Effects of Type A Botulinum Toxin in Obstructed Defecation Syndrome: a Phase II Randomized, Parallel-Group, Triple-Blind, Placebo-Controlled Trial
Phase: PHASE2
Conditions: Obstructed Defecation Syndrome (ODS)
Sponsor: Massachusetts General Hospital

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Effects of Botox in Obstructed Defecation Syndrome 
 
NCT02160288 
 
 

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Effects of Type A botulinum toxin in obstructed defecation syndrome: a Phase II randomized, 
parallel group, triple-blind, placebo- controlled trial 
 
 
 
I. 
BACKGROUND AND SIGNIFICANCE 
 
a. Historical background 
 
Constipation represents one of the five most common physician diagnoses for gastrointestinal 
disorders1. Obstructed defecation syndrome (ODS) accounts for 30%-50% of all patients with 
constipation and its prevalence, health care costs and impact on the quality of life can be assessed 
indirectly from data available on constipation2. 
 
A 2011 review and meta-analysis of chronic idiopathic constipation worldwide identified a pooled 
global prevalence of 14%2. Another recent review on the epidemiology of chronic constipation 
identified a median prevalence of 16% (ranging from 0.7%-79%) in adults overall and 33.5% in 
adults aged 60 to 101 years3. In North America, over 63 million people met the Rome II criteria for 
constipation8 .  
 
Although only a minority of patients suffering from constipation seeks medical advice4, constipation 
consumes significant health care resources because its prevalence is high10. The most recent data 
from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical 
Care Survey show that the number of ambulatory visits for constipation has doubled over a ten-year 
period5. From 1997 to 2006, a total of 52.7 million patient visits in the U.S. were related to 
constipation. The annual direct medical costs for constipation were estimated to exceed $230 
million6-7. Recent studies suggest that among patients with constipation in the community, quality of 
life scores were comparable to those suffering from depression, hypertension and diabetes9 . 
 
Symptoms of constipation can be secondary to mechanical obstructions of the colon, drug side 
effects, and neurologic or metabolic disturbances16. Most frequently, however, constipation is 
caused by disordered function of the colon, pelvic floor or anorectal apparatus. Based on assessment 
of colonic transit and anorectal function, patients can be categorized in three groups: normal transit 
constipation, slow transit constipation and defecatory disorders. Defecatory disorders (DD), also 
known as obstructed defecation, may coexist with slow transit constipation. The American 
Gastroenterological Association (AGA) and Rome III criteria both emphasize the need to diagnose 
DD, because when evacuatory defects are pronounced, soft stools and even enema fluid may be 
difficult to pass16. 
 
Obstructed defecation syndrome (ODS) is defined as the inability to defecate properly, despite a 
normal sensation of the need to do so13. This leads to the feeling of incomplete evacuation with long, 
frequent toilet visits, straining, digitation, and laxative abuse. In most cases of ODS, abnormal 
morphology of the pelvis, the pelvic floor and the colon and rectum may be present14. Although 
structural abnormalities coexist, the etiology of ODS is incompletely understood and may be 
conceptualized as maladaptive learning of sphincter contraction16. Even the findings of different 
tests (eg, anal manometry, defecography) may not concur. There is no gold standard for the 

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diagnosis and traditional treatment approaches (fiber, osmotic or stimulant laxatives and enemas) do 
not improve the anorectal muscular coordination and may exacerbate the problem. 
Biofeedback therapy improves corticoanal function26 and it alongside of medical management, is the 
mainstay of treatment of DD. Its main advantages are that it is noninvasive, free of morbidity and 
with a documented success rate of over 70%16. The short-term success rate for biofeedback therapy 
depends on the patient’s motivation, the operator’s expertise and skills, and the quality of their 
interaction with the patient. Successful protocols from tertiary centers have used 5-6 treatment 
sessions, lasting 30-60 minutes each at two weekly intervals17. While the short-term success rates 
support the use of biofeedback, there is a high failure rate of about 50%-70% at one year. The main 
drawbacks of biofeedback for ODS are the facts that it is expensive, time-consuming, and it has 
decreased availability and inconsistent outcomes which are very provider dependent. Because it is 
delivered in multiple clinic sessions, it is associated with a poorer patient compliance. 
There is no current standard of care for patients with refractory defecatory disorders who fail a trial 
of medication and biofeedback therapy. Options are limited to sacral nerve stimulation, botulinum 
toxin injection or surgical interventions. Patients who fail, refuse or do not finish biofeedback 
therapy may be offered botulinum toxin injections into the puborectalis muscle36. Sacral nerve 
stimulation has recently been proven to work for patients with defecatory disorders accompanied by 
rectal hyposensitivity, but studies are very small, uncontrolled and the response to treatment is 
inconsistent27. Studies assessing the value of partial division of the puborectalis muscle reported 
mixed results and permanent complications, including incontinence for gas, mucus or feces29,37. 
Total abdominal colectomy with ileorectal anastomosis is the surgical option reserved for patients 
with chronic constipation who have failed medical therapy. Preliminary studies have shown that it 
offers significant symptomatic improvement35, however, like any major surgical procedure, there is 
a higher risk for complications. An end ileostomy or, if colonic transit is normal, a colostomy are the 
options of last resort for most patients.  
 
b. Previous clinical studies 
 
Botulinum neurotoxin A is one of the seven neurotoxins produced by Clostridium botulinum.19-
20 When injected into the muscle, it binds very specifically to the presynaptic membrane of 
motoneuron nerve endings and produces chemodenervation that can last for 14 to 16 weeks21-
22. This long-lasting neuromuscular blockade is achieved through the cleavage of nine amino-
acid residues from the carboxyl terminus of synaptosome-associated protein with relative 
molecular mass 25K (SNAP-25)24-25. As a consequence, acetylcholine-containing synaptic 
vesicles can no longer fuse with the plasma membrane, resulting in the blockade of 
neurotransmission. The injected muscles become weak over 2-20 days and may recover over 
2-4 months as new terminal axons sprout and restore neurotransmission.23  
 
Botox was first documented for use in the treatment of anismus in 1988, with a symptomatic 
improvement in 4 of 7 patients (57%) at 4 weeks after the injection28. This was a pilot study 
and different doses of Botox were used. Two patients developed fecal incontinence that 
disappeared once the effect of Botox started to fade. 
 

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Several phase I and II trials since then demonstrated that Botox is a safe and effective 
therapeutic approach for ODS28-35. There were no severe adverse effects and the overall 
mortality rate was 0% in all of these studies.  Subject to the caveats that the majority of these 
studies were uncontrolled, with small sample sizes, variable doses, primary outcomes and 
administration modalities of Botox, their encouraging results led to Botox being increasingly 
used off-label for patients with pelvic floor disorders who failed medical management and 
biofeedback therapy.  It offers significant advantage in the fact that it can be administered in 
one session in the office. 
 
Joo et al. 31 injected a dose of Botox contingent with body mass (a total of 12-30 units) in 4 
patients with anismus who had failed biofeedback therapy. Symptomatic improvement was 
noted in all subjects (100%) at 1 and 3 months after the injection. The effect was maintained at 
one year in 50% of their patients. Shafik and El-Sibai35 injected 25 IU of Botox in the external 
anal sphincter of 15 patients with nonrelaxing puborectalis muscle syndrome. Straining at 
defecation disappeared and stool frequency normalized in 13 of 15 patients (87%) with a 
mean duration of effect of 4.8 +/- 1.4 SD months. None of the patients treated with Botox 
reported any adverse effects after the injection. 
 
In 2006, Maria et al. 30 injected 60 IU of Botox in the nonrelaxing puborectalis muscle of 24 
patients with chronic outlet obstruction constipation.  At 2 months, 19 of 24 patients (79%) 
had symptomatic improvement. The other five patients who did not respond to the first dose 
were offered a rescue treatment with 100 IU of Botox. All of them had symptomatic 
improvement after two months and this improvement persisted to the end of follow-up. At 4 
months, 4 of the 19 patients (21%) who initially improved suffered symptomatic recurrence 
and were successfully retreated with 100 IU of Botox. At an average follow-up of 39+/-17 
months, there was no symptomatic recurrence in any of the 24 patients. Two patients (8%) 
had mild flatus incontinence after the first injection, but there were no other short- or long-
term complications or side effects. 
 
Ron et al32 randomized 25 patients with anismus to receive 20 IU of Botox with two different 
methods of administration (local injection of Botox-10 units to each side of the puborectalis or 
20 units to the posterior aspect of this muscle). Only 29% had a symptomatic improvement in 
straining index after this dose and the overall satisfaction rate with the treatment was 58%. 
The reported adverse effects were: 0% incontinence, local infection or bleeding (these remained 
the same during follow-up after the 1st and 2nd injection). 12.5% of all patients developed mild pain 
after injection that increased at follow-up. 
 
Faried et al. 29 randomized sixty patients with anismus to receive biofeedback therapy, 100 IU 
of Botox or posterior division of the puborectalis muscle in. The groups differed significantly in 
terms of clinical improvement at 1 month (50% for biofeedback, 75% Botox injection, 95% 
posterior division of the puborectalis muscle, p=0.006). The symptomatic improvement 
persisted at 1 year in 30% of patients in the biofeedback group, 35% in the Botox group and 
70% in the surgery group (p=0.02). No adverse effects were reported for the Botox arm. Two 
patients in the surgery arm developed incontinence, compared to 0 patients in the Botox and 
biofeedback arms.  

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Hompes et al. 36 reported an excellent response of patients with anismus to 100 IU of Botox. 
Twenty-two (39%) of 56 patients responded initially and 21 ⁄ 22 (95%) underwent repeat injection. 
At a median follow-up of 19.2 (range, 7.0–30.4) months, 20 ⁄ 21 (95%) had a sustained response and 
required no further treatment. In 33 (97%) of 34 nonresponders, significant abnormalities were 
demonstrated at EUA: 31 (94%) had a grade 3–5 rectal prolapse, one had internal anal sphincter 
myopathy and one had a fissure. Exclusion of these alternative diagnoses revised the initial response 
rate to 96%. Of 56 patients who received the injection, 4 (7.1%) developed transient minor fecal 
incontinence (for gas rather than minor soiling). These adverse effects occurred in 4/16 patients who 
ultimately proved to have rectal prolapse. No Patient with ODS alone had any continence 
disturbance. 
 
In summary, doses between 50-100 IU of Botox are safe, well tolerated and have been shown 
in small studies without blinding to provide immediate symptomatic relief in the majority of 
patients with ODS constipation. For those who did not respond to low doses, higher doses of 
100 IU have been used successfully, with improvement in 90-100% of the cases. Based on the 
available evidence, Botox is a reasonable therapeutic option after failure of conservative 
management and before more invasive surgery is attempted 34. 
 
c. Rationale behind the proposed research and potential benefits to patients and society 
 
ODS is an undertreated condition, whose prevalence increases with age and is predicted to increase 
dramatically with the aging population. Botox has been proposed as an effective treatment and it has 
long been used off-label in ODS patients who refused or failed medical management and 
biofeedback therapy.  However, to this day, no randomized controlled trial has confirmed that Botox 
is superior to placebo for the treatment of ODS. 
 
We will use 100 IU of Botox, a dose with a good safety profile that has been proven to work in 
previous studies. We want to evaluate the efficacy of Botox 100 IU compared to placebo in addition 
to the standard of care (biofeedback therapy) in the treatment of patients diagnosed with ODS. We 
also plan to document patient compliance with biofeedback therapy. 
 
 
II. SPECIFIC AIMS 
 
Objective: 
To evaluate the efficacy and safety of Botox for the treatment of ODS. 
 
Hypotheses: 
Patients treated with Botox will have an improvement in the Altomare Obstructed Defecation 
Syndrome score (ODS-S) and Patient Assessment of Constipation- Quality of Life Score (PAC-
QoL) compared to the placebo group. 
 
 
 
 

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III.SUBJECT SELECTION 
 
a. Inclusion/exclusion criteria 
 
Inclusion criteria  
- 
Males and females older than 18 years of all races and backgrounds 
- 
Competent to give informed consent 
- 
Meet the Rome III diagnostic criteria for functional constipation 
- 
Inability to relax the puborectalis muscle at electromyography  
- 
Altomare Obstructed Defecation Syndrome score of 15 points or above  
- 
Failure of treatment with 2 conservative measures which may be as follows: 
o 1 laxative (osmotic or stimulant) for 2 weeks 
o 1 fiber supplement for one month 
o And/or trial of biofeedback for at least 4 sessions 
 
 
Exclusion criteria 
- 
Previous treatment with botulinum toxin (possible antibodies) 
- 
Known hypersensitivity to any of the components of the toxin 
- 
Presence of allergy or allergic reaction to bupivacaine 
- 
Medication regimen includes narcotics 
- 
Previous radiation therapy to the anal canal and rectum 
- 
Prior proctectomy 
- 
Presence of unhealed and symptomatic anal fissure 
- 
Presence of anal pain  
- 
Presence of fecal incontinence 
- 
Presence of full thickness rectal prolapse 
- 
Presence of internal sphincter myopathy 
- 
Inflammatory bowel disease or proctitis 
- 
Pregnancy or breast-feeding 
- 
Subject is currently enrolled/ just finished participating in a clinical trial in which the 
intervention/ its carry-over effect may interact with the intervention in this trial 
 
b. Source of subjects and recruitment methods 
 
All patients seen through the Pelvic Floor Disorder Service in colorectal surgery and 
gastroenterology at MGH who are diagnosed with outlet obstruction will be told about the option to 
participate in the study by their treating physician/ nurse practitioner. 
 
 
IV. SUBJECT ENROLLMENT 
 
a. Methods of enrollment 
 

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We will enroll 23 patients into the control and 23 patients into the placebo arm of the study. All 
patients with ODS who are evaluated in the Pelvic Floor Disorders Service at MGH through 
colorectal surgery and gastroenterology will be informed of the study.  
b. Lieba Savitt, N.P. and Holly Milch, NP, initially treats most patients presenting with ODS in our 
department. Patients with ODS who fail dietary modifications and medical therapy (laxatives 
and/or biofeedback) are then referred to Liliana Bordeianou, M.D., for discussion of surgical 
options. In order to avoid the possibility of patients feeling obligated to participate, patients who 
failed medical management and are interested in participating will initially discuss the study with 
one of the NPs and have all of their questions answered. Each patient will also receive 
individualized information about the available treatment options for his/her disease. If still 
interested, they will be screened based on inclusion and exclusion criteria, and those who qualify 
will be given the informed consent to take home, read carefully and call back if they wish to 
participate. Patients who call back will be seen again and allowed to discuss the study in detail 
with the PI. All further questions will be answered prior to signing consent. If still interested in 
participation, patients will sign the informed consent with their physician and then schedule their 
intervention following consent signing.  
 
c. Treatment assignment and randomization 
 
This will be a randomized controlled trial to determine the efficacy of Botox 100 IU compared to 
placebo for symptom control in adults diagnosed with ODS. Eligible patients who consented to 
participate are randomized in two groups in a 1:1 ratio to receive either 100 units of Botox or 
placebo (normal saline) administered under local anesthesia in one office session.  
 
A triple-blinded approach will be used in this study. Subjects, investigators and outcome assessors 
will be blinded to the group allocation. 
Patient treatment group allocation will be done using the method of randomly permuted blocks with 
random block sizes. This selected type of restricted randomization allows balancing group sizes 
especially in smaller randomized controlled trials. Subject randomization will be computer generated 
through the research pharmacy.  These results are subsequently kept in the research pharmacy and 
with the unblinded research nurse who will not interact with the patients 
 
On the day of the procedure, the research nurse will obtain the saline or Botox from the research 
pharmacy in a brown paper bag. She will then prepare the Botox or draw the normal saline and give 
it to the investigator for administration. In order to protect blinding, placebo and Botox will have the 
same characteristics, except for the active drug. The nurse who prepares the drug will also record the 
study arm in a file kept separate from patient information. Once this is recorded, information will be 
resealed and kept with patient information until the completion of the study. The nurse who prepared 
the composition will be the only unblinded member of the healthcare team and will not assist in the 
procedure.  
 
The adverse effects will be assessed by one standard questionnaire, which allows the description of 
idiosyncratic reactions and 2 validated questionnaires, which assess the Botox specific adverse 
effects of fecal incontinence. Outcome measurements and assessment of adverse effects in the office 
will be made by a research nurse blinded to treatment group allocation. 

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The PI who delivers the intervention will not take outcome measurements and will have no 
interaction with the data collectors. The data collectors will be blinded throughout the data entry and 
data cleaning processes. The statistical analysis will be made after the end of the data collection 
period. The statistician will only be unblinded once the database is locked. At the end of the study, 
blinding integrity will be evaluated in a sample of participants and data collectors. 
 
In case of medical emergency, if a study participant has encountered an urgent medical problem and 
the clinician needs to know his/her intervention group, the allocation code can be broken. 
Unblinding envelopes (labeled with the randomization number that contains allocation) are sealed by 
the study center and are only opened if emergency unblinding is necessary.  
 
 
 
V. STUDY PROCEDURES 
 
a. Study visits and parameters to be measured 
 
As part of this research study, patients will be asked to come for three visits (Visit 1= return of 
informed consent and schedule of intervention; Visit 2= intervention; Visit 3=one month after the 
intervention). They will afterwards be contacted by mail with questionnaires and then with follow-up 
phone calls (for those who did not return questionnaires) to increase response rate at 3, 6 and 12 
months after the intervention.  
 
All patients considered for the study will undergo pretreatment evaluation as per standard of care. 
This includes a history, clinical examination, and anorectal manometry. Once the patient is deemed 
eligible to participate, s/he will be offered the opportunity to participate in this trial. 
 
If interested, s/he will meet with the Principal Investigator and/or research nurse practitioner to find 
out more about this trial. At this time all questions will be answered. Afterwards, s/he will be offered 
an informed consent form, for review at home.  Patients will then be scheduled for a follow-up visit 
to review and sign consent with PI or study nurse practitioner.   
 
Once all questions are answered and consent is signed, patients will be asked to fill out baseline 
questionnaires at the visit when consent is signed.  
 
All questionnaires used in this study include validated scores. They will be used to assess the 
efficacy of the intervention in providing symptomatic improvement and improved quality of life 
(Altomare ODS score, generic SF-36 version 1, Patient Assessment of Constipation- Quality of Life 
questionnaire). We will also use 2 standard questionnaires to assess for Botox-specific adverse 
effects (Cleveland Clinic Fecal Incontinence Score and Fecal Incontinence Quality of Life Scale).  
 
Patients will receive the questionnaires at baseline and then be asked to complete them at their one 
month follow-up visit.   
 
At one month follow-up visit, patients will meet with their surgeon and the study nurse practitioner.  
They will first review any adverse reactions which they may have had. Patient will also be asked 

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about any adverse reactions which will be documented at that visit.  They will then undergo 
anorectal manometry and fill out the questionnaires.   
 
At 3, 6, and 12 months after the injection, patients will be mailed questionnaires.  Those participants 
who do not respond within a month will be contacted by phone to increase response rate.    
 
b. Drugs, devices and surgical procedures to be used 
 
Patients are divided in 2 groups: 
Group #1: Placebo 
 
Placebo consists of normal saline and has the same method and route of administration as the active 
treatment. 
 
Group #2: Botox 100 IU 
 
Each patient in Group #2 will receive a total of 100 units of botulinum toxin, stored in the research 
phramacy and dispensed to the clinic on the day of the procedure.  Botox will be resuspended in 5 ml 
of sterile saline to a ﬁnal concentration of 20 U/ml. 
 
For both groups, the interventions will be administered in the office under local anesthesia with 
0.25% Marcaine stored in the clinic at 20° to 25°C. We plan to use a 10 mL single dose vial of 
Marcaine (Bupivacaine Hydrochloride Injection, USP 0.25% (2.5 mg/mL)) administered as local 
infiltration. More or less drug may be used depending on each individual case. The MGH Research 
Pharmacy will perform the computerized randomization and send up medication or saline in paper 
bag based on randomization of the subject. Both saline and Botox will be brought from research 
pharmacy on the day of the procedure in a brown paper bag.   
 
The PI will use transanal ultrasound to clearly identify the puborectalis muscle. Once the muscle is 
identified, a 23-G needle will be used to inject the agent transanally into the puborectalis and 
external anal sphincter in three separate locations.  
 
c. Data to be collected  
 
All data are collected prospectively, at the pre-specified time points according to the protocol. All 
data will be collected in questionnaires attached (see above for specific description).  Data from 
baseline manometry will be taken from patient chart and recorded into REDCap database where data 
will be stored. Anorectal manometry from 1-month follow-up will also be stored in REDCap 
database. 
 
 
VI. BIOSTATISTICAL ANALYSIS 
 
a. Specific data variables being collected for the study 
 

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Data collection sheets are attached to this submission. They include the MRN to facilitate data 
extraction, demographic information (age, sex, race), diagnostic tests at baseline and the study 
endpoints collected at pre-specified times. 
b. Study Endpoints 
 
a) Primary endpoint: 
Baseline to 1 month after treatment changes in the sum of Altomare ODS score (ODS-S) and 
Patient Assessment of Constipation- Quality of Life score (PAC-QoL) 
 
b) Secondary endpoints: 
• Baseline to 1, 3, 6 and 12 months after treatment changes in Altomare ODS score (ODS-
S) and Patient Assessment of Constipation- Quality of Life score (PAC-QoL) 
• Changes in the generic SF-36 version 1, Cleveland Clinic Fecal Incontinence Score 
(CCFI) and Fecal Incontinence Quality of Life Scale (FIQoL) at 1, 3, 6 and 12 months 
from baseline 
• Relaxation of puborectalis with push measured by EMG at 1 month 
• Balloon expulsion test at 1 month 
• Manometric changes at 1 month- changes in anal sphincter function (resting sphincter 
pressure, maximal resting anal pressure, maximum squeeze pressure).  
• Change in defecation index [ Time Frame: Baseline, 1 month follow-up visit ]. The 
defecation index=maximum rectal pressure during attempted defecation/minimum 
anal residual pressure during attempted defecation. This is calculated based on 
measurements obtained from anorectal manometry and is a measure of treatment 
efficacy. 
 
c. Statistical methods 
 
All analysis will be based on intention-to-treat population in that all randomized subjects will be 
included in the analysis. 
 
Data will be expressed as mean+/- standard deviation (SD) for all continuous outcomes, and as 
counts and proportions for all categorical outcomes. The primary analysis (i.e., the comparison of 1-
month change in mean ODS-S and PAC-QoL between the 2 treatment arms) will be made by 
independent samples t-test. Comparison of treatment effect over time (i.e., 1- and 3-, 6- and 12 
months) on all scale scores will be performed by using longitudinal linear mixed effects model, 
which allows to specify the subject specific baseline levels and the time dependent response 
trajectories (i.e., slopes) random (SAS proc mixed). All p-values are two-tailed and considered 
significant if p<0.05.  
 
 
 
d. Power analysis 
 
The proposed sample size is 46 (i.e., 23 in each treatment arm). With an assumption of an attrition 
rate of up to 15%, we anticipate to attain 40 study completers.  The study is designed to detect at 

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least 25% decrease in mean ODS-S and PAC-QoL at 1 month after treatment with Botox with 80% 
power at a 5% significance level.  This effect size of ≥25% is equivalent to a decrease in mean ODS-
S decrease from 15 points at baseline to ≤ 11.4 points at 1 month37-38. 
VII. RISKS AND DISCOMFORTS 
 
a. Complications of surgical and non-surgical procedures 
 
We do not expect any unusual safety concerns in this study. The small foreseeable discomforts and 
complications will be treated as per standard of care.  
 
b. Drug side effects and toxicities 
 
Botulinum toxin (Botox) has been shown to be very safe and well-tolerated in prior studies, however 
variable doses of Botox were previously shown to have efficacy. Concerns may arise for potential 
issues with incontinence for gas, liquid or solid stool if higher doses of Botox are studied. The 
reported incidence of incontinence has been low in previous studies and it was mostly mild 
(gas>soiling>solid stool). If incontinence occurs, it may cause significant discomfort to patients who 
work in a public place and could account for a low recruitment rate and unblinding of patients who 
experience these adverse effects. Both the active treatment and placebo groups receive transanal 
injections into three sites. This can cause local discomfort/pain so we will co-administer a long-
acting local anesthetic. Patients will also be given instructions to take ibuprofen or acetaminophen as 
needed for pain relief after procedure. There is the additional risk of infection at the site of injection.  
The risk of this is low, but all patients will be instructed to call with any symptoms of infection, and 
will be seen by PI or research nurse practitioner and treated as necessary. 
 
c. Device complications/malfunctions 
 
Not applicable 
 
d. Psychosocial (non-medical) risks 
 
Psychosocial risks may include loss of productivity from appointments. We tried to limit this by 
administering our surveys via mail and phone and by asking the patients to come in only for the 
consent, intervention and one visit at 1 month afterwards.  
 
Patients who are in the control group may experience frustration with lack of improvement of their 
symptoms and frustration from the need to undergo further treatments and investigations at the end 
of the study. We tried to address this issue by encouraging all patients to receive the standard of care 
(biofeedback) prior to treatment. Also, at the end of the study, if the medication demonstrates 
efficacy for ODS, patients in the control group will be offered the option to receive Botox. These 
patients will be monitored per described plan for this study, but the subjects and investigator will no 
longer be blinded. 
 
It has been reported that patients enrolled in clinical trials are often frustrated by not knowing the 
results of their tests and the outcome of the study. To address this, patients will receive a written 
report of their objective measures (EMG, anorectal manometry, balloon expulsion test) at the one 

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month visit after the intervention. Also, we will send a letter to each patient when we receive the 
results, informing him/her of the overall outcome of this study.  
 
e. Radiation Risks 
 
Not applicable 
 
 
VIII. POTENTIAL BENEFITS  
 
a. Potential benefits to participating individuals 
 
For patients specifically, the potential benefits include an improvement of chronic constipation 
symptoms and quality of life with a minimally invasive treatment.  
 
b. Potential benefits to society 
 
For society, the potential benefits are great. At this time, few minimally invasive, easily to administer 
outpatient options for the treatment of ODS are available. The standard of care (biofeedback) is only 
available in a few select centers across the country and is not a “quick fix” taking multiple sessions 
to make progress. These may or may not accept the patients’ current insurance. On the other hand, 
the incidence of chronic constipation in the US population is clearly on the rise, as the baby boomers 
are reaching their 60s. Botox, should it be effective, could alleviate the profound suffering and 
discomfort associated with this condition. It could also provide an accessible and fast-acting option 
for the treatment of ODS. 
 
 
IX. MONITORING AND QUALITY ASSURANCE 
 
a. Independent monitoring of source data 
 
Monthly meetings will be organized to allow monitoring of recruitment of patients, and to assure 
that the IRB protocols are adhered to. The results of the study will be reviewed at 1/2 of recruitment 
goals. The study will be halted if a particular study arm appears to be more efficacious or if any 
unanticipated adverse events occur resulting in serious morbidity or mortality.  
 
 
b. Safety monitoring 
 
We do not expect any unusual safety concerns in this study as all of the treatments and procedures 
planned are FDA-approved for a different indication and are thought to be extremely safe. 
 
c. Outcomes monitoring 
 
The principal investigator will monitor completeness of data and assure the validity and integrity of 
data and adherence to the IRB-approved protocol. She will also review the accuracy and 

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completeness of case report form entries, source documents and informed consent. IRB will be 
notified of any major unforeseen complications associated with the study. 
 
d. Adverse event reporting guidelines 
 
Adverse events or other unanticipated problems will be reported to the PHRC as described in the 
PHRC policy on Adverse Event Reporting and Unanticipated Problems Involving Risks to Subjects 
or Others, which can be found on the PHRC website:  
http://healthcare.partners.org/phsirb/adverse_events.htm  
and  
http://healthcare.partners.org/phsirb/unantic.htm 
 
 
 
X. REFERENCES 
 
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5. Shah ND, Chitkara DK, Locke GR, et al. Ambulatory care for constipation in the United 
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6. Trinkley KE, Porter K, Nahata MC.  Prescribing Patterns for the Outpatient Treatment 
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7. Martin BC, Barghout V, Cerulli A. Direct medical costs of constipation in the United 
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