A Phase II Study of Sacral Nerve Stimulation for Low Anterior Resection Syndrome or Fecal Incontinence in Patients Following a Low Anterior Resection or Proctectomy With Coloanal Anastomosis or in Patients After Pelvic Chemoradiation (RESTORE)
Phase: PHASE2
Conditions: Low Anterior Resection Syndrome, Malignant Anal Neoplasm, Malignant Bladder Neoplasm, Malignant Cervical Neoplasm, Malignant Ovarian Neoplasm, Malignant Pelvic Neoplasm, Malignant Prostate Neoplasm, Malignant Uterine Neoplasm, Malignant Vaginal Neoplasm, Malignant Vulvar Neoplasm, Rectal Carcinoma
Sponsor: M.D. Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 1 of 20 
A PHASE II Study of Sacral Nerve Stimulation for Low Anterior Resection Syndrome or 
Fecal Incontinence in Patients Following a Low Anterior Resection or Proctectomy with 
Coloanal Anastomosis or in Patients after Pelvic Chemoradiation (RESTORE) 
Protocol 2016-0754 
Principal Investigator: 
Craig A. Messick, MD 
Collaborators: 
Department of Surgical Oncology: 
George Chang, MD, MS 
John Skibber, MD 
Miguel Rodriquez-Bigas, MD 
Nancy You, MD 
Barry Feig, MD 
Brian Bednarski, MD 
Department of Radiation Oncology: 
Prajnan Das, MD 
Department of Medical Oncology: 
Van Karlyle Morris, MD 
Department of Gynecologic Oncology: 
Nicole Fleming, MD 
Kathleen Schmeler, MD 
Department of Urology: 
Ouida L. Westney, MD 
Department of Biostatistics: 
Rebecca S. Slack 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 2 of 20 
Contents 
1. 
Objectives.............................................................................................................................................. 3 
2. 
Background and Rationale .................................................................................................................... 3 
3. 
Patient Eligibility ................................................................................................................................... 6 
Exclusion Criteria ....................................................................................................................................... 7 
4. 
Study Design.......................................................................................................................................... 8 
5. 
Study Methods ...................................................................................................................................... 8 
6. 
Statistical Considerations .................................................................................................................... 13 
6.1. 
Summary Statement ................................................................................................................... 13 
6.2. 
Analysis Subgroups ..................................................................................................................... 14 
6.3. 
Endpoints .................................................................................................................................... 14 
6.4. 
Sample Size ................................................................................................................................. 15 
6.5. 
Interim Analyses .......................................................................................................................... 15 
6.6. 
Analysis Plan ................................................................................................................................ 18 
7. 
Risk Management ............................................................................................................................... 18 
8. 
Data Management .............................................................................................................................. 18 
9. 
References .......................................................................................................................................... 19 
10. Appendices ……………………………………………………………………………………………………………………........... ..... 20 
 
 
 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 3 of 20 
1. 
 OBJECTIVES 
Primary Objectives  
1. To investigate the efficacy of sacral nerve stimulator placement in patients with fecal 
incontinence (FI) or low anterior resection syndrome (LARS) who have previously 
undergone chemoradiation treatment (XRT) and/or a restorative partial or complete 
proctectomy with colorectal or coloanal anastomosis for cancer treatment as per standard 
of care (restorative surgery cohort). 
 
2. To evaluate the feasibility of sacral nerve stimulator placement in patients with fecal 
incontinence (FI) or other defecatory dysfunction who have received pelvic radiation 
treatment without undergoing rectal or other pelvic surgery as per standard of cancer care 
(radiation only cohort). 
Secondary Objectives 
1. To evaluate the effectiveness of sacral nerve stimulation (SNS) as measured by validated 
questionnaires in patients with FI or LARS within both patient cohorts.  
2. To evaluate pelvic floor and sphincter physiology using anorectal manometry (ARM) 
before and after SNS in patients with FI or LARS within both patient cohorts. 
3. To assess potential impact of SNS on urinary incontinence measuring a post-void urinary 
bladder residual and validated urinary symptom questionnaires in both patient cohorts. 
4. To assess efficacy of SNS on long-term bowel dysfunction at 1 and 3 years post battery 
implantation as measured by validated questionnaires for both patient cohorts. 
 
2. 
 BACKGROUND AND RATIONALE 
Development of FI and LARS after Surgery 
Post-operative bowel dysfunction, specifically fecal incontinence (FI) and the low anterior 
resection syndrome (LARS), characterized by a change in bowel habits including urgency, 
alternating diarrhea and constipation, fragmentation, obstructive defecation and stacking, affects 
up to a reported 90% of patients following rectal surgery and is debilitating.[1, 2] The 
development of FI and LARS is likely complex and proposed mechanisms include internal anal 
sphincter dysfunction through injury or transection of sympathetic and parasympathetic pelvic 
nerves,[3-5] decreased anal canal sensation leading to loss of discrimination of feces from 
flatus,[6, 7] post-surgical loss of the rectal-anal inhibitory reflex (RAIR) due to disruption in 
nitric oxide signaling pathways from pelvic nerve injury,[8, 9] and loss of both compliance and 
reservoir capacity of the neorectum.[10, 11] Although historical primary treatment typically 
consists of fiber and dietary adjustments, alternate treatment options including pelvic floor 
physical therapy (biofeedback/pelvic floor rehab), anal sphincter repair, and frequent colonic 
irrigation, outcomes remain variable and are not readily available for all patients. An alternative 
treatment for FI, sacral nerve stimulation (SNS), was first reported in 1995.[12] Originally FDA 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 4 of 20 
approved for voiding dysfunction (urinary frequency, urgency, urge incontinence and non-
obstructive urinary retention), it has since been approved for use in patients with FI and now 
accepted as a promising alternative compared to previous strategies including an end colostomy 
for patients with benign disease causes for FI and LARS. For FI and LARS, SNS works through 
somatic afferent fibers enhancing anal sensation [13], which alters rectal and anal smooth muscle 
activity and facilitates external sphincter contraction [14] resulting in increased resting pressure 
and voluntary contraction of the rectum, reduction in the initial pressure for first sensation and 
urge to defecate, and a reduction in the rectal volume for urge sensation [15].  
Current Methods of Symptoms Control 
Historical management of FI has been ingestion of bulk-forming dietary foods including 
oatmeal, bananas, cheeses, and peanut butter. Additional therapy for LARS included additional 
Metamucil, a supplemental fiber taken as a slurry or as a dry wafer and used to absorb additional 
water essentially bulking the stool. For persistent uncontrolled bowel habits, the additions of 
Imodium or Lomotil have been included as primary medical options. Despite these treatments, 
patients may experience uncontrolled bowels and are unable to leave the house due to erratic and 
unpredictable bowel patterns. Physical therapy for the pelvic floor, or biofeedback, has been 
reportedly successful in improving bowel dysfunction in patients with FI, but compliance is 
low.[1] Best results are reported when patients complete six therapy sessions with a reported 10x 
greater odds ratio of success compared to those who fail to complete therapy.[16] While the 
majority of patients are women with prior vaginal deliveries, vaginal tears, or pelvic floor 
surgery including hysterectomy, very few studies report efficacy of biofeedback following rectal 
surgery. In the few publications, which are largely small studies, improvement in anal sphincter 
tone measured by anorectal manometry, episodes of FI, and frequency of bowel movements were 
all reported.[17-19] For FI due to sphincter defects from prior trauma, episiotomies or tears 
during labor, surgical repair by an overlapping sphincteroplasty is difficult to master and lacks 
sustainable long-term results. As a last resort, surgical removal of the anal canal may be 
considered and patients live with an end colostomy. 
Use of a Sacral Nerve Stimulator in Patients with FI, LARS, and Urinary Incontinence 
Early studies specifically excluded patients with rectal cancer and those with chemoradiation 
therapy, and though they reflected a very small group of patients with FI, outcomes were 
favorable decreasing median incontinence episodes per week from 7.5 to 0.67 and median 
incontinence days from 4 per week to 0.5 with sustained long-term results[1, 16-20] Although 
urinary symptoms were present in 40% of this patient population, the pre-SNS symptoms and 
responses have not been objectively quantified with a validated urinary-specific questionnaire. 
The largest study assessing SNS for FI was by Wexner et al, which included 14 US institutions 
and two international sites (Canada and Australia). They reported on 120 patients with a median 
follow-up of 28 months (range 2.2-69.5) with patients completing bowel diaries and FI 
questionnaires in 94% and 96%, respectively.[21] The authors defined success as ≥50% 
improvement from baseline FI questionnaires and stool diaries, and has been accepted as the 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 5 of 20 
marker for success with SNS. They reported an 83% success rate at 12 months, 85% at 2 years, 
and 87% at 3 years, p<0.0001.[21] Similar quality of life improvements were also reported. The 
results were significant and since its publication, the SNS procedure has become the favored 
surgical technique for FI in patients without prior pelvic radiation or rectal cancer. 
Despite the paucity of literature, reports of FI have certainly been reported following radiation 
alone and include radiation for cancers of the prostate, anal canal, and gynecologic organs 
(uterus, cervix, vagina, and vulva).  In 2012, Barraclough et al reported fecal urgency and FI at 3 
years post radiation treatment in 69% (40% daily) and 18%, respectively.[22]  Additionally, a 
systematic review of FI in radiation-treated prostate cancer in 2011 reported soiling and FI 
occurred in 58% and 57%, respectively.[23]  With regard to anal cancers (mostly squamous cell 
carcinoma), symptoms reported after completion of chemoradiation included fecal leakage 
(22%), difficulty controlling flatus (50%), daily use of a pad for accidents (39%), dietary 
adjustment to assist with control of bowels (35%), and significant daily lifestyle impairment 
(29%).[24]  Unfortunately, there are no published data of the use of SNS for FI or other 
defecatory dysfunction following radiation treatment without surgery. 
Rationale: FI and LARS are often debilitating and recalcitrant to current medical therapies 
including medicinal and biofeedback. A recent systematic review of the literature for patients 
with FI or LARS and who underwent SNS placement following chemoradiation and surgery for 
rectal cancer reported data on 42 patients from 7 articles with promising results.  Ramage et al 
reported an overall permanent implantation rate of 79.1% with the lowest reported at 47%.[25]  
The efficacy of SNS in these few patients revealed significant decrease in nocturnal defecation 
from 3 (pre-SNS) to 0.5 (post-SNS) episodes/night, decrease in incontinence from 7 (pre-SNS) 
to 0.2 (post-SNS) episodes/day episodes, and 67% of patients reported complete resolution of 
LARS (fragmented defecation, urgency, or soiling).[25]  The majority of literature specifically 
excluded patients with cancer and although reported in 42 patients following rectal cancer 
treatment (chemoradiation and surgery), this study aims to prospectively evaluate the efficacy of 
SNS placement in cancer patients who have undergone pelvic combined chemoradiation therapy 
for their rectal cancer treatment followed by a restorative proctectomy with either a low 
colorectal or coloanal anastomosis who exhibit subsequent significant, debilitating FI or LARS 
with or without urinary symptomatology.  Additionally, we aim to assess the feasibility of SNS 
placement in patients who have developed FI or defecatory dysfunction (including urgency and 
leakage) following radiation treatment without surgery for cancers including anus, prostate, 
uterus, cervix, vagina, and vulva as this has not been reported.    
The results of this study will be useful in the management of patients with bowel dysfunction 
either from FI or LARS following restorative rectal cancer surgery expanding available treatment 
alternatives including SNS. Future directions from this study include expansion of the patient 
population for a phase 2 trial and include an efficacy arm for patients treated with pelvic 
radiation without surgery including anal, gynecologic and urological malignancies.   
 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 6 of 20 
3. 
 PATIENT ELIGIBILITY 
Cohort 1: Restorative surgery cohort 
Inclusion Criteria:  
1. Patients with pathologically proven diagnosis of primary rectal cancer  
2. Patients who have previously undergone surgical resection and anastomosis (restorative) 
with curative intent treatment with or without chemoradiation  
3. Patients treated with restorative surgical resection without radiation 
4. Patients with any T-stage or N-stage rectal cancer that underwent treatment with radiation 
and restorative surgery 
5. Patients with self-reported FI or LARS  
6. Patients must be at least 18 years old and be able to speak and understand English 
7. Patients must be willing to and able to sign an approved informed consent document 
8. Patients must be ≥ 24 months post-resection of rectal cancer 
9. Patients must have failed prior conservative measures such as Metamucil and motility 
medications and already been assessed and treated in a pelvic floor rehabilitation program 
(biofeedback) designed to treat FI and LARS, and continue to experience significant 
defecatory dysfunction, allowable per PI discretion.  
10. Patients must be willing and able to complete Patient Reported Outcomes Questionnaires 
for before device placement, during the testing phase following lead placement, and after 
implantation of the battery 
11. Patients must be willing and able to undergo elective ARM testing to measure pelvic 
floor function 
12. Patients who have an average resting tone <40mmHg (normal >40mmHg) and maximal 
tolerance <200 milliliters (normal 200-300 milliliters) as measured by ARM 
 
Exclusion Criteria: 
1. Patients with co-morbid illnesses or concurrent disease, which in the judgment of the 
clinician obtaining informed consent, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and toxicity of 
the prescribed regimens 
2. Any diverting bowel ostomy at the time of consent to this study 
3. Patients with an ANC <1.7, INR >1.3, platelet count <50K within 30 days of consent  
4. Patients currently being treated with chemotherapy or within preceding 30 days at the 
time of consent 
5. Patients previously treated with a SNS for urinary or FI 
6. Patients who were documented to have an anastomotic leak following their restorative 
surgical resection 
7. Patients with an ECOG performance status >2 at the time of consent 
8. Patients with an active infection requiring systemic therapy at the time of consent 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 7 of 20 
9. Patients with a significant history of uncontrolled cardiac disease including, but not 
limited to hypertension, unstable angina, myocardial infarction within the last 4 months, 
and uncontrolled congestive heart failure 
 
Cohort 2: Radiation only cohort 
Inclusion Criteria 
1. Patients with pathologically proven malignancy of the pelvis, other than rectal cancer  
(e.g. prostate, bladder, anus, vagina, vulva, cervix, uterus, or ovary)  
2. Patients treated with standard of care radiation therapies without surgical resection 
3. Patients with self-reported FI or other defecatory dysfunction 
4. Patients must be at least 18 years old and be able to speak and understand English 
5. Patients must be willing to and able to sign an approved informed consent document 
6. Patients must be ≥ 18 months post-pelvic chemoradiation 
7. Patients must have already been assessed and treated in a pelvic floor rehabilitation 
program design to treat FI or other defecatory dysfunction and continue to experience 
significant defecatory dysfunction 
8. Patients must be willing and able to complete Patient Reported Outcomes (PROs) and 
bowel and bladder diaries (Medtronic) at multiple times during the study 
9. Patients must be willing and able to undergo elective ARM testing to measure pelvic 
floor function 
10. Patients who have an average resting tone <40mmHg (normal >40mmHg) and maximal 
tolerance <200 milliliters (normal 200-300 milliliters) as measured by ARM 
Exclusion Criteria 
1. Co-morbid illnesses or other concurrent disease, which in the judgment of the clinician 
obtaining informed consent, would make the patient inappropriate for entry into this 
study or interfere significantly with the proper assessment of safety and toxicity of the 
prescribed regimens 
2. Patients with an ANC <1.7, INR >1.3, platelet count <50K, within 30 days of consent 
3. Patients currently being treated with chemotherapy or within the preceding 30 days at the 
time of consent  
4. Patients previously treated with a sacral nerve stimulator for urinary or fecal incontinence 
5. Patients with an ECOG performance status >2 at the time of consent 
6. Patients with an active infection requiring systemic therapy at the time of consent  
7. Patients with a significant history of uncontrolled cardiac disease including, but not 
limited to hypertension, unstable angina, myocardial infarction within the last 4 months, 
and uncontrolled congestive heart failure 
8. Patients with an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a syndrome 
that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 8 of 20 
resolved childhood asthma/atopy would be an exception to this rule. Subjects that require 
intermittent use of bronchodilators or local steroid injections would not be excluded from 
the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s 
syndrome will not be excluded from the study 
4. 
STUDY DESIGN 
This study has two cohorts: 1) a restorative surgery cohort evaluating the efficacy of SNS for FI 
or LARS in patients who have previously undergone restorative partial or total proctectomy for 
treatment of rectal cancer with or without radiation as per standard of cancer care and 2) a 
radiation only cohort assessing the feasibility of SNS in patients treated with radiation without 
surgical intervention for treatment of a pelvic cancer, other than rectal cancer, as per standard of 
care, that developed FI or other defecatory dysfunction.  
 
5. 
 STUDY METHODS 
Patient Selection 
Both study cohorts will be evaluated and managed at the same. Total accrual to this study is 66 
patients for enrollment of 60 evaluable patients to the study, 30 patients into each cohort, at the 
UT MD Anderson Cancer Center (UTMDACC) in Sugar Land, Texas. Patients meeting study 
eligibility will be screened prospectively in relevant UTMDACC clinics, which are a likely 
source of patients to be identified for screening, or through physician referral to the study.  
Study Enrollment 
All patients will undergo a complete history and physical, per routine standard of care. Patients 
disclosing FI or LARS will sign consent and be pre-registered on the study in CORe for 
screening and will complete questionnaires (on paper, over the phone/teleconference system, or 
electronically through REDCap) related to general quality of life, FI severity, and LARS. 
Patients may access the questionnaires electronically in the REDCap system via a link sent to 
them by email or MyChart (Appendix K). Patients will then undergo an anorectal manometry for 
pelvic pressure readings per standard of care.  Then, patients who disclose appropriate bowel 
dysfunction (urgency, alternating diarrhea and constipation, fragmentation, obstructive 
defecation, and stacking) and with abnormal anorectal manometry readings and questionnaire 
responses indicating study eligibility, will proceed with enrollment in the study.  Patients who 
are found not to meet eligibility based on bowel dysfunction reporting, questionnaire responses 
and anorectal manometry results will be removed from the study. Patients meeting all eligibility 
criteria with insurance pre-authorization for all procedures will be enrolled on the study.  
 
Patients on-study with lab results described below before SNS placement will be given 30 days 
to improve and will be re-evaluated. Patients will have these tests ordered for routine standard of 
care based on the determination of the physician. If no improvement at 30 days, patients will be 
taken off study, data collected up to this point may be used in study reporting.  
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 9 of 20 
• ANC <1.7, INR >1.3, platelet count <50K 
On-study patients requiring systemic therapy for an infection before SNS placement will be 
given 30 days to improve and will be re-evaluated. If no improvement at 30 days, patients will be 
taken off study, data collected up to this point may be used in study reporting. 
Procedure to Obtain Informed Consent 
The investigator must obtain documentation of consent from each potential subject prior to 
participating in a clinical trial.   
The protocol and informed consent documentation for this study must conform to institutional 
regulations and local and national laws and regulations. As soon as a potential subject is 
considered for this study and prior to any other study procedures, each prospective subject will 
be given a full explanation of the purpose of the study, the procedures to be carried out and the 
potential hazards. Once this essential information is provided to the subject and once the 
Investigator believes that the subject understands the implications of participating in the study, 
the subjects will be asked to provide written informed consent and authorization to access 
medical records needed for study documentation.  Subjects will be required to read, sign, and 
date a properly executed written Informed Consent Form prior to enrollment and will be assured 
that they may withdraw from the study at any time without jeopardizing their medical care. They 
will be given a copy of their Informed Consent Form. 
Patients will either be consented in person, or contacted via phone, or through an Institutionally-
approved teleconferencing system (i.e., Zoom) and will complete the consent process through 
Institutionally-approved remote-consenting procedures. 
 
 
 
 
 
 
 
 
 
 
 
 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 10 of 20 
Study Procedures 
After study enrollment, patients will undergo 
scheduled, elective surgery for placement of 
the sacral nerve stimulator. The initial surgical 
placement is performed using fluoroscopy-
guidance to place a single electrode through 
the sacral foramen of nerve root 3 via passage 
through a needle. The SNS device is self-
anchoring and device migration is extremely 
rare; however, this can be surgically corrected. 
Stimulator migration rarely affects the device 
function although it impairs patient quality of 
life.[26] This technique has been previously 
described.[10] The electrode is then tunneled 
under the skin in the soft tissue of the buttocks 
and out the skin toward the hip where it is then 
connected to an external battery pack and 
covered, maintained in a sterile dressing and 
adjusted over the next 2 weeks by the patient. 
A bowel and bladder habit diary is maintained 
by the patients for the interval 2 week period.  
 
After 2 weeks, the patients return to the OR for 
either removal of the leads if the stimulator did 
not work, or implantation of a subcutaneous 
titanium battery with internalization of the 
electrode as per standard of care. Prior to lead extraction in patients who do not meet criteria for 
battery implantation, lead position will be re-investigated for appropriate positioning, and if 
incorrectly positioned due to migration, lead repositioning will be performed and the two week 
trial period restarted. The patients are discharged home from this outpatient surgery and will 
complete the bowel and bladder habit diaries. The patients will be required to return to the office 
at 1 month following their surgery to perform a wound check, symptom evaluation, and again 
complete study questionnaires (on paper, over the phone/teleconference system, or electronically 
through REDCap) for comparison, and undergo repeat anorectal manometry and a post-void 
residual bladder scan. 
 
Validated Questionnaires/Instruments: 
1. Fecal Incontinence Quality of Life (FIQoL): this is a quality of life instrument validated for 
patients with fecal incontinence.  This will be provided to all patients. 
2. Fecal Incontinence Severity Index (FISI): this is a scoring system validated to objectively 
quantify fecal incontinence severity.  This will be provided to all patients. 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 11 of 20 
3. EQ-5D-5L: This is a general quality of life instrument that is currently used in the GI surgery 
clinics as part of the prospective rectal cancer study that collects longitudinal quality of life 
and function outcomes.  This will be provided to all patients. 
4. Memorial Sloan Kettering Cancer Center Bowel Function Instrument (MSKCC BFI): This is 
a validated instrument for resected rectal cancer patients designed to assess bowel 
dysfunction including LARS.  This will be provided to patients in the restorative surgery 
cohort only. 
5. Cleveland Clinic Incontinence Score (CCIS): This is a validated instrument for FI 
specifically in patients whose rectums have not been surgically removed.  This will be 
provided to the radiation only cohort patients. 
6. Bowel Diary: Validated bowel diary provided by the device company used to collect daily 
bowel function.  
7. Bladder Diary: Validated urinary diary provided by the device company used to collect daily 
urinary function. 
8. International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract 
Symptoms (ICIS-FLUTS) if female and International Continence Society Male Short Form 
(ICSmaleSF) if male: Validated instruments to measure urinary dysfunction. 
9. Low Anterior Resection Syndrome (LARS) Bowel Function Questionnaire: This is a 
validated instrument, to be provided only to the restorative surgery cohort, designed to assess 
clinical severity of symptoms of LARS outside of just FI and will be a significant tool to 
address extending criteria for SNS use outside of FI. 
10. EORTC QLQ-CR29: this is a quality of life instrument validated for patients with colorectal 
cancer. This will be provided to all patients. 
 
  
Study Visits 
Initial Evaluation/Visit 1: Patients are referred to the clinic for reported refractory FI or LARS. 
Upon arrival to their initial clinic visit, the patients will complete the validated questionnaires 
and instruments (on paper, over the phone/teleconference system, or electronically through 
REDCap), as well as an ARM. A minimum score from the FISI will not be required as this was 
not required for the initial studies in the benign disease patients, though it is anticipated that their 
scores will be around a score of 30, a number defined as what is typical for patients who have a 
significant quality of life impairment due to their reported fecal incontinence. The results will 
then be reviewed for appropriateness to be considered eligible for the study. Patients will sign 
consent and then be enrolled after appropriate evaluation by the clinical and research teams and 
all inclusion and exclusion criteria are met. The remaining questionnaires will be completed and 
a complete review of symptoms and physical exam will be performed per standard of care. A 
post-void residual bladder scan will be performed at this visit after enrollment as well. After all 
objective data are collected, each patient will be scheduled for surgery for placement of a sacral 
nerve stimulator under general anesthesia in the operating room as per standard of care. All 
patients are asked to begin recording all daily bowel and bladder habits in the bowel and bladder 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 12 of 20 
trackers to serve as their baseline function. Necessary preoperative testing will be ordered and 
completed at UTMDACC including appropriate consultant visits as per standard of care for any 
operation. 
Visit 2 (Sacral Nerve Stimulator Lead Placement): Surgery for stage 1 sacral nerve stimulator 
placement will occur within 30 days after enrollment in the study. The patient will arrive at the 
pre-operative holding areas at UTMDACC’s main campus for their outpatient surgery. The 
representative for the implantable SNS company (Medtronic) will be present at the operation for 
assistance with placement of the leads per standard of care and for assistance with patient 
education following lead placement. The patients are sent home with a diary to record daily 
bowel and bladder habits during the interval period. 
Visit 3 (Assessment of Symptoms and Battery Implantation or Lead Removal): Surgery for 
stage 2 sacral nerve stimulator battery implantation or lead removal will occur around 2 weeks 
(+7 days) after SNS placement. The patient will arrive to the holding area with their post-
implantation bowel and bladder habit diary from visit 2. Review of the bowel diary information 
and a review of symptoms from visit 1 and visit 2 with the patient will be completed and then a 
decision made to either implant the battery or remove the stimulator leads as per standard of 
care. If the bowel diary reveals ≥50% decrease in FI or LARS symptoms between visit 1 and 
visit 2, the external temporary battery will be replaced with an implantable battery.  If the bowel 
diary reveals <50% decrease in FI or LARS symptoms, the previously placed leads and external 
battery will be evaluated for proper positioning and functioning in the OR and removed if they 
remain properly positioned. Following the procedure, the patient is discharged home. If the 
device is removed, their participation in the study is complete, but data collected to this point 
will still be used in study analysis and reporting. 
Visit 4 (Post-operative Assessment): Post-operative evaluation. The patients return to clinic at 
1 month (+/- 2 weeks) after completion of visit 3 for a wound evaluation, device check, and 
symptom review. At this point, the patients will complete study questionnaires (on paper, over 
the phone/teleconference system, or electronically through REDCap) and undergo a repeat 
ARM.  
Visits 5 (1-Year Follow Up) and 6 (3-Year Follow Up): Patients will return to clinic at 1 and 3 
years (+/- 3 months) for evaluation, per routine standard of care, from their SNS battery for 
evaluation.  Patients will again complete validated questionnaires (on paper, over the 
phone/teleconference system, or electronically through REDCap) at this visit. After collection of 
this data, their participation in this study is complete. If for any reason patients are not able to 
return to the clinic at these time points, study questionnaires may be filled out via mail or over 
the phone/teleconference system, or electronically through REDCap. 
Table 1. Study Assessment Calendar 
 
Initial 
Evaluation/ 
Visit 1 
Visit 2 
(+ 4 weeks) 
Visit 3 
(+ 7 
days) 
Visit 4 
(+/- 2 
weeks) 
Assessment 
at 1 and 3 
years* 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 13 of 20 
Physical exam + 
anorectal manometry + 
Post-void residual 
Bladder scan 
X 
 
 
X 
 
SNS Lead Placement 
 
X 
 
 
 
Battery Implantation or 
Lead Removal 
 
 
X 
 
 
FIQoL and FISI 
Instrument 
X 
 
 
X 
X 
MSKCC Bowel 
Function Instrument 
X 
 
 
X 
X 
LARS Score 
Questionnaire 
X 
 
 
X 
X 
EORTC QLQ-CR29 
X 
 
 
X 
X 
Cleveland Clinic 
Incontinence Score 
Instrument 
X 
 
 
X 
X 
EQ-5D-5L Instrument 
X 
 
 
X 
X 
ICSmaleSF or ICIS-
FLUTS (as appropriate) 
Instrument 
X 
 
 
X 
X 
Bowel/Bladder Diary 
X 
X 
 
 
 
Adverse Events** 
 
 
X 
 
 
* +/- 3 months 
** See Section 7. Risk Management 
Clinical Data Collection 
Data regarding patients, tumors, treatments, and disease/vital status will be obtained from 
existing medical records.  Patient data collected will include, but is not limited to: demographic 
information, lab values, comorbidities and medical history, medications, test results (i.e., EKG).  
Tumor data collected will include, but is not limited to: site, stage, histology, distance from anal 
verge, histologic grade, clinical TNM stage, method of clinical stage, tumor size, biomarker 
status (e.g., microsatellite status, KRAS, BRAF mutation status, etc.) as available.  Treatment 
data for the primary cancer diagnosis will be collected including chemotherapy and radiation 
regimens as well as surgical procedures, complications and outcomes.  Clinical data will be 
collected until the patient is taken off study. 
 
6. 
 STATISTICAL CONSIDERATIONS 
6.1. 
Summary Statement 
Patients will be in one of 2 cohorts, those receiving 1) curative intent surgical resection of 
primary rectal cancer or 2) radiation therapy without surgical resection for treatment of 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 14 of 20 
pelvic cancer, other than of the rectum.  For the patients who have had surgical resection, 
preliminary safety and efficacy data exist so this will be an efficacy trial confirming the 
preliminary data.  For patients who were treated with XRT only, this is a preliminary trial to 
establish safety and provide a first estimate of efficacy. In this initial study, stratification 
based on type of radiation, method and/or dose will only be conducted in a hypothesis 
generating manner to explore future trial options if battery implantation rates are extremely 
low in cohort 2.  While the methods will be carried out the same, the level of evidence for 
conclusions at the end of the trial will be different for each. 
6.2. 
Analysis Subgroups 
All patients who sign consent and take the visit 1 questionnaires, and do not have insurance 
denial as the reason for no SNS placement, will be considered evaluable for this study.  
Patients who return for their SNS placement appointment will be included in analyses of the 
endpoints.   
6.3. 
Endpoints 
Primary Endpoints 
The primary endpoint is SNS Success. SNS Success will be measured as a patient having the 
battery implanted at visit 3 which can only happen if they’ve achieved improvement in fecal 
incontinence at visit 3.   Patients who do not have the SNS placed, for any reason other than 
insurance coverage issues, will count as not having a success. 
 
Fecal incontinence will be measured by the physician as the total number of gas, mucus, 
liquid stool, and solid stool accidental leakage events reported in the bowel diaries.  
Improvement will be determined by the physician based on bowel diary comparisons 
recorded before SNS lead placement at visit 1 to after lead placement at visit 2.  This is done 
at visit 3 when the patient presents for consideration of placement of the implantable battery. 
Any patient who comes in for SNS placement but the SNS cannot be successfully placed for 
any reason other than insurance reasons will count as not having improvement. Patients 
meeting this improvement will have their battery implanted.  Patients will be counted as 
having their battery implanted if it is implanted at Visit 3 if they had the SNS placed at Visit 
2.  
 Secondary Endpoints 
• FISI overall questionnaire summary 
• FIQOL overall questionnaire summary 
• ARM score 
• EQ-5D-5L 
• ICSmaleSF or ICIS-FLUTS (females) 
• MSKCC BFQ (for restorative surgery cohort) 
• LARS Score Bowel Function Questionnaire (for restorative surgery cohort) 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 15 of 20 
• CCIS (for radiation only cohort) 
• Bowel Diaries 
• Bladder Diaries 
• EORTC QLQ-CR29 
• FISI, FIQOL, EQ-5D-5L, ICSmaleSF or ICIS-FLUTS, MSKCC, EORTC QLQ-
CR29 and CCIS will also be collected at 1 and 3 years for long-term evaluation.  
 
6.4. 
Sample Size  
Up to 30 patients will be entered in each cohort, monitored after every 6 patients according to 
the interim analyses plans below.  The selection of 30 patients per cohort combines 
feasibility of accrual and operating characteristics of the decision rules.  If a cohort accrues to 
full size and has a 50% SNS success rate (15/30) then the 90% credible interval using a prior 
of beta(1,1) would be (35.7%, 64.3%).  Patients who complete baseline measures and sign 
consent but who are not able to undergo SNS implant for insurance issues will not be 
evaluable for this study.  Accrual numbers have been inflated by 10% to allow for 
unevaluable patients taken off study for a total study enrollment of up to 66 patients to have 
an evaluable 60 patients.   
6.5. 
Interim Analyses 
A Bayesian sequential monitoring design (Thall et al. 1995 and 1998)[27, 28] will be used to 
monitor the trial for response and adverse events.  Interim assessments will be performed in 
groups of 6 patients, with accrual held for evaluation for each cohort until enough 
information is available to determine the outcome.  Each patient cohort will be evaluated 
separately and will continue if patients are exhibiting reasonable adverse event rates and SNS 
response rates. If one cohort stops, the other cohort will continue according to the monitoring 
rules.  Calculations were performed in MultcLean Desktop version 2.1.0.   
Interim Analyses for Futility 
A patient will be considered to have SNS success as defined above. The patient cohort will 
be stopped early if Pr[θS < 0.50 | data] > 0.95 , where θS denotes the SNS success rate.  That 
is, given the outcomes from the patients who have already been evaluated, if it is determined 
that there is a more than 95% chance that the response rate is less than 50% (constant), the 
arm will be stopped for futility. Assuming a prior distribution of θS for each experimental 
treatment of ~beta(1,1), pre-defined stopping boundaries corresponding to this probability 
criterion are provided in the following table.   
 
If there are this many patients evaluable for SNS success 
6 
12 
18 
24 
30* 
Stop the cohort if there are this many or fewer SNS successes 
0 
3 
5 
7 
10 
* The cohort will stop at 30 regardless of the number of SNS successes, but if there are 10 or 
fewer, then the implant is not promising enough for future trials in this patient cohort. 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 16 of 20 
Assuming the cohort does not stop for adverse events first, 6 patients will be accrued. If none 
of the 6 patients have SNS success, stop the cohort and the implant will be declared as 
ineffective for this population.  Patients will continue to be enrolled on the other cohort as 
long as it is open. If there is at least 1 success, the next 6 patients will be entered in the 
cohort, unless they need to stop according to the adverse event boundaries below.  Continue 
checking after every 6 patients for sufficient SNS success assuming the trial does not stop for 
adverse events first.  The operating characteristics for efficacy and adverse events are 
summarized after the adverse event rules below.   
 
Interim Analyses for Safety 
Under the same model described for SNS success, adverse events will be monitored 
assuming an a priori probability of limiting adverse events following Beta(0.6, 1.4) in the 
current patient cohort.   Cohort limiting events (CLE) are defined as perioperative 
cardiovascular events, readmission if it is related to the SNS procedure, SNS lead removal 
due to any reason other than failure, or perioperative death due to surgery or complications.  
The patient cohort will be terminated if Prob(CLE> 0.30 | data) > 0.95. The specific rules for 
stopping after each cohort are included in the table here. 
 
If there are this many patients (or more) with CLE 
5 
7 
9 
12 
14 
Stop the patient cohort if there are this many (or fewer) patients who are 
evaluable (have CLE, had battery implant without CLE, or had leads 
removed for failure without CLE. 
6 
12 
18 
24 
30* 
* The cohort will stop at 30 patients, but if 14 or more patients have CLE, then the implant is too 
dangerous for this cohort. 
Six patients will be accrued before the first analysis. If 5 or more of the 6 patients have CLE, 
stop the cohort and the implant will be declared as too dangerous for this population. If there 
are 4 or fewer CLEs, enroll the next 6 patients assuming the cohort didn’t stop for futility.   
The operating characteristics are summarized in the following table: 
 
The operating characteristics for each patient cohort are shown in the following table.   
 
 
Stop if Prob{ θS < 0.50 |data} > 0.95  
or  
Stop if Prob{CLE> 0.30 | data} > 0.95 
 
True  
True  
Pr(stop early) 
Mean Number of 
Median 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 17 of 20 
Adverse 
Event Rate 
Response 
Rate 
Patients 
(25th %ile, 75th %ile) 
0.1 
0.30 
0.68 
18.5 
12 (12, 30) 
0.2 
0.30 
0.68 
18.5 
12 (12, 30) 
0.3 
0.30 
0.71 
18.0 
12 (12, 30) 
0.4 
0.30 
0.79 
16.5 
12 (12, 24) 
0.5 
0.30 
0.90 
14.0 
12 (12, 18) 
0.1 
0.40 
0.33 
24.6 
30 (18, 30) 
0.2 
0.40 
0.33 
24.5 
30 (18, 30) 
0.3 
0.40 
0.38 
23.7 
30 (12, 30) 
0.4 
0.40 
0.55 
21.0 
18 (12, 30)  
0.5 
0.40 
0.79 
16.8 
12 (12, 24) 
0.1 
0.50 
0.10 
28.3 
30 (30, 30) 
0.2 
0.50 
0.11 
28.1 
30 (30, 30) 
0.3 
0.50 
0.18 
27.1 
30 (30, 30) 
0.4 
0.50 
0.40 
23.7 
30 (18, 30) 
0.5 
0.50 
0.72 
18.4 
18 (12, 30) 
0.1 
0.60 
0.02 
29.6 
30 (30, 30) 
0.2 
0.60 
0.03 
29.5 
30 (30, 30) 
0.3 
0.60 
0.10 
28.4 
30 (30, 30) 
0.4 
0.60 
0.34 
24.7 
30 (18, 30) 
0.5 
0.60 
0.69 
19.0 
18 (12, 30) 
0.1 
0.70 
0.003 
30.0 
30 (30, 30) 
0.2 
0.70 
0.01 
29.8 
30 (30, 30) 
0.3 
0.70 
0.08 
28.7 
30 (30, 30) 
0.4 
0.70 
0.33 
25.0 
30 (18, 30) 
0.5 
0.70 
0.68 
19.1 
18 (12, 30) 
 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 18 of 20 
 
6.6. 
Analysis Plan 
The proportion of patients who experience SNS success will be reported with a 90% credible 
interval using a beta(1,1) prior for each cohort.  For the patients in the reconstruction cohort, a 
success rate of 50% or better will establish confirmation of efficacy of SNS implant that would 
warrant offering SNS implant to alleviate bowel symptoms following anal reconstruction. In the 
chemoradiation therapy only cohort, a success rate of 50% or better would warrant studying SNS 
implant further in this patient population.  The secondary measures will be reported descriptively 
with graphs or tabulations for categorical survey outcomes, CLEs, and anorectal manometry 
measures.  Exploratory logistic regression models will be performed to identify patients who 
may be more likely to have SNS success using baseline measures and visit 2 bowel/bladder 
diaries. Analysis of SNS success, safety, and measures up through visit 4 measures will be 
completed and published once all patients are enrolled and complete the first 4 visits or are off 
study.  Additional analyses will be completed and published after the long-term 1 and 3 year 
follow-up questionnaires are completed.   
7. 
 RISK MANAGEMENT 
Restore is a low risk trial. Any of the risks encountered by the participant are those associated 
with surgery for the treatment of fecal incontinence or LARS. In the event that readmissions or 
SNS lead removals are high, the study will be terminated as described in the previous section. 
We feel that any risk associated with participation in Restore is minimal and will be offset by 
improved patient reported outcomes. The knowledge obtained by the study personnel regarding 
the feasibility of sacral nerve stimulation for the treatment of fecal incontinence and LARS in 
association with colorectal cancer will be used to assess the potential of expanded cohorts as 
previously described. Adverse events (AE), >/= grade 3, using CTCAE v. 4 and serious adverse 
events (SAE) related to the procedure that occur within 30 days after will be reported.  
Reportable AE and SAE would include, but are not limited to, lead migration, wound infection, 
pneumonia, intractable pain related to surgical complications such as wound infection, 
unplanned or unanticipated readmission within 30 days, stroke, myocardial infarction, 
perioperative cardiovascular events, readmission if it is related to the SNS procedure, SNS lead 
removal due to any reason other than failure, or perioperative death due to surgery or 
complications. 
 
8. 
 DATA MANAGEMENT 
The study team is committed to protecting patient confidentiality at all times and in all 
circumstances. No patient identifying information will be used in the publication of findings and 
all information extracted from the medical record will be entered onto coded data sheets which 
will be maintained on databases stored in approved locations and only accessible by delegated 
UTMDACC employees. All printable hard copies of study documents such as bladder and bowel 
diaries or other study related instruments, will be stored in a secured location on the UTMDACC 
campus. If needed, hard copies of the coded study data may also be stored in a locked cabinet in 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 19 of 20 
the principal investigator’s office.  All electronic data will be entered and stored in an 
institutionally approved database (e.g., REDCap) on a secured UTMDACC server. 
 
9. 
 REFERENCES 
1. 
Visser, W.S., et al., Pelvic floor rehabilitation to improve functional outcome after a low anterior 
resection: a systematic review. Ann Coloproctol, 2014. 30(3): p. 109-14. 
2. 
Bregendahl, S., et al., Bowel dysfunction after low anterior resection with and without 
neoadjuvant therapy for rectal cancer: a population-based cross-sectional study. Colorectal Dis, 
2013. 15(9): p. 1130-9. 
3. 
Ishiyama, G., et al., Nerves supplying the internal anal sphincter: an immunohistochemical study 
using donated elderly cadavers. Surg Radiol Anat, 2014. 36(10): p. 1033-42. 
4. 
Williamson, M.E., et al., Decrease in the anorectal pressure gradient after low anterior resection 
of the rectum. A study using continuous ambulatory manometry. Dis Colon Rectum, 1994. 
37(12): p. 1228-31. 
5. 
Farouk, R., et al., Endosonographic evidence of injury to the internal anal sphincter after low 
anterior resection: long-term follow-up. Dis Colon Rectum, 1998. 41(7): p. 888-91. 
6. 
Karanjia, N.D., D.J. Schache, and R.J. Heald, Function of the distal rectum after low anterior 
resection for carcinoma. Br J Surg, 1992. 79(2): p. 114-6. 
7. 
Tomita, R., S. Igarashi, and S. Fujisaki, Studies on anal canal sensitivity in patients with or without 
soiling after low anterior resection for lower rectal cancer. Hepatogastroenterology, 2008. 
55(85): p. 1311-4. 
8. 
Kaur, G., A. Gardiner, and G.S. Duthie, Rectoanal reflex parameters in incontinence and 
constipation. Dis Colon Rectum, 2002. 45(7): p. 928-33. 
9. 
Lee, S.J. and Y.S. Park, Serial evaluation of anorectal function following low anterior resection of 
the rectum. Int J Colorectal Dis, 1998. 13(5-6): p. 241-6. 
10. 
Heppell, J., et al., Physiologic aspects of continence after colectomy, mucosal proctectomy, and 
endorectal ileo-anal anastomosis. Ann Surg, 1982. 195(4): p. 435-43. 
11. 
Nesbakken, A., K. Nygaard, and O.C. Lunde, Mesorectal excision for rectal cancer: functional 
outcome after low anterior resection and colorectal anastomosis without a reservoir. Colorectal 
Dis, 2002. 4(3): p. 172-176. 
12. 
Matzel, K.E., et al., Electrical stimulation of sacral spinal nerves for treatment of faecal 
incontinence. Lancet, 1995. 346(8983): p. 1124-7. 
13. 
Haas, S., et al., Does Sacral Nerve Stimulation Improve Continence Through Enhanced Sensitivity 
of the Anal Canal? A Pilot Study. Dis Colon Rectum, 2016. 59(11): p. 1039-1046. 
14. 
Malouf, A.J., M.A. Kamm, and R.J. Nicholls, Effect of acute changes in sacral nerve stimulation 
amplitude on anorectal function in faecal incontinence. Colorectal Dis, 2000. 2(6): p. 336-9. 
15. 
Ganio, E., et al., Sacral nerve stimulation for treatment of fecal incontinence: a novel approach 
for intractable fecal incontinence. Dis Colon Rectum, 2001. 44(5): p. 619-29; discussion 629-31. 
16. 
Byrne, C.M., et al., Biofeedback for fecal incontinence: short-term outcomes of 513 consecutive 
patients and predictors of successful treatment. Dis Colon Rectum, 2007. 50(4): p. 417-27. 
17. 
Bartlett, L., et al., Biofeedback therapy for symptoms of bowel dysfunction following surgery for 
colorectal cancer. Tech Coloproctol, 2011. 15(3): p. 319-26. 
18. 
Ho, Y.H., et al., Biofeedback therapy for excessive stool frequency and incontinence following 
anterior resection or total colectomy. Dis Colon Rectum, 1996. 39(11): p. 1289-92. 
19. 
Kim, K.H., et al., Effectiveness of biofeedback therapy in the treatment of anterior resection 
syndrome after rectal cancer surgery. Dis Colon Rectum, 2011. 54(9): p. 1107-13. 
Proprietary of MD Anderson Cancer Center

2016-0754 
Revised October 20, 2021 
Page 20 of 20 
20. 
Uludag, O., et al., Sacral neuromodulation in patients with fecal incontinence: a single-center 
study. Dis Colon Rectum, 2004. 47(8): p. 1350-7. 
21. 
Wexner, S.D., et al., Sacral nerve stimulation for fecal incontinence: results of a 120-patient 
prospective multicenter study. Ann Surg, 2010. 251(3): p. 441-9. 
22. 
Barraclough, L.H., et al., Prospective analysis of patient-reported late toxicity following pelvic 
radiotherapy for gynaecological cancer. Radiother Oncol, 2012. 103(3): p. 327-32. 
23. 
Maeda, Y., et al., Faecal incontinence following radiotherapy for prostate cancer: a systematic 
review. Radiother Oncol, 2011. 98(2): p. 145-53. 
24. 
Knowles, G., et al., Late effects and quality of life after chemo-radiation for the treatment of anal 
cancer. Eur J Oncol Nurs, 2015. 19(5): p. 479-85. 
25. 
Ramage, L., et al., A systematic review of sacral nerve stimulation for low anterior resection 
syndrome. Colorectal Dis, 2015. 17(9): p. 762-71. 
26. 
Duelund-Jakobsen, J., et al., Sacral nerve stimulation for faecal incontinence - efficacy confirmed 
from a two-centre prospectively maintained database. Int J Colorectal Dis, 2016. 31(2): p. 421-8. 
27. 
Thall, P.F., R.M. Simon, and E.H. Estey, Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med, 1995. 14(4): p. 357-79. 
28. 
Thall, P.F. and H.G. Sung, Some extensions and applications of a Bayesian strategy for 
monitoring multiple outcomes in clinical trials. Statistics in Medicine, 1998. 17(14): p. 1563-1580. 
 
10. 
APPENDICES 
A. Combined Fecal Incontience Quality of Life Questionnaire (FIQoL) and Fecal 
Incontinence Severity Index (FISI) 
B. Memorial Sloan-Kettering Cancer Center  (MSKCC) Bowel Function Instrument 
C. Low Anterior Resection Syndrome (LARS) Score Bowel Function Questionnaire 
D. EuroQol Group EQ-5D-5L™ (EQ-5D-5L) 
E.  Cleveland Clinic Incontinence Score (CCIS) Instrument 
F. International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract 
Symptoms (ICIQ-FLUTS) 
G. International Continence Society Male Short Form (ICSmaleSF) 
H. Bladder Symptom Tracker (Medtronic) as part of the urinary diary 
I. Bowel Symptom Tracker (Medtronic) as part of the bowel diary 
J. EORTC QLQ – CR29© 
K. REDCap Survey Message and MyChart Survey Reminder 
 
 
Proprietary of MD Anderson Cancer Center