Prospective Randomized Controlled Trial Comparing Transvaginal Rectopexy and Ventral Mesh Rectopexy for Obstructed Defecation in Pelvic Organ Prolapse (PROD Trial)
Phase: NA
Conditions: Obstructed Defecation, Pelvic Organ Prolapse
Sponsor: Endeavor Health

PROD Trial – v4 Mar 14 2024 
 
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Prospective Randomized Controlled Trial Comparing 
Transvaginal Rectopexy and Ventral Mesh Rectopexy for 
Obstructed Defecation in Pelvic Organ Prolapse (PROD Trial) 
National Clinical Trial (NCT) Identified Number: NCT05747027 
Principal Investigators: Ghazaleh Rostami Nia MD MSc – NorthShore University HealthSystem 
Tirsit Shiferaw Asfaw MD – Weill Cornell Medical Center – New York Presbyterian 
Funded by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)  
Protocol Version: 6 
 
 
Date: 02/03/2025 
 
 
 

PROD Trial – v4 Mar 14 2024 
 
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Table of Contents 
Statement of Compliance ................................................................................................................................................... 4 
1. Protocol Summary ........................................................................................................................................................... 5 
1.1 Synopsis ..................................................................................................................................................................... 5 
1.2 Schema ...................................................................................................................................................................... 7 
1.3 Schedule of Activities (SOA) ...................................................................................................................................... 8 
2. Introduction .................................................................................................................................................................... 9 
2.1 Study Rationale ......................................................................................................................................................... 9 
2.2 Background ............................................................................................................................................................... 9 
2.3 Risk/Benefit Assessment ......................................................................................................................................... 11 
3. Outcomes and Measurements ...................................................................................................................................... 12 
4. Study Design .................................................................................................................................................................. 13 
4.1 Overall Design ......................................................................................................................................................... 13 
4.2 Scientific Rationale for Study Design ...................................................................................................................... 13 
4.3 Justification for Dose ............................................................................................................................................... 16 
4.4 End of Study Definition ........................................................................................................................................... 16 
5. Study Population ........................................................................................................................................................... 16 
5.1 Inclusion Criteria ..................................................................................................................................................... 16 
5.2 Exclusion Criteria ..................................................................................................................................................... 17 
5.3 Lifestyle Considerations .......................................................................................................................................... 17 
5.4 Screen Failure .......................................................................................................................................................... 17 
5.5 Strategies for Recruitment and Retention .............................................................................................................. 17 
6. Study Intervention ........................................................................................................................................................ 18 
6.1 Study Intervention(s) Administration ..................................................................................................................... 18 
6.2 Preparation/ Handling/ Storage/ Accountability .................................................................................................... 19 
6.3 Measures to Minimize Bias: Randomization and Blinding ...................................................................................... 19 
6.4 Study Intervention Compliance .............................................................................................................................. 20 
6.5 Concomitant Therapy .............................................................................................................................................. 20 
7. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ..................................................... 20 
7.1 Discontinuation of Study Intervention .................................................................................................................... 20 
7.2 Participant Discontinuation/ Withdrawal from the Study ...................................................................................... 20 
7.3 Lost to Follow-Up .................................................................................................................................................... 21 
8. Study Assessments and Procedures .............................................................................................................................. 21 
8.1 Study Assessments .................................................................................................................................................. 21 
8.2 Safety and Other Assessments ................................................................................................................................ 22 
8.3 Adverse Events and Serious Adverse Events .......................................................................................................... 22 

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8.4 Unanticipated Problems ......................................................................................................................................... 25 
9. Statistical Considerations .............................................................................................................................................. 26 
9.1 Statistical Hypothesis .............................................................................................................................................. 26 
9.2 Sample Size Determination ..................................................................................................................................... 26 
9.3 Populations for Analyses ......................................................................................................................................... 27 
9.4 Statistical Analyses .................................................................................................................................................. 27 
10. Supporting Documentation and Operational Considerations .................................................................................... 29 
10.1 Regulatory, Ethical, and Study Oversight Considerations ..................................................................................... 29 
10.2 Additional Considerations ..................................................................................................................................... 33 
10.3 Abbreviations ........................................................................................................................................................ 33 
11. References .................................................................................................................................................................. 34 
12. Appendices .................................................................................................................................................................. 39 
APPENDIX A – SOP: MR Defecography ......................................................................................................................... 40 
APPENDIX B – SOP: Dynamic Pelvic Ultrasound ........................................................................................................... 42 
APPENDIX C – SOP: Surgical Procedures ....................................................................................................................... 44 
APPENDIX D – SOP: Study Assessments and Procedures ............................................................................................. 46 
APPENDIX E – Schedule of Forms.................................................................................................................................. 49 
 
 
 

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Statement of Compliance  
 
The trial will be carried out in accordance with International Conference on Harmonization Good Clinical Practice (ICH 
GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 
50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the conduct, 
management, or oversight of NIH-funded clinical trials have completed Human Participants Protection and ICH GCP 
Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the 
Institutional Review Board (IRB) for review and approval.  Approval of both the protocol and the consent form must be 
obtained before any participant is enrolled.  Any amendment to the protocol will require review and approval by the IRB 
before the changes are implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 
 

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1. Protocol Summary  
1.1 Synopsis  
 
Title: 
 
Prospective Randomized Controlled Trial Comparing Transvaginal 
Rectopexy and Ventral Mesh Rectopexy for Obstructed Defecation in 
Pelvic Organ Prolapse (PROD Trial)  
Study Description: 
This is a collaborative 2-armed multi-center prospective clinical trial 
comparing: a) transvaginal sacrospinous rectopexy (TSR) with and without 
conventional vaginal prolapse surgery (CVPS); vs. b) laparoscopic 
abdominal ventral rectopexy (LAVR) with and without conventional vaginal 
prolapse surgery (CVPS). Women with vaginal prolapse who report 
obstructed defecation (OD) symptoms in more than 50% of their bowel 
movements with significant rectal hypermobility (more than 50% 
compression ratio in dynamic pelvic ultrasound) will be approached for 
enrollment. Eligible and consented participants will be randomized to 
undergo one of the two procedures: 1) laparoscopic abdominal ventral 
rectopexy with and without CVPS; 2) transvaginal sacrospinous rectopexy 
with and without CVPS. After the procedure, participants will be followed 
for 2-week, 2-month, 12-month, and 24-month post-operative visits. 
Symptom evaluation, pelvic exam, and dynamic pelvic ultrasound 
completed pre- and post-operatively will be used to compare the 
outcomes of the two procedures.  
Outcomes: 
 
Primary Outcome: Compare surgical success or failure in female 
participants with moderate to severe OD symptoms, and rectal 
hypermobility diagnosed by ultrasound, who are randomized to minimally 
invasive transvaginal sacrospinous rectopexy versus laparoscopic 
abdominal ventral rectopexy at 24 months after surgery. The primary 
outcomes will be measured by: 
1. The degree of rectal hypermobility measured via dynamic pelvic 
ultrasound (i.e. compression ratio). 
Secondary Outcomes:  
a. Compare efficacy and safety of the surgery. 
b. Compare the use of dynamic pelvic ultrasound imaging versus 
MR defecography to measure occult rectal hypermobility.  
c. Develop and validate a computational finite element model 
and statistical shape modeling approach to describe the 
mechanics of normal defecation and the role of rectal and 
vaginal support deficiencies in causing OD symptoms.  
Study Population: 
120 participants who are female, between the age of 18 and 80, and who 
may and may not have vaginal prolapse, who report OD symptoms in more 
than 50% of their bowel movements and with significant rectal 
hypermobility 
Phase: 
N/A 
Description of 
Sites/Facilities Enrolling 
Participants: 
Recruitment and informed consent will occur in two participating medical 
centers: 1) NorthShore University HealthSystem, and 2) Weill Cornell 
Medical Center- New York Presbyterian.  
Description of Study 
Intervention: 
Laparoscopic abdominal ventral rectopexy: This is an established surgical 
technique involving mesh implantation, commonly used to restore rectal 
support in women with obstructed defecation syndrome (ODS). 
Transvaginal sacrospinous rectopexy: This is a novel minimally invasive 
surgery which directly suspends and stabilizes the rectal wall to pelvic 
ligaments with no external incision and no mesh implantation. This novel 

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mesh-free operation may be a simpler, less invasive, and more 
anatomically accurate surgical approach for ODS.  
Study Duration: 
60 months  
Participant Duration: 
24 months  
 
 

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1.2 Schema  
 
 
 
 
 
 
Screening  
Visit (1) 
 
 
 
 
Initial Research  
Visit (2) 
 
 
MRI Visit (3) 
 
 
 
Anes. Clearance  
 
 
Randomization  
  
 
Pre-op Visit  
(4,5) 
 
 
Surgery 
 
 
2 week  
Post-op visit  
 
 
2 month  
Post-op visit  
 
 
12 month  
Post-op visit 
 
 
24 month 
Post-op visit  
 
 
Complete physical exam and questionnaire  
(refer to Section 1.3, Schedule of Activities for detail) 
Complete physical exam, questionnaire, and dynamic pelvic ultrasound 
(refer to Section 1.3, Schedule of Activities for detail) 
Complete physical exam, questionnaire, and dynamic pelvic ultrasound 
(refer to Section 1.3, Schedule of Activities for detail) 
Transvaginal sacrospinous 
rectopexy with and without CVPS 
Complete physical exam, questionnaire, and dynamic pelvic ultrasound 
(refer to Section 1.3, Schedule of Activities for detail) 
Randomize 
Obstructed defecation symptoms in more than 50% of bowel movements and detection 
of more than 50% rectal hypermobility in dynamic ultrasound with and without vaginal 
prolapse >= stage 2  
MR defecography  
Laparoscopic abdominal ventral 
rectopexy with and without CVPS 
Screen potential participants by inclusion and exclusion criteria; complete basic 
evaluation including disease assessment, questionnaires, physical exams, dynamic pelvic 
ultrasound per standard of care (refer to Section 1.3, Schedule of Activities for detail) 
Obtain consent; collect medical history, surgical history, and demographic information 
(refer to Section 1.3, Schedule of Activities for detail) 
Pre-operative visit with the surgeon (urogyn and/ or colorectal per randomization) 
Surgical clearance by anesthesiologist  

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1.3 Schedule of Activities (SOA)  
 
Procedures 
Screening Appt. 
Initial Appt. 
+/- 30 days 
MRI Appt. 
+/- 30  days 
Anesthesia 
Clearance 
Randomization 
Pre-op 
Day of Surgery 
2 wk Post-op 
+/- 5 days 
2 m Post-op 
+/- 10 days 
12 m Post-op 
+/- 10 days 
24 m Post-op 
+/- 30 days 
Demographics 
 
  
X 
 
 
 
 
 
 
 
 
 
Medical 
history 
 
X 
 
 
 
 
 
 
 
 
 
Surgical history 
  
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
Pre-op with 
surgeon 
 
 
 
 
 
X 
 
 
 
 
 
Inclusion/exclu
sion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Research 
consent  
 
X 
 
 
 
 
 
 
 
 
 
Surgical 
consent 
 
 
 
 
 
 
X 
 
 
 
 
Surgical 
procedure  
 
 
 
 
 
 
X 
 
 
 
 
Surgeon’s 
Report 
 
 
 
 
 
 
X 
 
 
 
 
Physical exam  
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Dynamic pelvic 
ultrasound 
X 
 
 
 
 
 
 
 
X 
X 
X 
MR 
defecography  
 
 
X 
 
 
 
 
 
 
 
 
Anesthesia 
Clearance  
 
 
 
X 
 
 
 
 
 
 
 
Bowel habit 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
POPQ 
assessment  
X 
 
 
 
 
 
 
 
X 
X 
X 
PFDI 
assessment 
X 
 
 
 
 
 
 
 
X 
X 
X 
Pain scale  
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Pain 
medication use 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Activity scale 
  
X 
 
 
 
 
 
 
X 
X 
X 
X 
Impression of 
improvement  
 
 
 
 
 
 
 
 
X 
X 
X 
PFIQ 
 
 
 
 
 
 
 
 
 
X 
X 
X 
SF-36 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
EQ-5D 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Brink scale 
  
 
 
 
 
 
 
 
 
X 
X 
X 
Research 
Participation  
 
 
 
 
 
 
 
 
 
 
X 
Adverse event/ 
unanticipated 
problems  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

PROD Trial – v4 Mar 14 2024 
 
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2. Introduction  
2.1 Study Rationale  
 
Obstructed defecation (OD), defined as incomplete emptying of stool, is a widely prevalent disorder in women’s health, 
occurring in roughly 25% of constipated women and resulting in major quality of life (QOL) and healthcare burdens (1-4). 
Symptoms include incomplete defecation, rectal pressure from retained or “pocketed” stool, and need for manual 
assistance to complete bowel movements. OD is often chronic, impacting some women for their entire adult lives. 
Successful management has been impaired, historically, by deficiencies relating to both diagnosis and treatment (5-7). 
First, there has been a persistent misconception that OD in the absence of dyssynergia (i.e., uncoordinated contraction of 
pelvic floor) results from prolapse of the posterior vaginal wall (‘rectocele’) and improves after its repair (5, 7). In fact, 
prior studies have confirmed that this form of OD results from support defects involving the rectum rather than vagina (8-
10), and moreover that rectocele repairs are unreliable in relieving OD symptoms (6, 7). Recent work from our center 
confirmed rectal detachment and hypermobility to be the major determinants of OD in the absence of dyssynergia 
irrespective of the presence of a rectocele (8). Secondly, traditional diagnostic modalities to assess rectal support as the 
source of OD are expensive (e.g. MR defecography) and/or invasive (e.g. anal manometry), and often generate findings 
with unclear clinical correlation and impact on care (11). Finally, available surgeries to repair rectal support defects have 
been limited to invasive transabdominal or perineal methods (15,16,17), typically involving mesh implantation and 
reserved for severe cases, e.g. those with overt rectal prolapse. Laparoscopic or open ventral mesh rectopexy is the most 
widely accepted operation to stabilize rectal support (12, 13). 
 
Our urogynecology division’s dedicated Women’s Bowel Clinic has focused substantial research effort on OD in women, and 
recent publications lay the foundation for the present study. On the diagnostic front, we established and validated a novel, 
anatomically-based and statistically robust criteria for diagnosing OD using dynamic pelvic ultrasound. We affirmed that 
OD symptoms in the absence of dyssynergia were associated with rectal support defects (4, 9, 10) and, contrary to 
conventional wisdom, had no relationship to vaginal prolapse / rectocele defects. During sonographic evaluation the 
presence or absence of rectal hypermobility, quantified using a new “compression ratio” metric developed and validated 
as part of this work, was highly predictive of the presence or absence of OD and appeared to obviate the need for MR 
defecography (5, 8, 14). On the surgical front, we developed a minimally invasive transvaginal surgery to directly suspend 
and stabilize the rectal wall to pelvic ligaments with no external incision, no mesh implantation, and thus far no significant 
morbidity (15). Our published case series demonstrated successful attachment of the rectal support defect, alleviation of 
OD symptoms and improved QOL in nearly all participants. This novel mesh-free operation appeared to be markedly 
simpler, less invasive, and more anatomically correct in contrast to standard laparoscopic abdominal ventral rectopexy. 
 
Based on this exciting preliminary data, the overall goal of this proposal is to explore the potential for an improved 
treatment outcome for women suffering OD symptoms, utilizing newly developed diagnostic procedures based on 
dynamic pelvic ultrasound, a new surgical approach (transvaginal sacrospinous rectopexy), and an improved 
understanding of the physics of defecation. We believe a prospective, randomized comparison of the novel 
(transvaginal sacrospinous rectopexy) to traditional (laparoscopic abdominal ventral rectopexy) surgical methods across 
two institutions is an essential next step. We are testing the hypothesis that OD symptoms in the absence of 
dyssynergia primarily result from deficiencies in rectal support and that patients presenting with OD symptoms with and 
without vaginal prolapse undergoing our new diagnostic evaluation and surgical treatment will have improved outcomes 
relative to the current standard of care at 24 months after surgery. Our study is designed to evaluate primary and 
secondary outcomes relating to the two rectopexy procedures on OD at 24 months follow up across two institutions. This 
clinical data will be complemented by a computational modeling approach that aims to provide insight into the most likely 
contributors to OD symptoms, i.e. vaginal versus rectal support defects. 
 
2.2 Background 
 
1. Constipation and obstructed defecation (OD) symptoms impact a large female population. 
Accounting for more than 2 million clinic visits per year, constipation is one of the most common problems seen by 
primary care physicians, colorectal and urogynecology surgeons. (10, 16). In broad terms, constipation can be 

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classified as either normal-transit constipation (often coexisting with irritable bowel syndrome), OD, or slow-transit 
constipation. Each of these conditions may occur in isolation or may coexist, and it is often difficult to predict which 
patients have isolated or concomitant pathologies. Isolated defecatory dysfunction is thought to be present in 25% 
of patients with chronic constipation (1, 3, 17). OD is a common condition that affects approximately 7% of all 
adults, but 15-20% of adult women (4, 18-20). Although the etiology of OD symptoms continues to be debated, it is 
hypothesized that the higher prevalence observed in women could be due to damage incurred by pelvic floor soft 
tissues and nerves during vaginal delivery (21, 22). 
 
2. The anatomic and pathophysiologic changes associated with OD are varying and incompletely understood, and 
traditional surgical methods have often been based on incorrect assumptions. 
OD may occur alongside other anatomical abnormalities such as pelvic organ prolapse (POP), internal rectal prolapse 
and/or solitary rectal ulcer, and/or functional factors relating to neuromuscular control. In trying to identify OD 
cases that are due to anatomic causes and therefore may be addressed with surgical repair (11), gynecologic 
surgeons have often assumed a causative relationship between OD symptoms and POP with a particular focus on 
rectoceles (posterior vaginal POP). However, available evidence indicates that this assumption is incorrect, as the 
severity of POP in participants with OD is not significantly different from that found in asymptomatic controls (23); in 
fact, at most, only weak associations have been identified between OD symptomatology and stage of rectocele. 
Similarly, the surgical repair of POP, and specifically the repair of rectoceles, has been associated with only limited 
improvements in OD symptoms regardless of the surgical approach (1, 2, 24-26). These findings suggest that key 
aspects underlying OD in the female population have been overlooked, misunderstood, or have yet to be quantified 
sufficiently, and that the conventional wisdom among gynecologic surgeons focusing on POP as a primary cause of 
OD appears to be unfounded. 
There is substantial evidence to suggest that OD symptoms may, in fact, be predominantly caused by a disorder in 
anorectal structure and/or function; that is, a problem resulting from deficient rectal rather than uterovaginal 
support (23). Unfortunately, several factors have limited our ability to reliably recognize and treat rectal support 
defects in women with OD. On the diagnostic level, defecography has remained a limited modality due to expense, 
patient inconvenience, and poor correlation between abnormal defecography findings and severity of OD 
symptoms. On the treatment front, existing rectal support surgeries have been relatively invasive and thus reserved 
for severe cases, and to-date there has been no minimally invasive surgical repair. These are critical knowledge and 
technology gaps relating to our understanding of key structural defects, resulting in inadequate solutions (diagnostic 
and surgical) for women suffering from this condition. 
 
3. No single test has been proven definitive or optimal for the evaluation of OD. 
A thorough medical history should be obtained in all patients with OD, as the condition may be multifactorial and 
numerous factors relating to diet, medications and neuromuscular function may be directly or indirectly linked to 
symptoms (2). Physical exams are essential as an initial workup and should include inspection of the anorectal 
region and rectum to detect external signs of anal disease, POP and/or descending perineum syndrome. Imaging 
modalities have proven to be useful in identifying structural defects associated with OD symptoms (27). OD 
symptoms are of the most common symptoms leading to dynamic evaluation of the pelvic floor via imaging (28). 
Magnetic resonance (MR) imaging defecography was introduced in 1993 (29) and is increasingly used to evaluate 
pelvic floor dysfunction, particularly in complex cases involving defecatory symptoms. Dynamic MR defecography 
enables real-time evaluation of pelvic floor dysfunction including descending perineum syndrome, rectal prolapse, 
rectal intussusception, an enterocele or rectocele (30-35). The American College of Radiology has stated that both 
the fluoroscopic defecography and MR defecography with rectal contrast are appropriate and equivalent with 
respect to the evaluation of pelvic floor disorders involving all compartments of pelvic support; however, MR 
defecography is preferred for the assessment of defecatory dysfunction (36). 
Nevertheless, no single test has been established as definitive for the evaluation of pelvic floor and/or defecatory 
dysfunction, and the expense and inconvenience associated with MR defecography make it difficult to utilize on a 
wide scale. Most tests, including clinical examination, rely on patient collaboration and often induce embarrassment 
with some degree of psychological inhibition. The unnatural clinical environment during testing may provoke 
‘laboratory’ artifact. Thus, interobserver reproducibility for many anorectal tests tends to be poor and abnormal test 

PROD Trial – v4 Mar 14 2024 
 
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results correlate poorly with symptoms (11). Lack of a reproducible, patient-friendly, highly accessible and cost-
effective diagnostic test for rectal support defects is a significant unmet need. 
 
4. The role of rectal support in normal defecation is unknown. 
The processes of normal rectal continence and evacuation are regulated through the coordinated interaction of 
multiple neuromuscular pathways and guided by mechanical support provided to the rectum (37-39). While these 
processes are complex, the functional endpoint that must be achieved is simple -- the body must generate 
intrarectal pressures that exceed atmospheric pressures externally, and the direction of that pressure gradient 
should pass through a relaxed anal sphincter. Failure to accomplish this results in symptoms of OD. Within the 
pelvis, the visceral organs are normally restrained from undergoing large motions, allowing for the passage of feces. 
However, when key structural defects exist, the motions of pelvic organs may no longer be optimally restrained, 
resulting in outlet obstruction or redirection of feces away from the anal canal. It has been previously suggested that 
for complete rectal prolapse to occur some, if not all, of the major supporting mechanisms of the rectum must be at 
least partially compromised (40, 41). While the rectum measures 12 to 15 cm in length, it is the lower half to one 
third that bears supportive attachments to other structures. Apically, the rectum is limited by the anterior peritoneal 
reflection that occurs at 7-9 cm from the anal verge in men and at 5-7.5 cm from the anal verge in women (42-44). 
Lateral support is provided by the lateral ligaments or stalks of the rectum; while anterior and posterior support are 
provided by the visceral pelvic fascia of Denonvilliers and the rectosacral fascia (a.k.a the fascia of Waldeyer), 
respectively (42, 43, 45). The superior/posterior aspect, which closely follows the sacral hollow, is entirely extra-
peritoneal. The specific role of these supports in allowing for normal defecation are currently unknown and this 
limits our understanding of why OD occurs and how best to repair it. 
 
2.3 Risk/Benefit Assessment 
2.3.1 Known Potential Risks  
Pelvic Exam 
There is no immediate or long-range risk from a speculum exam and a quantified assessment of prolapse. The exam may 
create mild transient discomfort. 
 
Written Questionnaires & Verbal Interviews 
Answering these questions may make some participants temporarily uncomfortable. While not specifically addressed in 
the instructions, participants may elect not to answer some personal questions. All acquired information will be kept 
confidential by identifying the forms with study numbers only, keeping the results and the list linking names to study 
numbers in a password-protected database. Access to file cabinets containing paper copies will only be granted to the PI 
and study coordinators. 
 
Dynamic Pelvic Ultrasound 
Ultrasounds are minimally invasive, part of routine urogynecology care, and conducted by trained medical personnel. The 
exam may cause transient, mild discomfort, but pose little to no immediate or long-range risk. 
 
MR Defecography  
The defecography may cause discomfort due to imaging in a closed environment, participants can stop the imaging 
anytime during the test if they feel uncomfortable. Patients at risk for injury from MR scans are those with pacemakers, 
aneurysm clips, or shrapnel fragments. There is a minimal risk of skin burns from the radiofrequency (RF) coil. The 
defecography poses little to no long-range risk. 
 
Surgical Procedures 
For the surgical procedure, standard risks of surgery apply including bleeding, infection, and injury to nearby organs 
including the bowel, bladder, and ureters. There is a potential risk of pain following the surgical procedure. There is 
potential mesh related risks including mesh erosion, pain, infection, and fistulas. 
 

PROD Trial – v4 Mar 14 2024 
 
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2.3.2 Known Potential Benefits  
Participants may receive direct personal benefits from participating in this research study. An immediate potential benefit 
of the study is a thorough assessment of obstructed defecation symptoms. All participants will complete a basic evaluation 
in which they will complete a disease assessment, questionnaires related to symptoms, physical exams, and dynamic pelvic 
ultrasound. Participants will have the opportunity to review this information with the participant’s provider. Participants 
who are randomized to undergo rectopexy may benefit in the long-term with obstructive defecation symptom 
improvement. 
 
2.3.3. Assessment of Potential Risks and Benefits 
We believe that the risks and benefits to the participants are balanced in this study design. Exam, questionnaires, and 
imaging used in the study are minimally invasive and part of routine urogynecology care. While standard risks of surgery 
apply to the surgical procedures, previous studies have demonstrated the safety of the two procedures. If participants in 
either treatment group develop new symptoms after surgery, treatment is available. Currently, patients with ODS receive 
treatment without follow-up that would allow sufficient assessment of the safety and efficacy of the surgical outcome, 
which could otherwise guide more effective clinical decisions. 
 
3. Outcomes and Measurements  
 
Primary Outcome: Compare surgical success or failure in female participants with moderate to severe OD symptoms, 
and rectal hypermobility diagnosed by ultrasound, who are randomized to minimally invasive transvaginal sacrospinous 
rectopexy versus laparoscopic abdominal ventral rectopexy at 24 months after surgery. The primary outcomes will be 
measured by: 
1. The degree of rectal hypermobility measured via ultrasound (i.e. compression ratio). 
a. “Compression ratio” will be calculated as a means to quantify the relative change in length of the 
rectovaginal septum (RVS), in other words the degree of hypermobility / sliding rectum, and is expressed 
as a percentage using the following formula:  𝐶𝑅 = (RVSr – RVSv)/ RVSRr * 100, where RVSr 
(Rectovaginal Septum) and RVSv represent the RVS length at rest and Valsalva. 
 
The criteria for surgical failure will be defined as follows: 
1. A participant will be considered a surgical failure if: 
a. Rectal hypermobility with compression ratio more than 20% is detected via ultrasound. 
2. Otherwise, a participant will be considered a surgical “success”.  
 
Secondary Outcome:  
- 
Compare efficacy and safety of the surgery measured by: 
1. Postoperative pain - Participants will complete the Pain Scale (67) and an assessment of pain medication 
use preoperatively, and then at 2 weeks and 2, 12, and 24 months postoperatively. 
2. Postoperative functional activity level – Participants will complete the Activity Assessment Scale (68) 
which measures functional activity preoperatively and then at 2 weeks and 2, 12, and 24 months 
postoperatively. 
3. Global improvement in bladder function – Participants will complete the Patient Global Impression of 
Improvement (69) at 2, 12 and 24 months postoperatively. 
4. Pelvic Floor Distress Inventory (PFDI) – Prolapse and colorectal symptoms as assessed by the Pelvic Organ 
Prolapse Distress Inventory (POPDI) and Colorectal Anal Distress Inventory (CRADI) (short-term) and 
urinary and colorectal symptoms as assessed by the Urinary Distress Inventory (UDI) and CRADI (long-
term) subscales at 2, 12, and 24 months postoperatively.  
5. Quality of life measured by Pelvic Floor Impact Questionnaire (PFIQ) (65), Short Form Health Survey (SF-
36) (70), EuroQol-5D (EQ-5D) (71) at 2, 12 and 24 months postoperatively. The SF-36 will also be 
administered to a subset of participants 2 weeks post-operatively to allow validation of the Pain and 
Activity Assessment Scale. 

PROD Trial – v4 Mar 14 2024 
 
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6. Pelvic muscle strength measured by the Brink Scale at 2, 12, and 24 months postoperatively (72). 
- 
Compare the use of posterior compartment dynamic pelvic ultrasound imaging versus MR defecography to 
measure occult rectal hypermobility.  
- 
Develop and validate a computational finite element model and statistical shape modeling approach to describe 
the mechanics of normal defecation and the role of rectal and vaginal support deficiencies in causing OD 
symptoms.  
 
4. Study Design  
4.1 Overall Design  
 
This is a collaborative multi-center 2-arm clinical trial comparing: a) transvaginal sacrospinous rectopexy (TSR) with and 
without conventional vaginal prolapse surgery (CVPS); vs. b) laparoscopic abdominal ventral rectopexy (LAVR ) with and 
without conventional vaginal prolapse surgery (CVPS) for ODS. A standardized common protocol for enrollment, treatment 
and data collection will be employed by the Clinical Sites and coordinated by the Data Coordinating Center (DCC). Women 
with and without vaginal prolapse who report OD symptoms in more than 50% of their bowel movements with significant 
rectal hypermobility (more than 50% compression ratio in dynamic posterior compartment ultrasound) will be approached 
for eligibility, consent, and enrollment. Participants who meet eligibility criteria and have provided informed consent will 
be randomly assigned to either abdominal or transvaginal rectopexy procedure (12, 62-64). Prior to randomization, eligible 
participants will undergo chart review by the anesthesiologist to ensure medical eligibility for both procedures.   
 
Participants will receive the allocated transvaginal sacrospinous rectopexy surgery along with or without CVPS or 
laparoscopic abdominal ventral rectopexy surgery with or without CVPS as indicated for each individual and as determined 
before surgery (exceptions are allowed during the surgery if the surgeon decides that changing the surgical plan is in the 
best interest of the patient; this will be recorded as a protocol deviation). CVPS includes vaginal prolapse repair surgeries 
(anterior vaginal repair, posterior repair, and vault suspension) and abdominal prolapse repair surgery (sacrocolpopexy). 
If the participants report stress urinary incontinence at baseline, they will also receive a Tension-Free Vaginal Tape 
(Advantage FitTM, Boston Scientific). The primary objective of the surgical intervention is to compare the surgical success 
of rectal hypermobility surgery using TSR to surgery using LAVR 24 months postoperatively. The secondary objectives 
include comparing the change in pelvic floor disorder symptoms including OD and fecal incontinence symptoms, QOL and 
the incidence of perioperative and postoperative complications of these two rectal suspension procedures. We will also 
describe the motivations and barriers for individual women’s participation in women’s health research at 24 months after 
surgery in all participants. Data collection will occur at baseline, surgery and during hospitalization, and at 2 weeks, and 2-
,12-, and 24-months postoperatively. 
 
4.2 Scientific Rationale for Study Design  
 
Ultrasound indicators of rectal support defects in 
women with obstructive defecatory symptoms (48) 
This retrospective cohort study included 65 women 
who were referred to our urogynecology clinic because 
of varied pelvic floor disorders between January 2013 
and January 2014. Patients completed a standardized 
interview including PFDI-20 questionnaire and 
received a standard examination, and assessment of 
their pelvic floor by 3D EVUS. Women were 
categorized to case (with OD symptoms) and control 
(without OD symptoms) based on their answers to 
Questions 7, 8 and 14 on the PFDI-20 (CRADI) 
questionnaire. In ultrasound images, women with OD 
symptoms had a significantly shorter span of 
attachment between the rectum and posterior vaginal 
Figure 1: 2D dynamic endovaginal posterior compartment ultrasound of a 
patient with obstructed defecation symptoms at rest (left image) and at strain 
(right image). Rendering of an aluminum can is used to illustrate the concept of 
the rectal compression seen above. LP: Levator Plate, RVS: Rectovaginal Septum 

PROD Trial – v4 Mar 14 2024 
 
Page 14 of 50 
wall (i.e. deeper cul de sac), and also had significantly increased descent of the cul de sac toward the anorectal junction 
when intraabdominal pressure was increased (Figure 1). A hypermobile ‘sliding rectum’ was observed that appeared to 
alter the fundamental biomechanics of defecation. These rectal mobility findings were extremely consistent among 
women reporting OD symptoms and not seen among asymptomatic controls.  
 
Compression Ratio Measured Via Dynamic Ultrasound and Validated Against MR Defecography is a Strong, 
Independent Predictor of OD  
As part of the above study, we established and validated a novel dynamics ultrasound measure (“compression ratio”) to 
quantify this observed rectal sliding / hypermobility. The term “compression” was initially utilized because the rectum, 
during dynamic ultrasound, appeared to behave like an empty aluminum beverage can being compressed from its ends 
(Figure 1, bottom). As the cul de sac descended toward the anorectal junction with increased intraabdominal pressure, 
the rigid support of the probe anteriorly (i.e. bottom of ultrasound image) caused the descent of the cul de sac to be 
linear, making it appear as if it was sliding and folding on itself relative to the posterior vaginal wall. In participants 
without OD symptoms, little to no sliding was observed. The compression ratio (see approach for details) in our study 
proved to represent a strong and independent predictor of both the presence or absence of OD symptoms and the 
severity. The risk of OD symptoms was 32 times greater among those with a high compression ratio (≥14) compared to 
those with low compression ratio (<14), after controlling for age, BMI, parity, stool type, and BM frequency per week. A 
similar compression ratio was also calculated using measurements obtained by MR defecography. While MR 
measurements added meaningfully to our conclusions, the absence of a probe anteriorly resulted in a less vivid “crushed 
can” appearance when compared to dynamic ultrasonography. Thus, the less expensive and more patient- friendly in-
office dynamic ultrasound appeared to be superior to MRI with regard to OD evaluation. 
 
OD Symptoms lack a correlation to rectocele 
It is worth emphasizing that along with the strong and robust correlations observed between OD symptoms and US-
detected rectal hypermobility, our findings indicated a clear lack of correlation between OD symptoms and the presence 
or absence of rectocele as diagnosed via pelvic examination. While posterior vaginal compartment prolapses (i.e. 
rectoceles) may certainly account for bothersome symptoms including vaginal bulging and laxity, rectoceles appear to 
have essentially no relationship to obstructive defecation which was related to only one anatomic finding: excessive 
mobility of the rectum that is usually occult and easily detected by ultrasound. This core observation would, arguably, 
make it unsurprising that rectocele repairs have performed poorly to resolve obstructive defecation symptoms (24, 25). 
Furthermore, this diagnostic/anatomic finding provided the basis for our proposed surgical approach, transvaginal 
sacrospinous rectopexy. 
 
OD symptoms persist after conventional vaginal prolapse repairs at 2 years follow up (5) 
The previous finding regarding the role of POP was further demonstrated when we performed a sub-analysis of two 
major clinical trials performed by the Pelvic Floor Disorders Network: the Colpopexy and Urinary Reduction Efforts 
(CARE) trial and the Operations and Pelvic Muscle Training in the Management of Apical Support Loss (OPTIMAL) trial 
(55, 56). The study aimed to address 2 questions: 1) is any conventional vaginal prolapse repair effective in curing OD 
symptoms, and 2) is there evidence to suggest that a sacrocolpopexy will increase the risk of worsening or newly onset 
OD symptoms? 
Regardless of trial, OD symptoms were present in more than half of the patients at the initial visit before the surgical 
intervention and interestingly about one third of the patients were symptomatic at the 24 -month follow- up interval in 
all conventional vaginal prolapse surgeries, with or without posterior vaginal wall repair (353 participants from OPTIMAL 
and 279 participants from CARE). It is also important to note that about 1/4 of the patients experienced worsening of 
their OD symptoms in the absence of anatomical failure. These data further support our overall hypothesis for this 
proposal that OD symptoms primarily result from structural defects in rectal support and not as a result of a loss in 
vaginal support, challenging the current standard for surgical treatment. 
 
Statistical shape modeling during evacuation suggests pelvic floor defects contribute to OD (57)  

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This study used MR defecography and statistical shape modeling to identify variation in pelvic floor shape. 16 women 
underwent MR defecography and were sorted by Group: case with OD symptoms (N=9) vs control (N=7) (57). The pelvic 
floors were segmented at the mid-sagittal 
slice as spline curves and a statistical shape 
analysis was performed. These results 
support the hypothesis that the mid-sagittal 
shape of the pelvic floor deforms 
significantly during evacuation and differs 
significantly between women with and 
without OD symptoms. Women with OD 
symptoms had a hyper-relaxed pelvic 
floor—with lower, straighter levator plates 
and straighter level III support (Figure 2). 
Interestingly, levator plate relaxation and 
perineal body straightening were similar 
during evacuation, indicating that the 
differences between groups observed in 
this study were structural rather than 
functional defects.  
 
Transvaginal sacrospinous rectopexy is safe and feasible for treating OD (15) 
This was a prospective case series study performed during December 2018-July 2020 and aimed to investigate the 
safety, efficiency, and durability of transvaginal sacrospinous rectopexy in women with OD symptoms and significant 
rectal hypermobility/folding (15). 20 patients underwent the procedure and completed the follow up at 2 and 12 
months postoperatively. Statistically significant improvements were observed in all OD symptoms and subjective 
improvement (94.7% ± 13.4 and 90.6% ± 18) at 2 and 12 months after the surgery, respectively. Mean rectal 
compression ratio, detected via ultrasound, improved from 45.5% ± 18.4 preoperatively to 9.2% ± 13.7 at 2 months (p 
<0.0001) and 19.6% ± 14.4 at 12 months (p<0.0012). Surgical failure, defined as combined subjective (OD symptoms > 
50% of bowel movements) and anatomical failure (rectal compression ratio >25%), occurred in two patients. Overall, 
this study demonstrated that transvaginal sacrospinous rectopexy was safe, feasible, and effectively treated OD 
symptoms within this cohort of women undergoing POP surgery with rectal hypermobility confirmed by dynamic 
ultrasound. 
 
The proposed Latin hypercube parametric study based on finite element analysis and statistical shape modeling was 
successful in identifying the relative contributions of urethral support (53, 54) 
Figure 2: Illustrations of midsagittal pelvic floor traces (the midsagittal slice of the pelvic floor muscles, 
including the levator ani and level III vaginal support structures, that run from the pubic symphysis to the tip 
of the coccyx) from 3 asymptomatic control women (blue) and 3 women with obstructed defecation 
symptoms (red) at rest and during peak evacuation. These midsagittal traces were segmented from MR 
defecography images. On average, the control levator plates appeared better supported (as demonstrated 
by more dramatic curvature and elevation) than levator plates at both rest and peak evacuation in ODS 
participants17. This supports that levator plate relaxation (as demonstrated by a straighter and more vertical 
levator plate) is likely either a contributing mechanism or the result of obstructed defecation symptoms. 

PROD Trial – v4 Mar 14 2024 
 
Page 16 of 50 
In a recent set of publications (53, 54), we utilized the finite element method and statistical shape modeling to elucidate 
the role of supportive tissues on the urethra during 
Valsalva. While these papers focused on the urethra, 
the methods and workflow will be similar to that 
utilized by this proposal. A finite element model of the 
urethra and its supports was created (Figure 3). 
Material properties were varied using Latin hypercube 
sampling to perform a sensitivity analysis resulting in 
50 simulation outcomes where the motion and shape 
of the urethra was predicted and compared to those 
obtained from clinical measurements from 76 total 
patients ranging from no, mild, to severe SUI 
(excluding women with a low urethral closure 
pressure, i.e. focusing on patients whose level of 
continence was likely resulting from the integrity of 
their structural support). The results showed that a 
reduction of the urethral stiffness and/or the 
parameters governing the stiffness of the perineal 
membrane resulted in simulated urethral motions and 
shapes associated with stress urinary incontinence. 
This represents a novel use of finite element modeling 
and statistical shape modeling to provide a mechanical 
basis explaining underlying clinical observations.  
 
4.3 Justification for Dose  
 
Not Applicable. 
 
4.4 End of Study Definition 
 
A participant is considered to have completed the study if she has completed all phases of the study including the last visit 
shown in the Schedule of Activities (SoA), Section 1.3. 
 
5. Study Population  
5.1 Inclusion Criteria  
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria:  
1. Female, between the age of 18 and 80 
2. OD symptoms as indicated by an affirmative response to either questions 7, 8 or 14 of the Pelvic Floor Distress 
Inventory (PFDI): 
a. Do you feel you need to strain too hard to have a bowel movement? 
b. Do you feel you have not completely emptied your bowels at the end of a bowel movement? 
c. Does part of your bowel ever pass through the rectum and bulge outside during or after a bowel 
movement? 
3. Rectal hypermobility defined as a compression ratio greater than 50% according to ultrasound 
4. Patient planning on undergoing surgery for the repair of pelvic organ prolapse within the next 12 months  
5. Patient who is not pregnant and does not intend to become pregnant in the next 2 years  
6. Available for 24-months of follow-up 
7. Stated willingness to comply with all study procedures and availability for the duration of the study  
8. Able to complete study assessments, per clinician judgment 
9. Able and willing to provide independent written informed consent 
Figure 3: Screenshots of the baseline finite element model at rest (top) and 
peak Valsalva (bottom). A) Images from the perspective of the sacrum 
facing anteriorly and inferiorly. B) Images from the patient’s right side with 
a midsagittal cut so the urethra can be seen clearly. C) Displays the same 
model view as B, but with the patient’s dynamic MRI images overlayed to 
demonstrate the agreement between the final model and in vivo imaging. 

PROD Trial – v4 Mar 14 2024 
 
Page 17 of 50 
10. Stable cardiovascular and respiratory status to meet candidacy in vaginal or laparoscopic surgeries  
 
5.2 Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Contraindication to abdominal (history of severe intrabdominal surgery) and  transvaginal rectopexy in the opinion 
of the treating surgeon 
2. History of previous surgery that included any type of surgery for rectal prolapse 
3. Pelvic pain or dyspareunia due to levator ani spasm that would preclude a PMT program 
4. Previous adverse reaction to synthetic mesh 
5. Current cytotoxic chemotherapy or current or history of pelvic radiation therapy within 12 months  
6. History of two inpatient hospitalizations for medical comorbidities in the previous 12 months 
 
5.3 Lifestyle Considerations  
 
Not Applicable.  
 
5.4 Screen Failure  
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently 
randomly assigned to the study intervention or entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) may not be rescreened. 
 
5.5 Strategies for Recruitment and Retention 
 
Recruitment and informed consent will occur in two participating medical centers: 1) NorthShore University HealthSystem, 
and 2) Weill Cornell Medical Center- New York Presbyterian. Participants will be recruited from principal investigator and 
colleague’s patient population. Female, between the age of 18 and 80, with and without vaginal prolapse who report 
obstructed defecation symptoms in more than 50% of their bowel movements with significant rectal hypermobility will 
be contacted directly during outpatient clinic visit to learn more about the study.  
 
In addition, an electronic medical records messaging system will be utilized for recruitment. A list of eligible patients will 
be identified using the inclusion criteria and ICD-10 codes. Once eligible patients are identified, permission will be obtained 
from the patients' clinicians to include them in the messaging outreach. With the clinicians' permission, the research team 
will send electronic medical record messages with study information. 
 
Because this study requires long-term participation, contact information for the participant will be collected during the 
consent process. Prior to each visit, participants will receive reminder calls regarding the upcoming visit.   
 
Compensation 
 
Participants will receive compensation for participating in the study. For the completion of MR defecography, the 
participant will be compensated $100. For the completion of the surgery, the participant will be compensated $100. For 

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Page 18 of 50 
each of the post-operation visits completed (2 weeks, 2-12-24 months), the participant will be compensated $50. In total, 
the participant can be compensated up to $400.  
 
Participants will be responsible for all costs that would normally incur as part of routine care, including costs related to 
the surgical treatment. There will be no charge associated with follow-up visits and post-operative ultrasounds.   
 
6. Study Intervention 
6.1 Study Intervention(s) Administration 
6.1.1 Study Intervention Description  
Transvaginal Sacrospinous Rectopexy Surgical Technique  
The posterior vaginal wall dissection is started with a horizontal 
incision in the mid-posterior vaginal wall. Dissection is carried 
down to the sacrospinous ligament (SSL) bluntly on each side. 
Sacrospinous ligament sutures are placed using a push-and catch 
suturing device (Capio Slim, Boston Scientific Corporation, USA) to 
deliver a single 0-polydiaxone suture (Monodek, Teleflex Medical 
OEM) into each ligament approximately 2-2.5 cm medial to the 
ipsilateral ischial spine (Figure 5). With one finger inside the 
rectum, the suture is passed through the lateral rectal ligament 
and rectal muscularis layer, as a two-bite running suture, at a 
point 7-8 cm cephalad to the anal verge. After tying down the knot 
on the first side, rectal suture placement is then performed on the 
contralateral side; this sequential suturing and tying down of left 
and right sided rectal suspensions allows for assessment and fine-
tuning of the rectal suspension and avoidance of excess tension 
or stretching of the rectal wall. After suspension of the rectum 
bilaterally, three additional interrupted 0 polydiaxone sutures are 
used to reattach the midline posterior vaginal wall to the midline 
anterior rectal wall at the same level (7-8 cm cephalad from the 
anal verge); these sutures provide reinforcement and tension 
relief to the midline rectum between each lateral SSL suspension 
suture and serve to close a potential enterocele space. 
 
Laparoscopic Abdominal Ventral Rectopexy Surgical Technique  
The surgery is performed under general anesthesia with patient in steep Trendelenburg position. Usually 4 ports are 
created. Supra-umbilical port is used as camera port. The rectosigmoid junction is identified and retracted to the left. A “J 
shaped” peritoneal incision is given extending from the sacral promontory to the anterior peritoneal reflection distally. 
Right hypogastric nerve and ureter are identified and safeguarded. With combined blunt and sharp dissection, a wide 
plane is developed in the Rectovaginal/rectovesical space. Any posterior rectal mobilization or lateral dissection is avoided 
at this stage. A strip of Prolene mesh (Ethicon Endosurgery, Blue Ash, Ohio, United States), trimmed to 3 cm × 17 cm, is 
prepared and inserted into the pelvic cavity. One end of mesh is fixed to the anterior surface of the distal most part of the 
rectum using polypropylene sutures. Similarly, it is fixed to the lateral borders of the rectum. Care is taken to avoid full 
thickness bite into the rectal wall in order to prevent mesh contamination. Finally, the proximal end of mesh is fixed to 
the sacral promontory using same sutures. Proximal traction on the rectum is avoided while fixing the mesh. The 
peritoneum is then re-approximated to completely cover the mesh. 
 
Conventional Vaginal Prolapse Surgery  

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To minimize the number of confounding variables and reduce the complexity of analysis, types of conventional vaginal 
prolapse surgery will be limited to the following: 
1. Vaginal prolapse repair surgery –  
a. Anterior vaginal repair surgery 
b. Posterior vaginal repair surgery 
c. Vault suspension  
2. Abdominal prolapse repair surgery –  
a. Sacrocolpopexy 
3. Tension-Free Vaginal Tape 
 
6.1.2 Dosing and Administration  
Not applicable.  
 
6.2 Preparation/ Handling/ Storage/ Accountability  
6.2.1 Acquisition and Accountability  
At both study sites, all investigators will perform the dynamic pelvic ultrasound. MR defecography will be performed by 
trained personnel at each site. Transvaginal sacrospinous rectopexy will be performed by urogynecologists. Laparoscopic 
abdominal ventral rectopexy will be performed by colorectal surgeons.   
 
Per Objective Structured Assessment of Technical Skill (OSATS), competency criteria for the novel transvaginal 
sacrospinous rectopexy will be performing three to five cases under the supervision of Dr. Ghazaleh Rostami Nia and/or 
Dr. Roger Goldberg until achieving the following milestone: 
1. The surgeon was able to perform all aspects of the procedure safely and competently. 
 
A second or third year urogynecology fellow or a second-year colorectal fellow will be able to assist in the surgeries 
under the direct supervision of investigators. 
 
6.2.2 Formulation, Appearance, Packaging, and Labeling  
Not applicable.  
 
6.2.3 Product Storage and Stability 
Not Applicable.  
 
6.2.4 Preparation 
Not Applicable.  
 
6.3 Measures to Minimize Bias: Randomization and Blinding  
 
Randomization  
Participants will be assigned with equal probability to one of the two groups for each intervention TSR with and without CVPR 
versus LAVR with and without CVPR. Participants will be randomized after anesthesiologist clearance for both surgical 
approaches and prior to the preoperative visit. Every effort will be made to minimize the time between randomization 
and the surgery. Participant will have the opportunity to review the surgery detail with the surgeon during the 
preoperative visit. Separate randomization schedules will be generated by the DCC for each Clinical Site using a random 
permutated block design. The DCC will provide treatment allocations to the Clinical Sites using REDCap randomization 
feature.  
 
Masking 

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The study surgeon is providing clinical care to enrolled participants, thus masking the surgeon to treatment allocation or 
participant symptoms is not practical or feasible, other than the allocation concealment prior to surgical randomization. 
Given the surgical procedure require a transvaginal or abdominal incision, it is clinically not possible to mask the 
participant or other research personnel. Every attempt will be made to keep the research coordinator blinded when 
assessing symptoms via questionnaires during follow up visits. The dynamic pelvic ultrasound image will be saved and re-
evaluated in a blinded manner retrospectively to confirm the results of the initial reading.  
 
6.4 Study Intervention Compliance  
 
Surgeons will comply with randomization assignments to the extent possible. Variations will be documented as protocol 
deviation and justification for allowing clinical decision-making to overrule randomized treatment assignment will be 
documented. Protocol deviations will be reviewed by both the IRB and the Data Safety Monitoring Board (DSMB).  
 
6.5 Concomitant Therapy  
 
No additional surgical procedures will be performed at the same time as the research procedure described in this protocol. 
If any additional procedures, unanticipated or incidental, are performed for medical necessity, they will be documented 
as protocol deviation and described fully to the IRB and DSMB. 
 
6.5.1 Rescue Medicine  
Not applicable.  
 
7. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal  
7.1 Discontinuation of Study Intervention 
 
Incomplete MR imaging does not mean discontinuation from the study, and remaining study procedures can be 
completed as indicated by the study protocol. Patient can withdraw from the study before surgery.  
 
If a clinically significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding, occurring or discovered after obtaining informed consent, will be reported as an adverse event (AE). 
 
7.2 Participant Discontinuation/ Withdrawal from the Study  
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation 
• 
Participant unable to receive MRI or surgery for 3 months 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case Report Form (CRF). 
Participants who sign the informed consent form and are randomized but do not receive the study intervention may be 

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Page 21 of 50 
replaced. Participants who sign the informed consent form, and are randomized and receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
 
7.3 Lost to Follow-Up 
 
A participant will be considered lost to follow-up if she fails to return to any scheduled visits and is unable to be contacted 
by the study site staff.  
 
The following actions must be taken if a participant fail to return to the clinic for any required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 30 days and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to regain 
contact with the participant (where possible, 3 calls/messages and, if necessary, a certified letter to the 
participant’s last known mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from the study 
with a primary reason of lost to follow-up. 
 
8. Study Assessments and Procedures  
8.1 Study Assessments  
 
The surgical success or failure of will be measured by: 
1. The degree of rectal hypermobility measured via dynamic pelvic ultrasound (i.e. compression ratio) 
 
The criteria for surgical failure will be defined as follows: 
1. A participant will be considered a surgical failure if: 
b. Rectal hypermobility with compression ratio more than 20% is detected via ultrasound. 
2. Otherwise, a participant will be considered a surgical “success”.  
 
In addition to dynamic pelvic ultrasound, the following assessments will be performed: 
1. Postoperative pain - Participants will complete the Pain Scale (67) and an assessment of pain medication use 
preoperatively, and then at 2 weeks, 2, 12 and 24 months postoperatively. 
2. Postoperative functional activity level – Participants will complete the Activity Assessment Scale (68) which 
measures functional activity preoperatively and then at 2 weeks, 2 months, 12 months, and 24 months 
postoperatively. 
3. Global improvement in bladder function – Participants will complete the Patient Global Impression of 
Improvement (69) at 2, 12 and 24 months after surgery. 
4. Pelvic Floor Distress Inventory (PFDI) – Prolapse and colorectal symptoms as assessed by the POPDI and CRADI 
(short-term) and urinary and colorectal symptoms as assessed by the UDI and CRADI (long-term) subscales. 
Change in symptoms from 2, 12, and 24 months will also be assessed. 
5. Quality of life measured by PFIQ (65), SF-36 (70), and EQ-5D (71) at 2, 12 and 24 months. The SF-36 will also be 
administered to a subset of participants 2 weeks post-operatively to allow validation of the Pain and Activity 
Assessment Scale. 
6. Pelvic muscle strength as assessed by the Brink Scale 2, 12 and 24 months. 
 
Based on measurements above, efficacy will be defined as follows: 
1. Time to anatomic recurrence (time to failure) 

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a. Urinary function: compare UDI scores (65) to assess urinary function generally and Hunskaar 
Incontinence Severity Index to assess the presence and severity of urinary incontinence specifically. 
Participants will also complete the Patients Global Impression of Improvement (PGI-I) (69) for 
impressions of bladder function. 
b. Bowel function: compare CRADI scores (65) 
c. Prolapse symptoms: compare POPDI scores (65) 
2. Non-surgical treatment for pelvic floor disorders 
a. Pessary use for prolapse 
b. Stress urinary incontinence 
c. Urge urinary incontinence and other overactive bladder symptoms 
d. Voiding dysfunction 
e. Defecating dysfunction and/or fecal incontinence 
3. QOL 
a. Global: compare SF-36 scores and sub-scales (73), EQ-5D. (71, 74) 
b. Disease-specific: compare urinary, bowel and prolapse scales of PFIQ score (65) 
4. Participants’ Perception of Motivation and Barriers to Continued Study Participation questionnaire 
 
8.2 Safety and Other Assessments  
Perioperative measures of morbidity include operative time (a risk factor for operative morbidity), estimated blood loss, 
and intra-operative and post-operative complications. Complications will be categorized using a modification of the Dindo 
Classification (77). Perioperative morbidity will be recorded at the completion of the surgery, at hospital discharge, and at 
the 2-week postoperative visit. 
 
In addition, the following specific adverse events will be assessed and reported: 
1. Intra-operative ureteral injury/obstruction (identified as no spill of urine from one or both ureteral orifices after 
prolonged observation (> 10 minutes) via cystoscopy; when indicated, other procedures may be used 
diagnostically or therapeutically, such as ureteral stent placement.) 
2. Removal/replacement of vault suspension sutures to relieve intra-operative ureteral obstruction 
3. Postoperative ureteral injury (delayed recognition) 
4. Intra-operative neural injury (as determined by post-operative neuropathic pain or other neurologic sequelae) 
that was new onset: Neuropathic pain attributable to the vaginal vault suspension will be defined as “Acute-onset 
pain involving the buttock, groin and/or lower extremity, usually unilateral, occurring on the side or sides where 
vault suspension stitches have been placed and within one week of the index surgery requiring an alteration of 
routine postoperative care (e.g., nerve block, physical therapy, return to OR for suture removal, the addition of 
medications used to treat neuropathic pain such as anticonvulsants or tricyclic anti-depressants, or the increase 
or persistence of narcotic pain medication use beyond 14 days after surgery).” 
5. Transfusion of blood products (e.g., whole blood, packed red blood cells, platelets) 
6. Vaginal granulation tissue requiring treatment 
7. Vaginal or perineal stricture (i.e., narrowing or scarring) prompting a treating physician to suggest or the 
participant to request treatment (surgical or non-surgical) 
8. Rectal injury 
9. Postoperative pain 
 
8.3 Adverse Events and Serious Adverse Events  
8.3.1 Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, whether 
or not considered intervention-related (21 CFR 312.32 (a)). 
 

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8.3.2 Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 Classification of an Adverse Event  
8.3.3.1 Severity of Event  
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will be used to 
describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. Moderate 
events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other 
treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the term “severe” 
does not necessarily equate to “serious”. 
 
8.3.3.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who examines and 
evaluates the participant based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. In a clinical trial, the study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out. The clinical event, including an abnormal laboratory test result, occurs in a plausible 
time relationship to study intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study intervention (dechallenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of a satisfactory 
rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time after 
administration of the study intervention, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred within a 
reasonable time after administration of the trial medication). However, other factors may have contributed to 
the event (e.g., the participant’s clinical condition, other concomitant events). Although an AE may rate only as 
“possibly related” soon after discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the event did not 
occur within a reasonable time after administration of the study intervention) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 

PROD Trial – v4 Mar 14 2024 
 
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• 
Not Related – The AE is completely independent of study intervention administration, and/or evidence exists 
that the event is definitely related to another etiology. There must be an alternative, definitive etiology 
documented by the clinician. 
 
8.3.3.3 Expectedness  
Principal investigator and co-investigators will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study intervention. 
 
8.3.4 Time Period and Frequency for Event Assessment and Follow-up  
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study personnel 
during study visits and interviews of a study participant presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate case 
report form (CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study product (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as baseline and not 
reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, it will be 
recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each level of 
severity to be performed. AEs characterized as intermittent require documentation of onset and duration of each 
episode. 
 
PI and co-investigators will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study visit, 
the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization. 
 
8.3.5 Adverse Event Reporting  
Each investigator is responsible for reporting adverse events to the IRB at their institution, to the Data Coordinating 
Center (DCC), and to the NIH Program Official. The DCC will summarize the case and report it to the NIDDK program 
official and the Executive Secretary of the DSMB, who will determine whether it should be shared with the DSMB 
immediately or reported as part of the next scheduled report to the DSMB. The investigator must promptly inform the 
Ethics Board or IRB of adverse event per local reporting requirement. The Chair of the DSMB can convene an emergency 
meeting of the DSMB.  
 
Every six months, or upon request of the NIDDK, the data coordinating center will summarize all adverse events (serious, 
expected, and unexpected) by treatment group in a report to the DSMB. In addition, the report will contain accrual, 
drop-out rates, and data quality metrics. The DSMB will summarize their findings to the NIH with a recommendation to 
continue the clinical trial, modify the trial, or terminate the trial.   
 
8.3.6 Serious Adverse Event Reporting  
The study clinician will immediately report to the sponsor any serious adverse event, whether or not considered study 
intervention related, including those listed in the protocol and must include an assessment of whether there is a 
reasonable possibility that the study intervention caused the event. Study endpoints that are serious adverse events 
(e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal 

PROD Trial – v4 Mar 14 2024 
 
Page 25 of 50 
relationship between the study intervention and the event (e.g., death from anaphylaxis). In that case, the investigator 
must immediately report the event to the sponsor and the IRB of record. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site investigator deems the 
event to be chronic or the participant is stable. Other supporting documentation of the event may be requested by the 
Data Coordinating Center/DSMB/NIH and should be provided as soon as possible. 
 
8.3.7 Reporting Events to Participants  
Participants will be informed of AEs during an office visit soon after detecting AEs to discuss the problem and treatment 
options. 
 
Participants will be informed of incidental findings soon after detecting them to discuss the problem and treatment 
options. 
 
8.3.8 Events of Special Interest  
Not applicable 
 
8.3.9 Reporting of Pregnancy 
Participants who become pregnant after entering the study will be withdrawn from the study and none of the study 
procedures will be performed.  
  
8.4 Unanticipated Problems 
8.4.1 Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to participants or 
others to include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in 
the protocol-related documents, such as the Institutional Review Board (IRB)-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 Unanticipated Problem Reporting  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board (IRB), the NIDDK 
program official, and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will include 
the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or are proposed in 
response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study sponsor within 30 
days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 30 days of the investigator 
becoming aware of the problem.  

PROD Trial – v4 Mar 14 2024 
 
Page 26 of 50 
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s written reporting 
procedures), the supporting agency head (or designee), and the Office for Human Research Protections (OHRP) 
within 30 days of the IRB’s receipt of the report of the problem from the investigator. 
 
8.4.3 Reporting Unanticipated Problems to Participants  
Participants will be informed of UPs during an office soon after detecting AEs to discuss the problem and treatment 
options. 
 
9. Statistical Considerations  
9.1 Statistical Hypothesis  
 
Primary Aim 
We anticipate that patients who received transvaginal sacrospinous rectopexy (TSR) will show significantly greater 
surgical success comparing to laparoscopic abdominal ventral rectopexy (LAVR) group, and this change is expected to 
remain at 24 months. TSR will result in superior outcomes over LAVR. 
 
Secondary Aim  
We anticipate that rectal hypermobility can be detected via both dynamic imaging, ultrasound and MR defecography. 
We expect the degree of a rectal support defect will correlate well between the two imaging modalities and with 
symptom severity. 
 
9.2 Sample Size Determination  
 
Based on our preliminary studies in literature (83-87), we assume an anatomic success rate in LAVR group is about 70% 
at 24 months. The investigators believe that a difference in success rates less than 25% will not change clinical practice, 
but also that the sample size should be large enough so that an observed difference in success rates of 20% would be 
significant; i.e., an inability to differentiate between the procedures will require an observed difference that is less than 
20%.  
 
The study will be individually randomized group-treatment trial (IRGT), which patients are randomized to surgical 
interventions through a common surgeon (88-90). There will be three surgeons performing each surgical treatment. The 
number of surgeons and patients will be the same in each clinical site. We anticipate an average of 16 individually 
randomized patients per surgeon in each treatment group. Outcomes for patients treated by the same surgeon tend to 
be more similar. We assume minimal variability, estimating a small intraclass correlation coefficient (ICC) of 0.01. The 
table below illustrates power to detect at least 23% difference between treatment groups with varying assumptions on 
ICC and dropout rates. A total of 96 patients (48 patients per group) would yield 86% power to differentiate between 
anatomical success rates of 70% and 93% assuming an ICC of 0.01 and a two-sided 5% level of significance. Projecting a 
20% dropout/loss to follow up rate over 2 years, we anticipate recruiting and up to 120 total patients.   
 
ICC 
% Dropout 
Total 
patients 
Average 
patients per 
surgeon 
Power 
0.01 
0 
120 
20 
92% 
10 
108 
18 
90% 
20 
96 
16 
86% 
0.02 
0 
120 
20 
90% 
10 
108 
18 
87% 
20 
96 
16 
83% 
0.05 
0 
120 
20 
82% 
10 
108 
18 
79% 
20 
96 
16 
76% 
 

PROD Trial – v4 Mar 14 2024 
 
Page 27 of 50 
Due to concerns that ICC is higher than expected or dropout rate is higher than 20% toward the end of 2-year follow-up, 
we calculated the sample size that would be needed for 87% power to differentiate between anatomical success rates of 
70% and 95% (a difference of 25%) in treatment groups with a two-sided 5% level of significance. The required sample 
size is 39 per group, or 78 total patients. 
 
9.3 Populations for Analyses  
 
Modified Intent-to-treat (mITT) Population 
The mITT population will include all randomized participants who received at least one post-op visit. Participants will be 
analyzed according to their randomized treatment assignment, regardless of the treatment actually received.  
 
Safety Population 
The safety population will include all participants who received any study treatment. All safety analyses will use the 
safety population. Participants will be analyzed according to the treatment they actually received, regardless of the 
treatment assigned.  
 
Per-protocol (PP) Population 
The PP population is a subset of the ITT population who completed the study without any major protocol violations. 
Analyses will exclude the following randomized participants: (83) those who did not receive TSR/LAVR surgery as 
planned; (84) those who died within 12 months of surgery and were not assessed on the primary outcome before their 
death; (85) those who withdrew from study and withdrew consent for use of their data. 
 
Full Analysis Set (FAS) 
The FAS will include all randomized participants who receive any study treatment and have at least one assessment 
since the baseline visit. Participants will be analyzed in their randomized treatment assignment, regardless of the 
treatment actually received.  
 
9.4 Statistical Analyses  
9.4.1 General Approach  
After examining for outliers and missing values, the distributions of continuous measures will be examined. When 
necessary, the data may be transformed or non-parametric tests will be used. Baseline measures will be compared 
between the treatment groups to identify imbalances. All statistical analyses will be performed using SAS 9.4 (SAS 
Institute Inc., Cary, NC) with two-sided 5% level of significance. 
 
Implementation of the planned statistical analysis will be described in the Statistical Analysis Plan (SAP) prior to locking 
the database. 
 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) 
Anatomical Surgical Outcome 
The primary endpoint for the surgical treatment is dichotomous: success or failure at 24 months after surgery. The 
primary outcome measure uses the rectal compression ratio at 24 months unless there has been retreatment at an 
earlier time. When there is retreatment, or when the 24-month ultrasound results and POPQ results are missing and the 
last observed measurements were consistent with the definition of failure, then the results at 24 months will be 
imputed to be a failure. A sensitivity analysis will be performed to study the effect on the primary endpoint of different 
methods of handling dropouts and missing data. It will be conducted by assuming various values for the imputed 
outcomes and comparing the results under those assumptions to the results of the primary analysis. 
 
Cochran-Mantel-Haenszel (CMH) test will be used to compare between surgical treatments adjusting for stratification 
factor. In addition, Generalized linear mixed-effects models (GLMMs) will be performed to yield an effect estimate of 
conditional on surgeon. Demographics and other characteristics at baseline (treatment group, age, BMI, menopausal 
status, parity, duration and severity of ODS) will be included. Surgeon will be included as a random effect to account for 

PROD Trial – v4 Mar 14 2024 
 
Page 28 of 50 
correlation between outcomes of patients treated by the same surgeon. Adjusted odds ratios (ORs) will be presented 
with 95% confidence intervals (CIs).  
 
9.4.3 Analysis of the Secondary Endpoint(s) 
Subjective Surgical Outcome 
The secondary endpoint is the presence of OD symptoms (yes/no) at 24 months after surgery. Questionnaires that assess 
the presence and severity of OD symptoms include pain/activity assessment scale, global improvement in bladder 
function, prolapse and colorectal symptoms as assessed by POPDI, CRADI, UDI, quality of life by PFIQ, SF-36, EQ-5D, and 
pelvic muscle strength measured by Brink Scale. Differences between surgical treatments will be analyzed using 
generalized linear mixed-effects models, as described for the primary endpoint. However, imputation of missing values 
will not be done for secondary measures. 
 
Validation  
There will be two forms of validation: statistical and radiological. For statistical validation, we expect to see a significant 
and positive correlation between measurements of the Compression ratio between the two modalities. However, since 
the Compression ratio as measured via MR defecography is not used clinically to diagnose abnormalities in rectal support 
(rectal prolapse or rectal intussusception), this does not validate the use of ultrasound for diagnostic purposes. Thus, 
radiological validation will be performed where the Compression ratio is also correlated with a radiologist’s diagnosis of 
an abnormality in rectal support. 
 
9.4.4 Safety Analysis  
Any endpoints that relate to safety will be analyzed using methods previously described.  
 
All adverse events collected will be coded. Events will be summarized cumulatively through the following time points: 2 
weeks, 2 months, 12 months, and 24 months postoperatively. Severity and frequency of AEs will be presented. In 
addition, the frequency and percentage of participants who had a Serious AE (SAE) or a related AE will be tabulated 
separately. 
 
9.4.5 Baseline Descriptive Statistics 
A summary table with descriptive statistics will be generated for baseline characteristics, including demographics and 
laboratory measurements based on the ITT population. Baseline characteristics will be presented by intervention groups 
in a table, but no formal statistical hypothesis testing will be performed. Continuous variables will be summarized using 
mean with standard deviation or median with interquartile range. Categorical variables will be summarized using 
frequency and percentage.  
 
Baseline characteristics include demographics, medical history, surgical history, physical exam, pelvic ultrasound, MR 
defecography, POPQ, PFDI, Pain Scale, Assessment of pain medication use, and Activity assessment scale.  
 
9.4.6 Planned Interim Analysis  
No interim analyses are planned. 
 
9.4.7 Sub-Group Analyses 
Subgroup analyses of the primary efficacy endpoint will be conducted for demographics (e.g., age, BMI, menopausal 
status, parity), duration and severity of ODS, and concomitant surgery. Descriptive statistics will be presented stratified 
by aforementioned variables. Data will be analyzed using the same method as described for the primary efficacy 
endpoint. 
 
9.4.8 Tabulation of Individual Participant Data  
Not Applicable  
 

PROD Trial – v4 Mar 14 2024 
 
Page 29 of 50 
9.4.9 Exploratory Analyses 
We will investigate the correlation between measurements of compression ratio between two modalities and present a 
cut-off for these measurements relevant to presence of OD symptoms in our secondary endpoints. For an optimal cut-
off, the sensitivity and specificity will be calculated based on receiver operating characteristic (ROC) curve. 
 
We will develop and validate a computational finite element model and statistical shape modeling approach to describe 
the mechanics of normal defecation and the role of rectal and vaginal support deficiencies in causing OD symptoms.  
 
10. Supporting Documentation and Operational Considerations  
10.1 Regulatory, Ethical, and Study Oversight Considerations  
10.1.1 Informed Consent Process  
10.1.1.1 Consent and Other Informational Documents Provided to Participants  
Consent forms describing in detail the study intervention, study procedures, and risks are given to the participant and 
written documentation of informed consent is required prior to starting intervention/administering study intervention. 
The risks and benefits of each surgical approach including the risk of prolapse recurrences will be discussed during 
consent and pre-operative visits. During the pre-operative visit, which will occur after anesthesiologist clearance and 
randomization, participants will have the opportunity to review the surgery details with the surgeon. Participants 
randomized to laparoscopic ventral rectopexy will complete the preoperative visit with a colorectal surgeon. Those 
assigned to transvaginal sacrospinous rectopexy will complete the preoperative visit with a urogynecologist. Every effort 
will be made to minimize the time between randomization and the surgery. Surgical failure resulting from either surgical 
approach will be addressed per current guidelines for surgical failures which include symptoms assessment for 
conservative or surgical management.  
 
10.1.1.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and continues 
throughout the individual’s study participation. Consent forms will be Institutional Review Board (IRB)-approved and the 
participant will be asked to read and review the document. Written informed consent will be obtained from all study 
participants. Consent will be obtained by study-related personnel who are knowledgeable of the study and who have 
training in the consent process and in the protection of human participants. No study-related procedures (interview, chart 
abstraction, research ultrasound studies, questionnaires) will be undertaken before a signed consent form has been 
completed. During the process of obtaining informed consent, potential participants will have the nature of the study, 
specimen collection, data collection procedures, study ultrasound procedures, the importance of compliance to study 
procedures, and the potential risks and benefits explained to them. Potential participants will be told that there is no 
obligation to participate, that there will be no penalty for declining to participate and that their treatment will not be 
compromised if they choose not to participate or cease participation at any time. Ample time will be provided for each 
potential participant to read and understand the consent form and to ask questions. The potential participant will be able 
to take the consent form/informational form home to discuss participation with family/friends/personal physician. A 
separate visit will be scheduled for the potential participant to return to the clinic to ask questions and sign the consent 
form with the research coordinator or research assistant. A participant who consents to the study will be given a copy of 
the signed consent form for their personal records. A copy will be placed in their medical record. The original signed copy 
will be kept in a locked file at the clinical site with other confidential information on the participant. 
 
10.1.2 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to study participants, investigator, funding agency, and regulatory authorities. If the study is 
prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule. 

PROD Trial – v4 Mar 14 2024 
 
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Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the 
sponsor and IRB. 
 
10.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their interventions. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board 
(IRB), or regulatory agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during the study. 
At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the 
reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted 
to and stored at the Data Coordinating Center. This will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification number. The 
study data entry and study management systems used by clinical sites and by Data Coordinating Center research staff 
will be secured and password protected. At the end of the study, all study databases will be de-identified and archived 
at the Data Coordinating Center. 
 
10.1.4 Future use of Stored Specimen and Data  
Data collected for this study will be analyzed and stored at the Data Coordinating Center. After the study is completed, 
the de-identified, archived data will be transmitted to and stored at the ClincialTrials.gov for use by other researchers 
including those outside of the study.  
 
When the study is completed, access to study data will be provided through the ClinicalTrials.gov. 
 
10.1.5 Key Roles and Study Governance  
Principal Investigator 
Ghazaleh Rostami Nia, MD, MSc, 
Director of Research Division of 
Urogynecology, 
NorthShore University 
HealthSystem, Clinical Assistant 
Professor, University of Chicago 

PROD Trial – v4 Mar 14 2024 
 
Page 31 of 50 
Pritzker School of Medicine, 
Female Pelvic Medicine and 
Reconstructive Surgery 
Division, Department of 
Obstetrics and Gynecology 
NorthShore University 
HealthSystem 
9650 Gross Point Rd. 
Suite 3900 
Skokie, IL 60076 
224.251.2374 
 
 
The Clinical Centers: 
NorthShore University HealthSystem – Skokie, IL; PI Ghazaleh Rostami Nia, MD, MSc, Co-I Roger Goldberg, MD, MPH 
Weill Cornell Medical Center- New York Presbyterian – New York, NY; PI Tirsit Shiferaw Asfaw, MD, Co-I Jeffrey Wilson, 
MD, Co-I Kelly Garrett, MD 
 
Biostatistician: 
NorthShore University HealthSystem – Skokie, IL; Cecilia Chang, MS  
 
Bioengineer: 
University of Pittsburg - Pittsburgh, PA; Steven Abramowitch, PhD 
 
The Data Coordinating Center: 
NorthShore University HealthSystem – Skokie, IL; PI Ghazaleh Rostami Nia, MD, MSc 
 
The NIDDK Program Director: 
Dana K. Andersen, M.D. 
 
10.1.6 Safety Oversight  
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB), chartered by the NIDDK, 
composed of individuals with the appropriate expertise. Members of the DSMB should be independent from the study 
conduct and free of conflict of interest, or measures should be in place to minimize perceived conflict of interest.  The 
DSMB will meet at least semiannually to assess safety and efficacy data on each arm of the study. The DMSB will operate 
under the rules of an approved charter that will be written and reviewed at the organizational meeting of the DSMB. At 
this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to 
NIDDK. The NIDDK program official will communicate the DSMB’s recommendations to the PI. The PI is responsible for 
providing the DSMB documentation to the IRB of record and other study personnel as appropriate. 
 
10.1.7 Clinical Monitoring  
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that the 
reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol/amendment(s), with International Conference on Harmonization Good Clinical Practice (ICH 
GCP), and with applicable regulatory requirement(s).  
 
Study PI and co-PI at each site will conduct the clinical site monitoring every 20 participants recruited with 
comprehensive review of all 20 participants’ data. 
 

PROD Trial – v4 Mar 14 2024 
 
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10.1.8 Quality Assurance and Quality Control  
Each clinical site will perform internal quality management of study conduct, data collection, documentation and 
completion.  An individualized quality management plan will be developed to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will 
be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
 
Following the protocol, the monitors will verify that the clinical trial is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, International Conference on Harmonization Good Clinical 
Practice (ICH GCP).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the 
purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
 
10.1.9 Data Handling and Record Keeping 
10.1.9.1 Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site investigator. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.   
 
Hard copies of the study visit worksheets will be provided for use as source document worksheets for recording data for 
each participant enrolled in the study. Data collected from the worksheet and participants’ Electronic Medical Record 
System will be recorded and stored in REDCap, a secure, password-protected interspace. Hard copies of the study visit 
worksheet will be kept locked in office with limited access. The principal investigator, co-investigator, and research staff 
will have access to the REDCap. The research coordinator of the Data Coordinating Center will be responsible for creating 
the REDCap template to be distributed to the collaborating center for consistency in data collection. Research coordinators 
of each site will be responsible for inputting data into the REDCap. The principal investigator and co-investigator will be 
responsible for reviewing the data inputted in the REDCap for accuracy.  
 
10.1.9.2 Study Record Retention 
Study documents should be retained for 2 years after the last approval of a marketing application in an International 
Conference on Harminosation (ICH) region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development of the study 
intervention. These documents should be retained for a longer period, however, if required by local regulations.  
 
10.1.10 Protocol Deviation  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 

PROD Trial – v4 Mar 14 2024 
 
Page 33 of 50 
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations within 15 
working days of identification of the protocol deviation, or within 15 days of the scheduled protocol-required activity.  All 
deviations must be addressed in study source documents, reported to NIDDK Program Official and Data Coordinating 
Center. Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The site 
investigator is responsible for knowing and adhering to the reviewing IRB requirements.  
 
10.1.11 Publication and Data Sharing Policy  
This study will be conducted in accordance with the following publication and data sharing policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published results 
of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds 
to the digital archive PubMed Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial 
Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered 
at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt 
will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers 
3 years after the completion of the primary endpoint by contacting principal investigator of the study.  
 
10.1.12 Conflict of Interest Policy  
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical.  
Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any 
aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of 
this trial.  The study leadership in conjunction with the NIDDK has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest. 
 
10.2 Additional Considerations  
 
Not applicable.  
 
10.3 Abbreviations  
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CONSORT Consolidated Standards of Reporting Trials 
CRADI 
Colo-Rectal Anal Distress Inventory 
CRF 
Case Report Form 
CVPS 
conventional vaginal prolapse surgery 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
EQ-5D 
EuroQol-5 Dimension 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 

PROD Trial – v4 Mar 14 2024 
 
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LAVR 
laparoscopic abdominal ventral rectopexy 
MR 
Magnetic Resonance 
NCT 
National Clinical Trial 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
OS 
obstructed defecation 
PFDI 
Pelvic Floor Distress Inventory Questionnaire 
PFIQ 
Pelvic Floor Impact Questionnaire 
PI 
Principal Investigator 
POP 
Pelvic Organ Prolapse 
POPDI 
Pelvic Organ Prolapse Distress Inventory  
POPQ 
Pelvic Organ Prolapse Quantification system 
QC 
Quality Control 
QOL 
Quality of Life 
RF 
Radiofrequency 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SF-36 
36-item short-form 
TSR 
Transvaginal sacrospinous rectopexy 
SOA 
Schedule of Activities 
UDI 
Urinary Distress Index 
UP 
Unanticipated Problem 
US 
United States 
 
11. References 
  
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40. 
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41. 
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42. 
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hazards of rectal mobilisation. International journal of colorectal disease. 1987;2(3):158-66. 
43. 
Nano M, Dal Corso H, Lanfranco G, Ferronato M, Hornung J. Contribution to the surgical anatomy of the 
ligaments of the rectum. Diseases of the colon & rectum. 2000;43(11):1592-7. 
44. 
Bredenoord A, Tack J, Smout A. Anorectum. Functiestoornissen van het maag-darmkanaal: Springer; 2010. p. 99-
110. 
45. 
Stoker J. Anorectal and pelvic floor anatomy. Best practice & research Clinical gastroenterology. 2009;23(4):463-
75. 
46. 
Dietz H, Beer‐Gabel M. Ultrasound in the investigation of posterior compartment vaginal prolapse 
andobstructed defecation. Ultrasound in obstetrics & gynecology. 2012;40(1):14-27. 
47. 
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ultrasound: the distinction between true rectocele, perineal hypermobility and enterocele. Ultrasound in 
Obstetrics and Gynecology: The Official Journal of the International Society of Ultrasound in Obstetrics and 
Gynecology. 2005;26(1):73-7. 
48. 
Rostaminia G, Javadian P, Awad C, Shobeiri SA. Ultrasound Indicators of Rectal Support Defect in Women With 
Obstructive Defecatory Symptoms. Female pelvic medicine & reconstructive surgery. 2018. 
49. 
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Int Urogynecol J. 2014. 
50. 
Routzong MR, Abramowitch SD, Chang C, Goldberg RP, Rostaminia G. Obstructed Defecation Symptom Severity 
and Degree of Rectal Hypermobility and Folding Detected by Dynamic Ultrasound. Ultrasound Quarterly. 2021. 
51. 
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females: functional outcome of mesh sacrocolpopexy and rectopexy as a combined procedure. Diseases of the 
colon & rectum. 2007;50(9):1412-21. 
52. 
Watadani Y, Vogler SA, Warshaw JS, Sueda T, Lowry AC, Madoff RD, et al. Sacrocolpopexy with rectopexy for 
pelvic floor prolapse improves bowel function and quality of life. Diseases of the colon & rectum. 
2013;56(12):1415-22. 
53. 
Routzong M, Chang C, Goldberg R, Abramowitch S, Rostaminia G. Urethral Support in Female Urinary 
Continence Part 1: Dynamic Measurements of Urethral Shape and Motion. International urogynecology journal. 
2021;Spring. 
54. 
Routzong M, Martin L, Rostaminia G, Abramowitch S. Urethral Support in Female Urinary Continence Part 2: A 
Computational, Biomechanical Analysis of Valsalva. International urogynecology journal. 2021;Spring. 
55. 
Barber MD, Brubaker L, Menefee S, Norton P, Borello-France D, Varner E, et al. Operations and pelvic muscle 
training in the management of apical support loss (OPTIMAL) trial: design and methods. Contemporary clinical 
trials. 2009;30(2):178-89. 
56. 
Visco AG, Brubaker L, Nygaard I, Richter HE, Cundiff G, Fine P, et al. The role of preoperative urodynamic testing 
in stress-continent women undergoing sacrocolpopexy: the Colpopexy and Urinary Reduction Efforts (CARE) 
randomized surgical trial. International urogynecology journal. 2008;19(5):607. 

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Controls vs Women with Obstructed Defecation. AUGS/IUGA Joint Scientific Meeting 2019; 2019: AUGS/IUGA. 
58. 
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Diseases of the Colon & Rectum. 2014;57(12):1446-7. 
59. 
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using the Uphold™ Vaginal Support System: a 1-year multicenter study. International urogynecology journal. 
2016;27(9):1337-45. 
60. 
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Hysterectomy or Uterine Preservation for the Treatment of Pelvic Organ Prolapse. Scientific reports. 
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Michigan four-wall sacrospinous ligament suspension for prolapse. Obstetrics and gynecology. 2013;122(5). 
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prolapse. British journal of surgery. 2004;91(11):1500-5. 
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prolapse and intussusception. Colorectal disease. 2010;12(6):504-12. 
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sacrocolpo-or hysteropexy for the treatment of concurrent rectal and pelvic organ prolapse. Female pelvic 
medicine & reconstructive surgery. 2018;24(5):336-40. 
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specific quality of life instruments for women with pelvic floor disorders. American journal of obstetrics and 
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12. Appendices  
 
Appendix A – SOP: MR Defecography  
Appendix B – SOP: Dynamic Pelvic Ultrasound  
Appendix C – SOP: Surgical Procedures  
Appendix D – SOP: Study Assessments and Measurements  
Appendix E – Schedule of Forms  
 
 

PROD Trial – v4 Mar 14 2024 
 
Page 40 of 50 
APPENDIX A – SOP: MR Defecography  
PROD Trial 
Research Standard Operating Procedure 
SOP TITLE:  MR Defecography  
Version # 1 
SOP NUMBER:  PROD_SOP_1 
Page 40 of 50 
 
PURPOSE:  
To describe expectations for completing MR Defecography for the PROD Trial. 
 
PERSONNEL RESPONSIBLE:   
Trained personnel at each study site.  
 
PROCEDURES:  
 
1. MR imaging will be in the supine position with hips and knees bent at 45° using a closed-configuration 1.5T 
magnet (Siemens, Magnetom Avanto) and a Synergy body phased-array coil.  
a. As with routine dynamic pelvic floor MRI examinations performed at NorthShore University 
HealthSystem, intravenous contrast will not be used.  
b. No bowel preparation or intraluminal contrast material will be administered.  
2. Subjects will be instructed to empty their bladder three hours before the examination to result in a moderately 
full urinary bladder during MRI.  
3. Static multiplanar images of the pelvis will be acquired for anatomic evaluation using a 3-mm slice thickness with 
a 0-mm gap, for sagittal and axial T2-weighted sequences (echo time, 105 milliseconds; repetition time, 3000 
milliseconds).  
a. These will be used to collect anatomical geometries for use in modeling.  
4. The rectum will then be filled with 60 mL of ultrasound gel (1% Gd-DTPA-GEL-Mixture).  
5. The pelvis will be visualized in three planes (transversal, coronal, sagittal, T1 and T2) to find the appropriate 
sagittal plane in which all relevant pelvic floor organs could be acquired during defecation.  
6. The sequence will take ~36s at a frequency of one shot per 1.1 s (True Fast Imaging with Steady State 
Precession; TR: 1.8 ms, TE: 1.01 ms).  
7. Slice thickness will be 6 mm (field of view: 300 mm x 270 mm, image matrix: 256 x 256).  
8. During the examination, patients will be instructed via headphones to first relax and then to perform a squeeze 
maneuver.  
a. This will be followed by instructions to perform straining and evacuation maneuvers with the goal of 
emptying the rectum as completely as possible. 
9. For measurements, three anatomic measurements relating to rectal support will be recorded at rest, and then 
also at the moment of maximum evacuation, which will be defined as the image in which the posterior cul de 
sac makes its closest approach to the anorectal junction.  
a. The first measurement will be the straight distance between the posterior cul de sac and anorectal 
junction.  
b. The second measurement will be the perpendicular distance between the cul de sac and the pubo-
coccygeal line.  
c. The third measurement will be the perpendicular distance between the anorectal junction and the 
pubo-coccygeal line.  
10. The relative change in length of the straight distance between the posterior cul de sac and the anorectal 
junction (CDS to ARJ) as observed on MR defecography will be used to define a compression ratio, which will 

PROD Trial – v4 Mar 14 2024 
 
Page 41 of 50 
again be calculated as a percentage using the following formula:  Compression ratio = 100 * (CDS to ARJ length 
at rest – CDS to ARJ septum length at evacuate) / CDS to ARJ length at rest. 
 
 

PROD Trial – v4 Mar 14 2024 
 
Page 42 of 50 
APPENDIX B – SOP: Dynamic Pelvic Ultrasound  
PROD Trial 
Research Standard Operating Procedure 
SOP TITLE:  Dynamic Pelvic Ultrasound  
Version # 1 
SOP NUMBER:  PROD_SOP_2 
Page 42 of 50 
 
PURPOSE:  
To describe expectations for completing Dynamic Pelvic Ultrasound for the PROD Trial. 
 
PERSONNEL RESPONSIBLE:   
Trained investigators of the PROD Trial.  
PROCEDURES:  
 
- 
The ultrasound procedure will be performed and read by trained investigators, including Drs. Ghazaleh Rostami 
Nia and Roger Goldberg at NorthShore University HealthSystem and Drs. Tirsit Shiferaw Asfaw and Kelly Garrett 
at Weill Cornell Medical Center- New York Presbyterian. 
o The dynamic pelvic ultrasound image will be saved and re-evaluated in a blinded manner retrospectively 
to confirm the results of the initial reading. 
- 
The competency criteria for the ultrasound procedure will be performing three to five cases under the 
supervision of Dr. Ghazaleh Rostami Nia and/or Dr. Roger Goldberg until achieving the following milestone: 
o The physician was able to perform all aspects of the procedure safely and competently. 
- 
The principal investigator of the study, Dr. Ghazaleh Rostami Nia, will review the data quality of the ultrasound 
procedures for the first ten ultrasounds completed. 
 
Dynamic Pelvic Ultrasound: 
1. Imaging will be obtained at the time of the study visit using: 
a. BK Medical bk3000 with 
b. 3D X14L4 (9038) Endocavity Transducer (frequency range: 14-4 MHz, focal range: 3-60 mm) 
2. All ultrasound studies will be performed in the office setting with the patient in the dorsal lithotomy position, 
with hips flexed and abducted.  
3. No preparation will be required, and no rectal or vaginal contrast will be used. 
4. Patients will be instructed to arrive to the office with a partially full bladder, and to avoid excessive pressure on 
surrounding structures that might distort the anatomy, the probe will be inserted into the vagina in a neutral 
position.  
5. 360 degree endovaginal ultrasound volumes and dynamic ultrasound videos will be saved for further analysis. 
6. For measurements, the distance between the posterior cul de sac and anorectal junction (“rectovaginal septum 
length”) will be measured both at rest and during Valsalva straining efforts using a dynamic imaging protocol in 
the mid-sagittal plane, allowing posterior compartment structures to be visualized. It should be noted that for 
Valsalva straining efforts, patients will be instructed to relax their pelvic floor while increasing intra-abdominal 
pressure. All images will include the cul de sac apically and the levator plate/anorectal junction caudally in order 
to standardize framing of the anatomy, and the dynamic recording will be started with the patient at rest and 
captured for 5 seconds of Valsalva straining (see Figure 1 top left & right). 

PROD Trial – v4 Mar 14 2024 
 
Page 43 of 50 
a. “Compression ratio” will be 
calculated as a means to quantify the 
relative change in length of the 
rectovaginal septum (RVS), in other 
words the degree of hypermobility / 
sliding rectum, and is expressed as a 
percentage using the following 
formula:  𝐶𝑅 = (RVSr – RVSv)/ RVSR * 
100 where RVSr (Rectovaginal 
Septum) and RVSv represent the RVS 
length at rest and Valsalva.  
 
 
 
 
Figure 1: 2D dynamic endovaginal posterior compartment ultrasound of a 
patient with obstructed defecation symptoms at rest (left image) and at strain 
(right image). Rendering of an aluminum can is used to illustrate the concept of 
the rectal compression seen above. LP: Levator Plate, RVS: Rectovaginal Septum 

PROD Trial – v4 Mar 14 2024 
 
Page 44 of 50 
APPENDIX C – SOP: Surgical Procedures  
PROD Trial 
Research Standard Operating Procedure 
SOP TITLE:  Surgical Procedures  
Version # 1 
SOP NUMBER:  PROD_SOP_3 
Page 44 of 50 
 
PURPOSE:  
To describe expectations for completing surgical procedures (Transvaginal Sacrospinous Rectopexy and Laparoscopic 
Abdominal Ventral Rectopexy) for the PROD Trial. 
 
PERSONNEL RESPONSIBLE:   
Investigators performing surgical procedures of the PROD Trial.  
 
Per Objective Structured Assessment of Technical Skill (OSATS), competency criteria for the novel transvaginal 
sacrospinous rectopexy will be performing three to five cases under the supervision of investigator at NorthShore 
University HealthSystem until achieving the following milestone: 
2. The surgeon was able to perform all aspects of the procedure safely and competently with no or minimal need 
for help, or in the context of an unexpectedly difficult case, may have needed more assistance for the more 
difficult aspects of the procedure.  
 
A second or third year urogynecology fellow or a second-year colorectal fellow will be able to assist in the surgeries 
under the direct supervision of investigators. 
 
PROCEDURES:  
 
Laparoscopic Abdominal Ventral Rectopexy Surgical Technique  
1. The surgery is performed under general anesthesia with patient in steep Trendelenburg position.  
2. Usually 4 ports are created. Supra-umbilical port is used as camera port. The rectosigmoid junction is identified 
and retracted to the left.  
3. A “J shaped” peritoneal incision is given extending from the sacral promontory to the anterior peritoneal 
reflection distally.  
4. Right hypogastric nerve and ureter are identified and safeguarded. With combined blunt and sharp dissection, a 
wide plane is developed in the Rectovaginal/rectovesical space.  
5. Any posterior rectal mobilization or lateral dissection is avoided at this stage. A strip of Prolene mesh (Ethicon 
Endosurgery, Blue Ash, Ohio, United States), trimmed to 3 cm × 17 cm, is prepared and inserted into the pelvic 
cavity.  
6. One end of mesh is fixed to the anterior surface of the distal most part of the rectum using polypropylene 
sutures.  
7. Similarly, it is fixed to the lateral borders of the rectum.  
8. Care is taken to avoid full thickness bite into the rectal wall in order to prevent mesh contamination.  
9. Finally, the proximal end of mesh is fixed to the sacral promontory using same sutures.  
10. Proximal traction on the rectum is avoided while fixing the mesh.  
11. The peritoneum is then re-approximated to completely cover the mesh. 
 
Transvaginal Sacrospinous Rectopexy Surgical Technique  
1. The posterior vaginal wall dissection is started with a horizontal incision in the mid-posterior vaginal wall.  

PROD Trial – v4 Mar 14 2024 
 
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2. Dissection is carried down to the sacrospinous ligament (SSL) bluntly on each side. Sacrospinous ligament 
sutures are placed using a push-and catch suturing device (Capio Slim, Boston Scientific Corporation, USA) to 
deliver a single 0-polydiaxone suture (Monodek, Teleflex Medical OEM) into each ligament approximately 2-2.5 
cm medial to the ipsilateral ischial spine (Figure 5).  
3. With one finger inside the rectum, the suture is passed through the lateral rectal ligament and rectal muscularis 
layer, as a two-bite running suture, at a point 7-8 cm cephalad to the anal verge.  
4. After tying down the knot on the first side, rectal suture placement is then performed on the contralateral side; 
this sequential suturing and tying down of left and right sided rectal suspensions allows for assessment and fine-
tuning of the rectal suspension and avoidance of excess tension or stretching of the rectal wall.  
5. After suspension of the rectum bilaterally, three additional interrupted 0 polydiaxone sutures are used to 
reattach the midline posterior vaginal wall to the midline anterior rectal wall at the same level (7-8 cm cephalad 
from the anal verge); these sutures provide reinforcement and tension relief to the midline rectum between 
each lateral SSL suspension suture and serve to close a potential enterocele space.  
 
 
 
 
Figure 5: This computational 3D model is created based on MRI images of a 
normal nulligravid healthy volunteer. The suturing sites on rectum and 
sacrospinous ligament used for transvaginal sacrospinous rectopexy and related 
landmarks are demonstrated here in coronal (A) and sagittal (B) views 

PROD Trial – v4 Mar 14 2024 
 
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APPENDIX D – SOP: Study Assessments and Procedures  
PROD Trial 
Research Standard Operating Procedure 
SOP TITLE:  Study Assessments and Measurements   
Version # 1 
SOP NUMBER:  PROD_SOP_4 
Page 46 of 50 
 
PURPOSE:  
To describe expectations for completing study assessments and measurements for the PROD Trial. 
 
PERSONNEL RESPONSIBLE:   
All investigators and research coordinators of the PROD Trial.  
 
PROCEDURES:  
 
Pelvic Organ Prolapse Quantification (POP-Q) Assessment 
POP-Q assessment will be completed by investigators during screening, 2-month, 12-month, and 24-month post-
operative appointments. Participants will be asked to empty the bladder and if feasible empty the rectum. The 
participant is then positioned where the utmost magnitude of the prolapse is shown and can be confirmed by the 
patient. A Sim’s speculum can be used to draw back the anterior and posterior vaginal walls during the examination.  
The plane of the hymen will be defined as zero and all measures in centimeters above/proximal (negative number) or 
below /distal (positive number) to the hymen. All measurements should be recorded to the nearest half-centimeter (i.e., 
0.0 or 0.5). The measurement parameters will include six distinct locations: 
1. Point Aa is at the midline of the anterior vaginal wall. Where no prolapse is present this location is 3cm up from 
the hymen (merely interior to the vaginal opening). Parameters from the hymen can be -3cm indicating no 
anterior vaginal prolapse or +3cm, which is a full prolapse. 
2. Point Ba refers to the most distal portion of the remaining upper anterior side of the vaginal wall.  
3. Point C is the lowest edge of the cervix or the vaginal cuff (i.e. hysterectomy scar).  
4. Point D is the topmost point of the posterior vaginal wall.  
5. Point Ap is located midline of the posterior vaginal wall 3cm proximal to the hymen. The parameters for this 
point can range from -3cm to +3cm relative to hymen. 
6. Point Bp refers to the most distal portion of the remaining upper posterior side of the vaginal wall. Its location 
can range from -3 to +6 or +7 in severe cases. 
Furthermore, three anatomical markers can be examined: 
1. GH is the 'Genital hiatus' that records the length from the urethral opening to the posterior vaginal opening/ 
hymen. 
2. PB is the 'perineal body' and is recorded from the posterior aspect of the hymen to the mid-anal opening.   
3. TVL refers to the 'total vaginal length' measured from the hymen to the most distal point. Knowing this allows 
the depth of prolapse to be assessed and reassessed post-surgical repair. 
The position of the six distinct locations is measured during a maximum Valsalva or cough with regard to the hymen. The 
measurement of TVL should be recorded at rest when the prolapse is decreased.  
 
Brink Scale 
Brink assessment will be completed by investigators during 2-month, 12-month, and 24-month post-operative 
appointments. Participants will be asked to be in the dorsal lithotomy position. The Brink assessment will be performed 
by placing 1 or 2 lubricated fingers vaginally during a single Kegel contraction. The brink scale consists of 3 separate 4-
point rating scales for vaginal pressure, vertical displacement of examiner’s fingers, and duration of contraction. The 
pressure felt by examining fingers is rated 1 (“no response”), 2 (“weak squeeze”), 3 (“moderate squeeze”), or 4 (“strong 
squeeze”). The vertical displacement is rated 1 (“none”), 2 (“finger base moves anteriorly”), 3 (“whole length of fingers 
move anteriorly”), or 4 (“whole fingers move anteriorly, are gripped and pulled in”). Duration of contraction (in seconds) 

PROD Trial – v4 Mar 14 2024 
 
Page 47 of 50 
is timed and scored 1 (“none”), 2 (“<1 second”), 3 (“1–3 seconds”), or 4 (“>3 seconds”). Ratings are summed to obtain 
total scores, with a possible range of scores of 3 to 12. 
 
Bowel Habit 
Bowel habits will be assessed by the research personnel during screening, 2-month, 12-month, and 24-month post-
operative appointments. The participant will be asked about the average frequency of bowel movements in the past 3 
months (more than 3 times per day, 2 to 3 times per day, once per day, 2 to 4 times per week, or less than once a week). 
Then the participant will be asked to identify one of the seven stool types that applies to their usual bowel movement in 
the past 3 months. 
 
Pelvic Floor Distress Inventory (PFDI) Assessment 
PFDI assessment will be completed by the research personnel during screening, 2-month, 12-month, and 24-month 
post-operative appointments. PFDI has 20 items and 3 scales of symptoms. All items use the format with a response 
scale from 0 (symptom is not present) to 4 (symptom is present quite a lot). The mean value of all the answered items 
within each scale will be multiplied by 25 to obtain the scale score (range 0 to 100). Missing items are dealt with by using 
the mean from answered items only. The PFDI summary score will be obtained by adding the scores from the 3 scales 
together (range 0 to 300). 
 
Pain Scale and Pain Medication Use 
Pain scale and pain medication use assessment will be completed by the research personnel during screening, 2-week, 
2-month, 12-month, and 24-month post-operative appointments. Participants will be asked to rate the average amount 
of pain within the past 24 hours while at rest, with normal activities, with exercise, and worst pain of the today. All items 
use the format with a response scale from 0 (no pain sensation) to 10 (most intense pain imaginable). Then the 
participant will be asked if they are currently taking narcotic pain medication.  
 
Activity Scale 
Activity scale will be completed by the research personnel during screening, 2-week, 2-month, 12-month, and 24-month 
post-operative appointments. Participants will be presented with 13 activities in which they will be asked to rate how 
difficult it was for them to perform them in the past 24 hours. The rating will be 1 (no difficulty), 2 (a little difficulty), 3 
(some difficulty), 4 (a lot of difficulty), 5 (not able to do it), and 6 (did not do it for other reasons). Then, participants will 
be asked 5 additional questions regarding activity in the past month.  
 
Impression of Improvement  
Impression of improvement assessment will be completed by the research personnel during 2-month, 12-month, and 
24-month post-operative appointments. Participants will be asked to indicate a number that best describes their current 
post-operative condition in comparison to how it was pre-operatively. The rating will be 1 (very much better), 2 (much 
better), 3 (a little better), 4 (no change), 5 (a little worse), 6 (much worse), and 7 (very much worse).   
 
Pelvic Floor Impact Questionniare (PFIQ) 
PFDI assessment will be completed by research personnel during 2-month, 12-month, and 24-month post-operative 
appointments. The PFIQ-7 consists of 7 questions that need to be answered 3 times each considering symptoms related 
to the bladder or urine, vagina or pelvis, and bowel or rectum and its effect on function, social health, and mental health 
in the past 3 months. The responses for each question range from 0 (not at all) to 3 (quite a bit). To get scale scores, the 
mean of each of the 3 scales is individually calculated, which ranges from 0-3. This number is then multiplied by 100 and 
then divided by 3. The scale scores are then added together to get the total PFIQ-7 score, which ranges from 0-300.  
 
Short Form (SF) - 36 
SF-36 assessment will be completed by the research personnel during 2-week, 2-month, 12-month, and 24-month post-
operative appointments. SF-36 is comprised of 36 questions that cover eight domains of health: limitations in physical 
activities because of health problems, limitations in social activities because of physical or emotional problems, 
limitations in usual role activities because of physical health problems, bodily pain, general mental health (psychological 
distress and well-being), limitations in usual role activities because of emotional problems, vitality (energy and fatigue), 

PROD Trial – v4 Mar 14 2024 
 
Page 48 of 50 
and general health perceptions. Participants will be asked to fill out the questionnaire by themselves. Then the research 
personnel will input the questionnaire results into an online scoring calculator (https://orthotoolkit.com/sf-36/). 
 
EuroQol-5 Dimension (EQ-5D) 
EQ-5D assessment will be completed by the research personnel during 2-month, 12-month, and 24-month post-
operative appointments. The EQ-5D covers 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), and each dimension has 5 levels: no problems, slight problems, moderate problems, severe 
problems, and extreme problems/unable to. There are 3,125 possible health states defined by combining one level from 
each dimension, ranging from 11111 (full health) to 55555 (worst health). 
 
 
 
 

PROD Trial – v4 Mar 14 2024 
 
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APPENDIX E – Schedule of Forms 
 
 
Screening 
Appt 
Initial Appt 
+/‐ 30 days 
MRI Appt 
+/‐ 30  days 
Anesthesia 
Clearance 
Randomization 
Pre‐op 
Day of Surgery 
2 wk PO 
+/‐ 5 days 
2 m PO 
+/‐ 10 days 
12 m PO 
+/‐ 10 days 
24 m PO 
+/‐ 30 days 
Form 01 
Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
Form 02 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
Form 03 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
Form 04 
Baseline PE 
X 
 
 
 
 
 
 
 
 
 
 
Form 05 
Follow‐up PE 
 
 
 
 
 
 
 
 
X 
X 
X 
Form 06 
Surgeon’s 
report 
 
 
 
 
 
 
X 
 
 
 
 
Form 07 
2 week post‐op 
visit 
 
 
 
 
 
 
 
X 
 
 
 
Form 08 
Activity 
Assessment 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Form 09 
Pain Scale  
X 
 
 
 
 
 
 
X 
X 
X 
X 
Form 10 
EQ‐5D 
 
 
 
 
 
 
 
 
X 
X 
X 
Form 11 
SF‐36 
 
 
 
 
 
 
 
X 
X 
X 
X 
Form 12 
PFIQ 
 
 
 
 
 
 
 
 
X 
X 
X 
Form 13 
PFDI 
X 
 
 
 
 
 
 
 
X 
X 
X 
Form 14 
Global 
Impression  
 
 
 
 
 
 
 
 
X 
X 
X 
Form 15 
Bowel Habit 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Form 16 
Research 
Participation 
 
 
 
 
 
 
 
 
 
 
X 
Form 17 
Adverse Event 
 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
Form 18 
Unanticipated 
Problem 
 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
Form 19 
Protocol 
Deviation 
 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
Form 20 
Study Exit  
 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
X 
(if 
applicable) 
  

PROD Trial – v4 Mar 14 2024 
 
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