    [reviewer notes¬]  
 
4.9 
Upload all consent documents for watermarking: 
 
 
Draft Consent Forms for editing: 
 
Name 
Modified Date 
Consent Form 10/26/2018 10:02 AM 
 
 
 
Approved Consent Form(s): 
Name 
Modified Date 
Consent Form 10/26/2018 10:02 AM 
 
  
      
    [reviewer notes¬]  
4.10 
Will all potential adult subjects be capable of providing direct consent for study 
participation? 
 
*  
Yes 
 
 
  
  
    [reviewer notes¬]  
4.11 
At what point will you obtain the informed consent of potential research subjects 
or their authorized representative? 
 
After performing certain of the screening procedures, but prior to performing any of the 
research interventions/interactions 
  
4.11.1 
Address why you feel that it is acceptable to defer obtaining written informed 
consent until after the screening procedures have been performed. 
 
Study flow will be optimized by making an assessment of inclusion and exclusion criteria 
before approaching patients; there is no benefit to obtaining written informed consent in 
an individual not eligible for the study, and there wasted time and effort (for both patient 
and investigative team) in doing so. There is no appreciable harm (i.e. HIPPA will be 
preserved) if our study coordinator pre-screened patients with upcoming appointments to 
  


Section: Section 4 - Recruitment and Informed Consent Procedures
the UPMC MS center. Lastly, the most substantial screening will be performed using an 
already IRB-approved MS patient registry designed specifically for this purpose 
(PRO12010609, “UPMC Multiple Sclerosis and Related Disorders Registry”). 
4.11.2 
Taking into account the nature of the study and subject population, indicate how 
the research team will ensure that subjects have sufficient time to decide 
whether to participate in this study.  In addition, describe the steps that will be 
taken to minimize the possibility of coercion or undue influence. 
The patients enrolled via the MS patient registry or those identified by screening the list of 
patients with upcoming MS clinic visits will have several days to even weeks before 
deciding to participate in the study. Patients identified by MS care physicians during the 
course of routine care are already referred to the PI/Co-PI. These referrals could trigger an 
inquiry into their interest in study participation. Due to the schedules of the PI/Co-PI, these 
consultations often are scheduled at least 6-8 weeks prior to being seen. Thus, there 
should be ample time for participants to consider their decision to enroll in the study. Our 
study coordinator will contact patients by phone and present the study paradigm in a non-
judgmental way, emphasizing that the decision to enroll will in no way influence their 
access to care. Additionally, at the point of first contact, patients will not have direct 
interaction with the PI / Co-PI, and thus there is no clear way that the PI/Co-PI could exert 
coercion on potential study candidates at that early point. 
  
    [reviewer notes¬]  
4.12 
Describe the process that you will employ to ensure the subjects are fully 
informed about this research study. 
 
*  Addressed below: 
This description must include the following elements: 
• 
who from the research team will be involved in the consent process (both 
the discussion and documentation); 
• 
person who will provide consent or permission;  
• 
information communicated; and 
• 
any waiting period between informing the prospective participant about the study 
and obtaining consent 
In addition, address the following if applicable based on your subject population: 
• 
process for child assent and parental permission 
o 
continued participation if a child subject turns 18 during participation 
• 
process for obtaining proxy consent and assent for decisionally impaired subjects 
o 
continued participation if subject regains capacity to consent 
 
Most of our participants are likely to be identified via the "UPMC Multiple Sclerosis and 
Related Disorders Registry” or by screening individuals with MS upcoming clinic visits. A 
potential participant who is deemed eligible via these screening procedures may be 
contacted and then sent the consent form for review prior to the study visit if they are 
interested. Thus, the potential participant will be given substantial time (days to weeks) to 
review the consent form and have an opportunity to contact study staff with any questions 
prior to enrollment. Our study coordinator will again provide a detailed review of the study 
with special focus on the potential benefits and risks of the study, and all of the potential 
subject's questions should be answered at the time of the consenting. The subject will be 
reminded that participation is voluntary and that if s/he does not want to participate, then 
refusal will not impact subsequent care. If the subject is still interested in participating, 
  


Section: Section 4 - Recruitment and Informed Consent Procedures
then one of the investigators (PI/Co-PI) will obtain informed consent and sign the 
Certification of Informed Consent. A copy of the consent form will be given to the subject. 
4.13 
Are you requesting an exception to either IRB policy related to the informed 
consent process? 
• 
For studies involving a drug, device or surgical procedures, a licensed physician 
who is a listed investigator is required to obtain the written informed consent 
unless an exception to this policy has been approved by the IRB  
• 
For all other studies, a listed investigator is required to obtain consent (Note: In 
order to request an exception to this policy, the study must be minimal risk) 
 
*  No 
If Yes, provide a justification and describe the qualifications of the individual who will 
obtain consent: 
 
  
  
4.14 
Will you inform research subjects about the outcome of this research study 
following its completion? 
 
*  Yes 
  
If Yes, describe the process to inform subjects of the results: 
Patients and the PI/Co-PI will be debriefed after Phase 3 by the study coordinator. They 
will then be seen by the PI/Co-PI in a standard follow up clinic visit. The debriefing is a 
necessary part of the patient's continuity of care, as it may direct changes in patient 
management (i.e. if a patient did not have a clinical improvement in the placebo arm, they 
may be offered study medication or its equivalent). As a patient reported outcome is the 
primary outcome measure, the "results" of the study should be self-evident to patients. 
Section: Section 5 - Potential Risks and Benefits
    [reviewer notes¬]  
5.1 
Describe potential risks (physical, psychological, social, legal, economic or 
other) associated with screening procedures, research 
interventions/interactions, and follow-up/monitoring procedures performed 
specifically for this study:  
 
*  
View 
Research Activity: Bowel Diary   
Common Risks: 
No Value Entered  
Infrequent Risks: 
All efforts will be made to keep the information secure. However, 
there is a small chance of a breach in confidentiality with any 
medical record keeping.   
Other Risks: 
No Value Entered  
View 
Research Activity: Medical Record Review  
Common Risks: 
No Value Entered  
Infrequent Risks: 
There is a small chance of a breach in confidentiality with any 
medical record review, either by Care Team staff as a part of 
routine care, or by the study coordinator in the process of 
  


Section: Section 5 - Potential Risks and Benefits
accessing information from the “UPMC Multiple Sclerosis and 
Related Disorders Registry” (PRO12010609).  
Other Risks: 
No Value Entered  
View 
Research Activity: Research Intervention  
Common Risks: 
The study medication, bisacodyl 10 mg rectal suppository, is 
available over-the-counter for routine use for constipation. Side 
effects of bisacodyl rectal suppositories include stomach 
discomfort, nausea, faintness, rectal burning, mild cramps, and 
diarrhea but these are potential issues are uncommon. There are 
no side effects to taking placebo, but patients could have a risk 
of continued bowel dysfunction if they do not receive the study 
drug.   
Infrequent Risks: 
No Value Entered  
Other Risks: 
No Value Entered  
View 
Research Activity: Screening and Enrollment  
Common Risks: 
Minimal risk of patient's concern that participation is expected or 
that their care would be impacted by opting out.   
Infrequent Risks: 
No Value Entered  
Other Risks: 
No Value Entered  
View 
Research Activity: Study Survey Data  
Common Risks: 
No Value Entered  
Infrequent Risks: 
All efforts will be made to keep the information secure. However, 
there is a small chance of a breach in confidentiality with any 
medical record keeping.   
Other Risks: 
No Value Entered  
  
5.1.1 
Describe the steps that will be taken to prevent or to minimize the severity of the 
potential risks: 
 
  
The study coordinator will contact patients to make sure that they are not having any 
problems during the study period. Patients will be encouraged to contact study staff 
regarding any concerns during the study period at any time. 
 
Our study coordinator will emphasize that participation is completely voluntary, that 
patients can always opt out even once enrolled, and that their decision to participate or 
not will have no impact on care decisions. 
 
 
  
5.2 
What steps will be taken in the event that a clinically significant, unexpected 
disease or condition is identified during the conduct of the study? 
 
*  Not Applicable 
5.3 
All the risk questions (screening, intervention/interaction, follow-up) have been merged 
into one question (5.1). 
    [reviewer notes¬]  


Section: Section 5 - Potential Risks and Benefits
5.4 
Do any of the research procedures pose a physical or clinically significant 
psychological risk to women who are or may be pregnant or to a fetus? 
 
* No 
  
    [reviewer notes¬]  
5.5 Do any of the research procedures pose a potential risk of causing genetic mutations 
that could lead to birth defects? 
 
*  No 
  
    [reviewer notes¬]  
5.6 
Are there any alternative procedures or courses of treatment which may be of 
benefit to the subject if they choose not to participate in this study? 
 
*  No 
 
If Yes, describe in detail: 
 
  
  
    [reviewer notes¬]  
5.7 
Describe the specific endpoints (e.g., adverse reactions/events, failure to 
demonstrate effectiveness, disease progression) or other circumstances 
(e.g., subject's failure to follow study procedures) that will result in discontinuing 
a subject’s participation? 
 
*  Not applicable - There are no anticipated circumstances that would lead to discontinuing 
a subject’s participation in this research study. 
 
 
  
    [reviewer notes¬]  
5.8 
Will any individuals other than the investigators/research staff involved in the 
conduct of this research study and authorized representatives of the University 
Research Conduct and Compliance Office (RCCO) be permitted access to 
research data/documents (including medical record information) associated 
with the conduct of this research study? 
 
*  No 
 
   
5.9 
Has or will a Federal Certificate of Confidentiality be obtained for this research 
study? 
*  No 
  
5.10 
Question has been moved to 5.17 
5.11 
Question has been moved to 5.16 


Section: Section 5 - Potential Risks and Benefits
  
    [reviewer notes¬]  
5.12 
Does participation in this research study offer the potential for direct benefit to 
the research subjects? 
 
Yes - Describe the direct benefit that subjects may receive as a result of study 
participation. Indicate if all, or only certain, of the subjects may derive this potential 
benefit. 
  
Describe the benefit: 
Most patients are likely to see some subjective improvement in bowel function (even those 
in the placebo arm), since all patients will be will be recommended to use some 
intervention to alter stool form (i.e. laxatives or anti-diarrheals). The study participants 
assigned to the active medication arm may derive subjectively greater improvement in 
bowel related symptoms (the primary hypothesis). 
  
5.13 
Describe the data and safety monitoring plan associated with this study. If the 
research study involves multiple sites, the plan must address both a local and 
central review process. 
 
The Principal Investigator, Dr. Levinthal, will meet with Klaus Bielefeldt (Co-PI) every 8 
weeks to evaluate the progress of the research study, including assessment of data quality 
and subject recruitment. 
 
Data and Safety will be further monitored by a joint meeting every 6 months between the 
PI, Co-PI, and Margie O'Leary, a nurse manager of the UPMC MS Clinic who oversees 
clinical trials for the group. This group will be responsible for the following: 1) reviewing 
the data accumulated from the ongoing study; 2) advising the principal investigator or 
study sponsor of necessary changes to elements of the study that affect subject safety; 3) 
determining whether there has been any change to the risk-to-benefit assessment during 
the course of the study; and 4) determining whether the study should continue as 
designed. They will also review, on an ad hoc basis, any serious adverse events (SAE) that 
are directly related to the study medication as given according the study protocol. The 
results of the DSMB meetings will be submitted to the IRB at the time of the annual 
renewal. 
 
  
  
    [reviewer notes¬]  
Section 5 - Potential Risks and Benefits of Study Participation 
5.14 What precautions will be used to ensure subject privacy is respected? (e.g. the 
research intervention will be conducted in a private room; the collection of sensitive 
information about subjects is limited to the amount necessary to achieve the aims of the 
research, so that no unneeded sensitive information is being collected, drapes or other barriers 
will be used for subjects who are required to disrobe) 
  
The interactions between patients and the study coordinator/study staff (informed consent, 
study questionnaires) will be conducted in a private room, likely within the MS Clinic on initial 
study entry and in the DDC at study close. 
 
Enrolled patients undergoing anorectal manometry testing will have the testing performed in a 
private room in the DDC GI Lab, adjacent to a private bathroom / changing area. 
  
 
5.15 What precautions will be used to maintain the confidentiality of identifiable 
information? (e.g., paper-based records will be kept in a secure location and only be 
accessible to personnel involved in the study, computer-based files will only be made available 
to personnel involved in the study through the use of access privileges and passwords, prior to 
  
 


Section: Section 5 - Potential Risks and Benefits
access to any study-related information, personnel will be required to sign statements 
agreeing to protect the security and confidentiality of identifiable information, whenever 
feasible, identifiers will be removed from study-related information, precautions are in place to 
ensure the data is secure by using passwords and encryption, because the research involves 
web-based surveys, audio and/or video recordings of subjects will be transcribed and then 
destroyed to eliminate audible identification of subjects) 
  
All paper-based records (informed consent forms, study questionnaires and daily bowel 
diaries) will be kept in a secure location and only be accessible to personnel involved in the 
conduct and analysis of the study. 
 
Electronic files used in the analysis will contain only de-identified data. 
  
  
  
  
5.16 If the subject withdraws from the study, describe what, if anything, will happen to 
the subject’s research data or biological specimens. 
If the subject withdraws from the study after having passed Phase 1 (i.e. baseline measures of 
bowel dysfunction and quality of life), we would keep the data for an "intention-to-treat" 
analysis (with the assumption of an non-response). If a subject has not completed Phase 1, 
then the research data will be destroyed. 
 
  
 
5.17 Following the required data retention period, describe the procedures utilized to 
protect subject confidentiality. (e.g., destruction of research records; removal of 
identifiers; destruction of linkage code information; secured long-term retention) 
We will destroy primary research records with any identifiers, but may opt to retain de-
identified electronic data on a secured server for future re-analysis. Per University of 
Pittsburgh guidelines, research records will be archived for a minimum of seven years after 
final reporting or publication of a project. 
  
 
  
Section: Section 6 - Costs and Payments
    [reviewer notes¬]  
  
6.1 
Will research subjects or their insurance providers be charged for any of the 
procedures (e.g., screening procedures, research procedures, follow-up 
procedures) performed for the purpose of this research study? 
*   
Yes; charges will be billed only for procedures performed as part of the subject's routine 
clinical care as addressed in question 2.9 
  
    [reviewer notes¬]  
6.2 
Will subjects be compensated in any way for their participation in this research 
study? 
 
*  No 
  
Section: Section 7 - Qualifications and Source(s) of Support 
    [reviewer notes¬]  


Section: Section 7 - Qualifications and Source(s) of Support 
7.1 
Summarize the qualifications and expertise of the principal investigator and 
listed co-investigators to perform the procedures outlined in this research 
study.               
 
The PI (Levinthal) is an MD, PhD adult neurogastroenterologist with expertise in GI 
motility disorders, particularly those arising in patients with underlying neurological illness. 
He has already conducted clinical studies investigating the prevalence and associations of 
GI disorders in the MS population at UPMC. 
 
Key personnel includes Rock Heyman, an MD and the Director of the Neuroinflammation / 
MS Division in the Department of Neurology at UPMC. He is in charge of clinical operations 
of the MS clinic and has extensive experience running clinical trials involving the MS 
population. 
 
The PI (Levinthal) has the appropriate privileges to perform and evaluate all proposed 
clinical procedures (including the anorectal function testing). 
 
  
    [reviewer notes¬]  
7.2 Indicate all sources of support for this research study. 
 
*  
Selections 
Foundation: Upload a copy of the research plan that was submitted to the agency 
 
  
 
 
If Federal support, provide the sponsor information: 
  Federal sponsor 
Grant Title Grant number Awardee institution 
Federal grant application 
 
  
 
 
 
 
 
For projects not supported by a federal grant, upload the research plan that was submitted for 
funding: 
 
Name 
Modified Date 
PilotResearch_Guidelines_ApplicationForm June 2015 - LEVINTHAL .pdf 10/26/2015 1:13 PM 
 
If Industry support, provide the sponsor information and level of support: 
 
 
 
If Foundation support, provide the sponsor information: 
Consortium of Multiple Sclerosis Centers (CMSC) 
 
 
If Other support, provide the support information and level of support: 
 
    [reviewer notes¬]  
  
7.3 
Is this study funded in part or whole by a PHS Agency? 
 *  No 
  


Section: Section 7 - Qualifications and Source(s) of Support 
 
Does any investigator* involved in this study (select all that apply): 
 
  
Name 
 
 
A. Have equity in a publicly-traded entity that either sponsors** this research or 
owns the technology being evaluated or developed that exceeds a 5% ownership 
interest or a current value of $10,000? 
 
 
B. Have equity in a non-publicly-traded entity that either sponsors this research 
or owns the technology being evaluated or developed? 
 
 
C. Receive salary, consulting fees, honoraria, royalties or other remuneration from 
an entity that either sponsors this research or owns the technology being evaluated 
or developed that is expected to exceed $10,000 during the past or next 12 
months? 
 
 
D. Have rights as either the author or inventor of intellectual property being 
evaluated or developed in this research that is the subject of an issued patent or 
has been optioned or licensed to an entity? 
 
 
E. Have an officer or management position**** with a Licensed Start-up 
Company overseen by the COI Committee that either sponsors this research or 
owns the technology being evaluated or developed? 
 
 
F. Receive compensation of any amount when the value of the compensation would 
be affected by the outcome of this research, such as compensation that is explicitly 
greater for a favorable outcome than for an unfavorable outcome or compensation 
in the form of an equity interest in the entity that either sponsors this research or 
owns the technology being evaluated or developed? 
 
 
None of the above options apply and there are no other financial conflicts 
of interest in the conduct of this research. 
*Investigator means the PI, co-investigators, and any other member of the study team, 
regardless of title, who participates in the design, conduct, or reporting of this research, 
as well as his/her spouse, registered domestic partner, dependents, or other members of 
his/her household. The PI is responsible for ensuring that s/he and all other 
relevant members of the study team review the above questions describing 
Significant Financial Interests.  
**through the provision of funds, drugs, devices, or other support for this research 
****Such as serving on the Board of Directors or Board of Managers or a position that 
carries a fiduciary responsibility to the company (e.g., CEO, CFO, CTO, or CMO). 
  
  
Section: Supporting Documentation
    [reviewer notes¬]  
  
Supporting Documentation Section 
References and Other Attachments 
  
Additional documents: 
Name 
Modified Date 
Version 
FRIAR - OSPARS Form -- 
LEVINTHAL 2015.docx 
10/27/2015 
5:38 PM 
0.01 
Please use the Add button to the left to 
upload additional documents if needed. 
 


Section: Supporting Documentation
 
  
    [reviewer notes¬]  
ClinicalTrials.gov is a registry and results database of publicly and privately supported 
clinical studies of human participants conducted around the world. 
"Applicable clinical trials" are required by federal law to be registered in ClinicalTrials.gov. 
Applicable Clinical Trials (ACTs) are studies that meet the following criteria: 
• 
The study is an interventional study AND  
• 
The study intervention is a drug, biologic, medical device, radiation or genetic AND 
• 
The Study is not Phase 0 or 1 AND 
• 
The study has at least one site in the United States or is conducted under an investigational 
new drug application or investigational device exemption 
NIH Policy 
Effective January 18, 2017, revised NIH Policy requires that all clinical trials funded in whole or in part 
by the NIH be registered and results information posted on ClinicalTrials.gov.  
As defined by the NIH, a clinical trial is: 
A research study in which one or more human subjects are prospectively assigned to one or more 
interventions (which may include placebo or other control) to evaluate the effects of those 
interventions on health related biomedical or behavioral outcomes. 
The NIH Policy extends beyond the Food and Drug Administration Amendment Act (FDAAA 801) 
requirements in that it requires registration and results reporting of: 
• 
clinical trials of behavioral, surgical and other types of health and medical interventions 
• 
phase 1 studies of drugs and biological products 
• 
small feasibility studies of device products 
Failure to submit all required registration and results information requested on ClinicalTrials.gov can 
jeopardize University grant funding, the future funding of the grantee and subject the University of 
Pittsburgh to future monetary penalties. 
In addition, to promote transparency of the clinical trials process, the International Committee of 
Medical Journal Editors (ICMJE) has established a policy requiring the entry of clinical trials in a public 
registry, such as ClinicalTrials.gov, prior to subject enrollment as a condition of consideration for 
publication of the trial results. 
* Based on the above information, will this study be registered in ClinicalTrials.gov?